SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI (selective serotonin re-uptake inhibitor) or SNRI antidepressant medications. The condition often begins between the time of reduction in dosage or complete discontinuation,[specify] depending on the elimination half-life of the drug and the patient's metabolism.

The particulars of the syndrome, in light of the multitude of prescribed agents, have been disputed.[1] Nonetheless, double-blind placebo-controlled studies[2] demonstrate statistically and clinically significant indications of difficulties with the discontinuing of SSRIs.

[edit] Signs and symptoms

The indicators of SSRI discontinuation syndrome are the following:

• Interruption, cessation, or reduction of dosage in an SSRI treatment that has lasted four or more weeks.
• Symptoms which:
  • interfere with normal social, occupational, or other functioning.
  • are not due to another medical condition, drug use, or discontinuation.
  • are not due to a relapse of the condition for which the SSRI was originally prescribed.

[edit] Neurological

Symptoms described as "brain zaps", "brain shocks", "brain shivers", "head shocks", or "cranial zings" are withdrawal symptoms experienced during discontinuation (or reduction of dose) of antidepressant drugs.[3][4] The symptoms are widely variable in description and are of unknown etiology;[4] common descriptions include dizziness, electric shock-like sensations, sweating, nausea, insomnia, tremor, confusion, nightmares, and vertigo.[3][4] The MedDRA "preferred term" for coding these types of symptoms in adverse drug reaction reports (for use in pharmacovigilance databases such as under the Yellow Card Scheme) is paraesthesia.[5][6]

In a 1997 survey in north-east England, a "sizable minority" of medical professionals were not confidently aware of the existence of antidepressant withdrawal symptoms.[7] A 2005 review of adverse event reporting showed that descriptions of "electric shocks" from patients on paroxetine had been reported more frequently than some other symptoms.[5]

[edit] History

The first report of withdrawal symptoms occurring after SSRI discontinuation was for fluvoxamine[8] (brand names Luvox (US), Faverin (UK)) in 1992. The Committee on Safety of Medicines in the United Kingdom reported withdrawal symptoms involving paroxetine[9] (Paxil, Seroxat) in 1993, and the American Journal of Psychiatry revealed the same for sertraline[10] (Zoloft, Lustral) the following year.

In 1996, Eli Lilly and Company sponsored a symposium to address the increasing number of reports of patients who had difficult symptoms after going off their antidepressants:

By then it had become clear that drug-company estimates that at most a few percent of those who took antidepressants would have a hard time getting off were far too low. Jerrold Rosenbaum and Maurizio Fava, researchers at Massachusetts General Hospital, found that among people getting off antidepressants, anywhere from 20 percent to 80 percent (depending on the drug) suffered what was being called antidepressant withdrawal (but which, after the symposium, was renamed “discontinuation syndrome”).[11]

The World Health Organization (WHO) continues to track withdrawal syndrome, and notes:

SSRIs are an example of how a conceptual confusion over terminology can affect proper reporting, interpretation and communication of adverse drug reactions related to dependence. To avoid the association with dependence, an increasing number of researchers have used a different term, discontinuation syndrome, instead of withdrawal syndrome. The number of hits for discontinuation syndrome in searches of the international medical literature began to increase, relative to the occurrence of withdrawal syndrome, in 1997 after [the Eli Lilly] symposium on antidepressant discontinuation syndrome held in 1996. In fact, dependence syndrome has been reported to the Uppsala Monitoring Centre for all SSRIs through the same postmarketing surveillance systems, although there are significantly fewer reports of dependence syndrome than of withdrawal syndrome.[12]

The same WHO note ranks antidepressants according to withdrawal, with paroxetine having the highest number of withdrawal syndrome reports and fluoxetine the highest number of drug dependence reports; the note concludes, "Three SSRIs are among the 30 highest-ranking drugs in the list of drugs for which drug dependence has ever been reported to the Uppsala Monitoring Centre database; a total of 269 reports had been received as of June 2002 (109 reports for fluoxetine, 91 for paroxetine and 69 for sertraline)."[12]

The cause is the abrupt cessation of one of the SSRIs or SNRIs.

• citalopram (Celexa, Cipramil, Celepram, Emocal, Sepram, Seropram)
• escitalopram (Lexapro, Cipralex, Esertia, Esipram)
• fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin [EUR])
• paroxetine (Paxil, Seroxat, Pexeva, Aropax, Deroxat, Paroxat)
• sertraline (Zoloft, Lustral, Serlain)
• dapoxetine (Priligy)
• fluvoxamine (Luvox, Faverin, Favoxil)
• venlafaxine (Effexor, Efexor)
• desvenlafaxine (Pristiq)
• duloxetine (Cymbalta)
• tramadol (Ultram)
• vilazodone (Viibryd)

[edit] Post-SSRI sexual dysfunction

According to one source, post-SSRI sexual dysfunction (PSSD) is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRI antidepressants.[13]

While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. This condition has not been well-established or proven in the field of medicine, thus patients are not warned of the potential condition by their physicians and it is not listed in consumer information leaflets.

One or more of the following sexual symptoms may persist or begin after the discontinuation of SSRIs:

[edit] Diagnosis

Although most SSRIs are widely used and generally considered safe, an abrupt cessation, or rapid tapering of SSRI use may result in a discontinuation syndrome that can mimic serious illness and can be very distressing and intensely uncomfortable. Several pharmacokinetic and pharmacodynamic factors influence the frequency and onset of these symptoms. When allowed to run its course, the syndrome duration is variable (usually one to several weeks) and ranges from mild-moderate intensity in most patients, to extremely distressing in a smaller number of patients who may have side effects for months.

With the lack of a definition based on consensus criteria for the syndrome, a discontinuation panel met in Phoenix, Arizona in 1997 and stated:

"SSRI discontinuation symptoms... may emerge when an SSRI is abruptly discontinued, when doses are missed, and less frequently, during dosage reduction. In addition, the symptoms are not attributable to any other cause and can be reversed when the original agent is reinstituted, or one that is pharmacologically similar is substituted. SSRI discontinuation symptoms, in most cases, may be minimized by slowly tapering antidepressant therapy, but there have been several case reports where symptoms occurred consistently even through repeated attempts to taper therapy. Physical symptoms include problems with balance, gastrointestinal and flu-like symptoms, and sensory and sleep disturbances. Psychological symptoms include anxiety and/or agitation, crying spells, irritability and aggressiveness."[14]

A 2000 study at the Department of Psychiatry at Dalhousie University in Halifax, Nova Scotia constructed diagnostic criteria for SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.[15]

Due to the lack of peer reviewed diagnostic criteria, many physicians, unaware of the potential severity of discontinuation syndrome, do not get informed consent at the time of initial prescription from the patient (though patients in clinical trials do), so this syndrome can be an unexpected barrier to patients attempting to discontinue the drug. In addition, warnings to patients not to stop taking the drug without doctor's approval, while indicated, may lead to a reluctance to discontinue SSRI therapy in patients who need not take the drugs long-term.

[edit] Definition of withdrawal

As described in the History section above, SSRI withdrawal syndrome began to be called SSRI Discontinuation syndrome following a symposium in 1996; since then, the terms have been used interchangeably. SSRIs are not addictive in the conventional medical use of the word (i.e. animals given free access to the drug do not actively seek it out and do not seek to increase the dose), but discontinuing their use can produce both somatic and psychological symptoms.[16]

Critics argue that the pharmaceutical industry has a vested interest in creating a distinction between addiction to recreational or illegal drugs and dependence on antidepressants. Arguments against the use of the term "withdrawal" are primarily predicated on not frightening patients or alienating potential customers who may or may not need the medication.[17] According to the consensus definition by the American Academy of Pain Medicine, withdrawal is a symptom of "Physical Dependence", not of "Addiction" and thus arguments against SSRIs being "addictive" do not clearly make the use of the term "withdrawal" inappropriate to the symptoms caused by ceasing an SSRI.

[edit] Mechanism

The exact mechanism of SSRI withdrawal syndrome is unknown, and may be due to a variety of factors. Continuing research on discontinuation/withdrawal syndrome has attributed SSRI withdrawal syndrome to electrophysiological changes in the brain (particularly on the 5-HT receptor), and electrophysiological changes in the body (nerve growth factor) in the absence of the SSRI, as well as dopamine dependency, and an over-excited immune system.

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. Desired drug effects may be mediated by such compensatory changes which may explain the delayed onset of therapeutic effect of antidepressants. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome. Pharmacodynamic factors explain why withdrawal syndromes are often a class issue and why the administration of a drug in the same class often relieves withdrawal symptoms. Formal studies have not characterized the relative risk.

One theory states that SSRI withdrawal syndrome is associated with a rostral anterior cingulate Cho/Cre metabolite ratio decrease that may reflect dynamics of rostral anterior cingulate cortex (ACC) function. The ACC appears to play a role in a wide variety of autonomic functions, such as regulating heart rate and blood pressure, and is vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion. Neuroscientists indicate the dorsal anterior cingulate cortex is primarily related to rational cognition while the ventral is more related to emotional cognition.[18]

A separate study demonstrated that changes in regional central blood volume of left prefrontal cortex and left caudate nucleus correlate with the emergence of withdrawal symptoms and increased Hamilton Depression Rating Scale after interruption of paroxetine treatment. The findings supported the hypothesis that brain regions implicated in depression, with extensive serotonergic innervation, would exhibit changes in activity associated with emergence of symptoms following drug discontinuation. Cerebral blood volume maps were obtained via dynamic susceptibility functional magnetic resonance imaging (fMRI).[18]

There is speculation concerning the possibility of a temporary deficiency of synaptic serotonin with abrupt withdrawal of an SSRI. This deficiency is compounded by the fact that down-regulated receptors will remain in their relatively hypoactive state for days to weeks. This is believed to result in antidepressant discontinuation syndrome directly or indirectly via downstream effects on other neurotransmitter systems (e.g., norepinephrine, dopamine, and g-aminobutyric acid) implicated in depressive and anxiety disorders.

Another possible mechanism is by inhibition of dopaminergic neurotransmission.[19]

[edit] Prevention and treatment

Patients should be advised of the elimination half-life times of their specific medication, and patients should be aware if changing from a long half-life medication such as fluoxetine (Prozac), to a shorter one, that taking their dose regularly becomes much more important. Patients taking fluoxetine can often miss several doses without noticing any discomfort, but the shorter halflife of other SSRIs such as venlafaxine, paroxetine, duloxetine, escitalopram oxalate, and sertraline (ranging approximately 10 hours) means that a single missed dose may cause withdrawal symptoms. When discontinuing an SSRI with a short half-life, switching to a drug with a longer half-life (e.g. fluoxetine or citalopram) and then discontinuing from that can decrease the likelihood and severity of withdrawal syndrome.[20][21]

If one wishes to stop taking an SSRI medication, one method is to switch to a long half-life medication such as fluoxetine for several days at a relatively low dose and then stop taking any SSRI altogether. The longer half-life of fluoxetine will avoid any withdrawal symptoms because this medication effectively tapers itself from the patient's system over a few days.

SSRI withdrawal symptoms may be alleviated by either recommencing the original or lesser dose of the SSRI (or a similar SSRI), or slowly reducing the dosage over several weeks or months. While slowly reducing the dosage does not guarantee that a patient will not experience the discontinuation syndrome, it is considered a safer method than abrupt discontinuation. Gradual discontinuation, or tapering, or titration, can be accomplished by breaking pills into parts or using a graduated oral syringe with the liquid form. Alternatively, a compounding pharmacy may take one's prescription and divide it into smaller graduated doses. For example, a 20 mg prescription of Cymbalta, which comes in gel capsules containing tiny sphere-shaped pellets, may be divided into 20, 15, 10, 5, and 2.5 mg doses.

Treatment is dependent on the severity of the discontinuation reaction and whether or not further antidepressant treatment is warranted. In cases where further antidepressant treatment is required then the only step required is restarting the antidepressant; this is usually the case following patient noncompliance with the drug. If antidepressants are no longer required, treatment depends on symptom severity. Mild reactions may only require reassurance. Moderate cases may require symptom management. Benzodiazepines may be used for insomnia, although it's very important to note that benzodiazepine withdrawal is known to be severe and long-lived. If symptoms of SSRI discontinuation are severe, or do not respond to symptom management, the antidepressant can be reinstated and then withdrawn more cautiously.[22]

People experiencing severe withdrawal symptoms may taper dosage by 5% per week (or month, or even longer) in order to avoid a drastic drop in serotonergic activity; however, even gradual reductions can produce withdrawal symptoms in some cases.[23] Switching to an SSRI with a longer half-life, then tapering off that, may eliminate withdrawal symptoms; see "Fluoxetine as intervention in SSRI Discontinuation Syndrome" below.

[edit] Persistent adverse effects

In a very few cases, discontinuation of SSRIs may result in sexual dysfunction (loss of libido, genital anesthesia, erectile dysfunction) that persists for years or forever after the fact.[24][25]

Long term withdrawal syndromes outside of sexual dysfunction from SSRIs are not well documented. One Italian study found that in patients with panic disorder and agoraphobia, 45% exhibited a discontinuation syndrome that disappeared within a month in all but 11%.[26] Symptoms of the discontinuation syndrome include agitation, anxiety, akathisia, panic attacks, irritability, hostility, aggressiveness, worsening of mood, dysphoria, crying spells or mood lability, overactivity or hyperactivity, depersonalization, decreased concentration, slowed thinking, confusion, and memory/concentration difficulties.[26]

[edit] Discontinuation of SNRIs

SNRIs affect both reuptake inhibition of serotonin and norepinephrine. The two mostly widely prescribed SNRIs are venlafaxine and duloxetine. To these has been added desvenlafaxine. In addition, the widely used analgesic Tramadol, which is molecularly similar to venlafaxine, has been cited as it has SNRI properties which typically are known to affect patients after 3 months or more use in theraputic doses of 400 mg per day.

[edit] Venlafaxine

Sudden discontinuation of venlafaxine (brand name Effexor) has a high risk of causing potentially severe withdrawal symptoms. Even missing a single dose can cause symptoms of withdrawal.[27][28] The high risk of withdrawal symptoms reflects venlafaxine's short half-life as well as its effect as a dual uptake inhibitor.[22] Discontinuations have a tendency to be significantly stronger than the withdrawal effects of other antidepressants including the tricyclic antidepressants, but are similar in nature to those of SSRIs with a short half-life such as paroxetine.

Symptoms of discontinuation are similar to other antidepressants including irritability, restlessness, headache, nausea, fatigue, excessive sweating, dysphoria, tremor, vertigo, irregularities in blood pressure, dizziness, visual and auditory hallucinations, feelings of abdominal distension, and paresthesia. Other non-specific mental symptoms may include impaired concentration, bizarre dreams, delirium, cataplexy, agitation, hostility, and worsening of depressive symptoms. Online help groups consistently mention withdrawal from venlafaxine as triggering dreams of a particularly distressing and hellish quality.[22][27][28][29][30][31][32]

Electric shock sensations have also been reported[28][31] with many patients describing the symptoms as "brain zaps". It has been suggested the sensations may represent an alteration of neuronal activity in the central nervous system.[33]

Studies by Wyeth-Ayerst, the maker of venlafaxine, and others have reported severe withdrawal cases, including withdrawal as the presentation of a stroke, as well as neonatal withdrawal (neonatal withdrawal has also been reported with paroxetine, fluoxetine, sertraline, and citalopram). In some venlafaxine withdrawal cases, successful discontinuation was eventually achieved by the addition of fluoxetine, which was later discontinued itself without difficulty. Additionally, use of tramadol has been proven effective as anti-depressant withdrawal aid especially with venlafaxine.

[edit] Duloxetine

Eli Lilly and Company, the manufacturer of duloxetine (brand name Cymbalta) warns that "one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction." These responses could constitute physical dependence on the drug, but SSRI users do not experience the craving, impulsive use, or long-term relapse risk seen in drug addiction.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, aggressiveness, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.[34]

Many patients on the drug longer than the Lilly test trials on discontinuation (which only studied patients after 9 weeks of exposure to Cymbalta), report anecdotal evidence of major withdrawals from Cymbalta lasting from weeks to many months. Since duloxetine is a newer drug (FDA-approval 2004), not many peer-reviewed articles have been published on its adverse effects or withdrawal phenomena, and effects of long term use is still unknown.

[edit] Fluoxetine as an intervention

Many doctors advise patients who are suffering from SSRI discontinuation syndrome to use fluoxetine as a substitute for their current drug.[35] Substituting fluoxetine in the final stages of SSRI discontinuation, or post discontinuation, provides a rate of reduction of antidepressant which can minimize or eradicate withdrawal symptoms in the patient. Fluoxetine migrates slowly from the brain to the blood. The active metabolite of fluoxetine remains a long time in the brain because it is lipophilic, with a biological half-life of 4 to 8 days (the longest of any SSRI). Therefore the level of the drug in the body falls slowly at a rate to which the brain can adjust when the dosage is reduced. Fluoxetine is also available in a liquid formula, allowing the physician to titrate the drug with greater ease (e.g., with an oral syringe).

In a randomized trial, abrupt interruption of antidepressant therapy for 5–8 days was associated with the emergence of new somatic and psychological symptoms with the highest degree in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine.[36]

• Fluoxetine for clomipramine withdrawal symptoms was reported in 1999 by F. Benazzi.[37]

• Fluoxetine was indicated to cover serotonergic discontinuation syndromes for cessation of paroxetine associated with withdrawal or discontinuation symptoms.[38]

[edit] Neonatal withdrawal

The U.S. Food and Drug Administration (FDA) issued a warning on July 19, 2006 that nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Although SSRIs have not been associated with congenital malformations, some evidence suggests that they are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPH).

SSRI withdrawal syndromes have been documented in neonates. Investigators found that by November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a study published in The Lancet concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.[39]

[edit] See also

[edit] References

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2. ^ Michelson D, Fava M, Amsterdam J, et al. (April 2000). "Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial". Br J Psychiatry 176: 363–8. DOI:10.1192/bjp.176.4.363. PMID 10827885. http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=10827885. 
3. ^ a b Aronson J (8 October 2005). "Bottled lightning". BMJ 331: 824. DOI:10.1136/bmj.331.7520.824. 
4. ^ a b c Christmas MB (2005). "'Brain shivers': from chat room to clinic". Psychiatric Bulletin 29 (6): 219–21. DOI:10.1192/pb.29.6.219. http://pb.rcpsych.org/cgi/content/full/29/6/219. 
5. ^ a b Medawar C, Herxheimer A (2003/2004). "A comparison of adverse drug reaction reports from professionals and users, relating to risk of dependence and suicidal behaviour with paroxetine" (PDF reprint). International Journal of Risk & Safety in Medicine 16: 5–19. http://www.socialaudit.org.uk/YELLOW%20CARD%20REVIEW.pdf. 
6. ^ MHRA (March/April 2003). "MAIL 136". http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON008299&RevisionSelectionMethod=LatestReleased. Retrieved 18 April 2009. 
7. ^ Young AH, Currie A (1997). "Physicians' knowledge of antidepressant withdrawal effects: a survey". J Clin Psychiatry 58 (Suppl 7): 28–30. PMID 9219491. 
8. ^ Szabadi E (1992). "Fluvoxamine withdrawal syndrome". Br J Psychiatry 160: 283–4. PMID 1540778. 
9. ^ Gelenberg AJ, ed. (1993). "Postmarketing watch: paroxetine in the UK". Biol Ther Psychiatry 16: 25–8. 
10. ^ Louie AK, Lannon RA, Ajari LJ (1994). "Withdrawal reaction after sertraline discontinuation". Am J Psychiatry 151 (3): 450–1. PMID 8109661. 
11. ^ Stutz, Bruce (2007-05-06). "Self-Nonmedication". The New York Times. http://www.nytimes.com/2007/05/06/magazine/06antidepressant-t.html?pagewanted=5&fta=y. Retrieved 2010-05-24. 
12. ^ a b http://www.who.int/medicinedocs/en/d/Js4896e/9.html
13. ^ Bahrick AS. (2006). "Post SSRI Sexual Dysfunction" (PDF). Tablet (American Society for the Advancement of Pharmacotherapy) 7 (3): 2–10. http://www.division55.org/Tablet/Vol7No3.pdf. 
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18. ^ a b Kaufman MJ, Henry ME, Frederick B, Hennen J, Villafuerte RA, Stoddard EP, Schmidt ME, Cohen BM, Renshwa PF (2003). "Selective serotonin reuptake inhibitor discontinuation syndrome is associated with a rostral anterior cingulate choline metabolite decrease: a proton magnetic resonance spectroscopic imaging study". Biol Psychiatry 54 (5): 534–9. DOI:10.1016/S0006-3223(02)01828-0. PMID 12946882. 
19. ^ Damsa C, Bumb A, Bianchi-Demicheli F, et al. (August 2004). ""Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review". J Clin Psychiatry 65 (8): 1064–8. DOI:10.4088/JCP.v65n0806. PMID 15323590. http://article.psychiatrist.com/?ContentType=START&ID=10001001. 
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21. ^ http://www.benzo.org.uk/healy.htm
22. ^ a b c Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183–97. DOI:10.2165/00002018-200124030-00003. PMID 11347722. 
23. ^ http://www.citypages.com/2002-10-16/news/paxil-is-forever
24. ^ Csoka AB, Bahrick A, Mehtonen OP (January 2008). "Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors". J Sex Med 5 (1): 227–33. DOI:10.1111/j.1743-6109.2007.00630.x. PMID 18173768. 
25. ^ Bolton; Sareen, J; Reiss, JP (2006). "Genital anaesthesia persisting six years after sertraline discontinuation". J Sex Marital Ther. 32 (4): e327. DOI:10.1080/00926230600666410. PMID 16709553. 
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28. ^ a b c Parker G, Blennerhassett J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry 32 (2): 291–4. DOI:10.3109/00048679809062742. PMID 9588310. 
29. ^ van Noorden M, Vergouwen A, Koerselman G (2002). "[Delirium during withdrawal of venlafaxine]". Ned Tijdschr Geneeskd 146 (26): 1236–7. PMID 12132141. 
30. ^ Nissen C, Feige B, Nofzinger E, Riemann D, Berger M, Voderholzer U (2005). "Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine". J Sleep Res 14 (2): 207–8. DOI:10.1111/j.1365-2869.2005.00447.x. PMID 15910521. 
31. ^ a b Baboolal N (2004). "Venlafaxine withdrawal syndrome: report of seven cases in Trinidad". J Clin Psychopharmacol 24 (2): 229–31. DOI:10.1097/01.jcp.0000117427.05703.f2. PMID 15206672. 
32. ^ Agelink M, Zitzelsberger A, Klieser E (1997). "Withdrawal syndrome after discontinuation of venlafaxine". Am J Psychiatry 154 (10): 1473–4. PMID 9326838. 
33. ^ Reeves R, Mack J, Beddingfield J (2003). "Shock-like sensations during venlafaxine withdrawal". Pharmacotherapy 23 (5): 678–81. DOI:10.1592/phco.23.5.678.32198. PMID 12741444. 
34. ^ Cymbalta patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
35. ^ Benazzi F (1998). "SSSRI discontinuation syndrome treated with fluoxetine". Int J Geriatr Pyschiatry 13 (6): 421–2. DOI:10.1002/(SICI)1099-1166(199806)13:6<421::AID-GPS774>3.0.CO;2-Y. PMID 9658279. 
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37. ^ Benazzi, Franco (April 1999). "Fluoxetine for Clomipramine Withdrawal Symptoms". Am J Psychiatry 156 (4): 661. http://ajp.psychiatryonline.org/cgi/content/full/156/4/661a. 
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Bipolar disorder or bipolar affective disorder, historically known as manic-depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or more depressive episodes. The elevated moods are clinically referred to as mania or, if milder, hypomania. Individuals who experience manic episodes also commonly experience depressive episodes, or symptoms, or a mixed state in which features of both mania and depression are present at the same time. These events are usually separated by periods of "normal" mood; but, in some individuals, depression and mania may rapidly alternate, which is known as rapid cycling. Severe manic episodes can sometimes lead to such psychotic symptoms as delusions and hallucinations. The disorder has been subdivided into bipolar I, bipolar II, cyclothymia, and other types, based on the nature and severity of mood episodes experienced; the range is often described as the bipolar spectrum.

Estimates of the lifetime prevalence of bipolar disorder vary, with studies typically giving values of the order of 1%, with higher figures given in studies with looser definitions of the condition.[2] The onset of full symptoms generally occurs in late adolescence or young adulthood. Diagnosis is based on the person's self-reported experiences, as well as observed behavior. Episodes of abnormality are associated with distress and disruption and an elevated risk of suicide, especially during mixed and depressive episodes. In some cases, it can be a devastating long-lasting disorder. In others, it has also been associated with creativity, goal striving, and positive achievements. There is significant evidence to suggest that many people with creative talents have also suffered from some form of bipolar disorder.[3] It is often suggested that creativity and bipolar disorder are linked.

Genetic factors contribute substantially to the likelihood of developing bipolar disorder, and environmental factors are also implicated. Bipolar disorder is often treated with mood stabilizing medications and, sometimes, other psychiatric drugs. Psychotherapy also has a role, often when there has been some recovery of the subject's stability. In serious cases, in which there is a risk of harm to oneself or others, involuntary commitment may be used. These cases generally involve severe manic episodes with dangerous behavior or depressive episodes with suicidal ideation. There are widespread problems with social stigma, stereotypes, and prejudice against individuals with a diagnosis of bipolar disorder.[4] People with bipolar disorder exhibiting psychotic symptoms can sometimes be misdiagnosed as having schizophrenia, another, different, serious mental illness.[5]

The current term bipolar disorder is of fairly recent origin and refers to the cycling between high and low episodes (poles). A relationship between mania and melancholia had long been observed, although the basis of the current conceptualisation can be traced back to French psychiatrists in the 1850s. The term "manic-depressive illness" or psychosis was coined by German psychiatrist Emil Kraepelin in the late nineteenth century, originally referring to all kinds of mood disorder. German psychiatrist Karl Leonhard split the classification again in 1957, employing the terms unipolar disorder (major depressive disorder) and bipolar disorder.

Signs and symptoms

Bipolar disorder is a condition in which people experience intermittent abnormally elevated (manic or hypomanic) and, in many cases, abnormally depressed states for periods of time in a way that interferes with functioning. Not everyone's symptoms are the same, and there is no simple physiological test to confirm the disorder. Bipolar disorder can appear to be unipolar depression. Diagnosing bipolar disorder is often difficult, even for mental health professionals. What distinguishes bipolar disorder from unipolar depression is that the affected person experiences states of mania and depression. Often bipolar is inconsistent among patients because some people feel depressed more often than not and experience little mania whereas others experience predominantly manic symptoms. Additionally, the younger the age of onset—bipolar disorder starts in childhood or early adulthood in most patients—the more likely the first few episodes are to be depression.[6] Because a bipolar diagnosis requires a manic or hypomanic episode, many patients are initially diagnosed and treated as having major depression.

Depressive episode

Signs and symptoms of the depressive phase of bipolar disorder include persistent feelings of sadness, anxiety, guilt, anger, isolation, or hopelessness; disturbances in sleep and appetite; fatigue and loss of interest in usually enjoyable activities; problems concentrating; loneliness, self-loathing, apathy or indifference; depersonalization; loss of interest in sexual activity; shyness or social anxiety; irritability, chronic pain (with or without a known cause); lack of motivation; and morbid suicidal ideation.[7] In severe cases, the individual may become psychotic, a condition also known as severe bipolar depression with psychotic features. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant.[8] A major depressive episode persists for at least two weeks, and may continue for over six months if left untreated.[9][Full citation needed]

Manic episode

Mania is the signature characteristic of bipolar disorder and, depending on its severity, is how the disorder is classified. Mania is generally characterized by a distinct period of an elevated mood, which can take the form of euphoria. People commonly experience an increase in energy and a decreased need for sleep, with many often getting as little as three or four hours of sleep per night, while others can go days without sleeping.[10] A person may exhibit pressured speech, with thoughts experienced as racing.[11] Attention span is low, and a person in a manic state may be easily distracted. Judgment may become impaired, and sufferers may go on spending sprees or engage in behavior that is quite abnormal for them. They may indulge in substance abuse, particularly alcohol or other depressants, cocaine or other stimulants, or sleeping pills. Their behavior may become aggressive, intolerant, or intrusive. People may feel out of control or unstoppable, or as if they have been "chosen" and are "on a special mission" or have other grandiose or delusional ideas. Sexual drive may increase. At more extreme phases of bipolar I, a person in a manic state can begin to experience psychosis, or a break with reality, where thinking is affected along with mood.[12] Some people in a manic state experience severe anxiety and are very irritable (to the point of rage), while others are euphoric and grandiose.

To be diagnosed with mania according to the Diagnostic and Statistical Manual of Mental Disorders (DSM), a person must experience this state of elevated or irritable mood, as well as other symptoms, for at least one week, less if hospitalization is required.[13]

Severity of manic symptoms can be measured by rating scales such as self-reported Altman Self-Rating Mania Scale[14] and clinician-based Young Mania Rating Scale.[15]

Hypomanic episode

Hypomania is generally a mild to moderate level of mania, characterized by optimism, pressure of speech and activity, and decreased need for sleep. Generally, hypomania does not inhibit functioning like mania.[16] Many people with hypomania are actually in fact more productive than usual, while manic individuals have difficulty completing tasks due to a shortened attention span. Some people have increased creativity while others demonstrate poor judgment and irritability. Many people experience signature hypersexuality. These persons generally have increased energy and tend to become more active than usual. They do not, however, have delusions or hallucinations. Hypomania can be difficult to diagnose because it may masquerade as mere happiness, though it carries the same risks as mania.

Hypomania may feel good to the person who experiences it. Thus, even when family and friends learn to recognize the mood swings, the individual often will deny that anything is wrong.[17] Also, the individual may not be able to recall the events that took place while they were experiencing hypomania.[6] What might be called a "hypomanic event", if not accompanied by complementary depressive episodes ("downs", etc.), is not typically deemed as problematic: The "problem" arises when mood changes are uncontrollable and, more importantly, volatile or "mercurial". If unaccompanied by depressive counterpart episodes or otherwise general irritability, this behavior is typically called hyperthymia, or happiness, which is, of course, perfectly normal.[citation needed] Indeed, the most elementary definition of bipolar disorder is an often "violent" or "jarring" state of essentially uncontrollable oscillation between hyperthymia and dysthymia. If left untreated, an episode of hypomania can last anywhere from a few days to several years. Most commonly, symptoms continue for a few weeks to a few months.[18]

Mixed affective episode

In the context of bipolar disorder, a mixed state is a condition during which symptoms of mania and clinical depression occur simultaneously.[19] Typical examples include tearfulness during a manic episode or racing thoughts during a depressive episode. Individuals may also feel incredibly frustrated in this state, since one may feel like a failure and at the same time have a flight of ideas. Mixed states are often the most dangerous period of mood disorders, during which substance abuse, panic disorder, suicide attempts, and other complications increase greatly.[20]

Associated features

Associated features are clinical phenomena that often accompany the disorder but are not part of the diagnostic criteria for the disorder. There are several childhood precursors in children who later receive a diagnosis of bipolar disorder. They may show subtle early traits such as mood abnormalities, full major depressive episodes, and ADHD.[21] Bipolar disorder is also accompanied by changes in cognitive processes and abilities. These include reduced attentional and executive capabilities and impaired memory. How the individual processes the world also depends on the phase of the disorder, with differential characteristics between the manic, hypomanic and depressive states.[22] Some studies have found a significant association between bipolar disorder and creativity.[23] Some patients may have difficulty in maintaining loving relationships.[24][25]

Causes

The causes of bipolar disorder likely vary between individuals. Twin studies have been limited by relatively small sample sizes but have indicated a substantial genetic contribution, as well as environmental influence. For bipolar I, the (probandwise) concordance rates in modern studies have been consistently put at around 40% in monozygotic twins (same genes), compared to 0 to 10% in dizygotic twins.[26] A combination of bipolar I, II and cyclothymia produced concordance rates of 42% vs 11%, with a relatively lower ratio for bipolar II that likely reflects heterogeneity. The overall heritability of the bipolar spectrum has been put at 0.71.[27] There is overlap with unipolar depression and if this is also counted in the co-twin the concordance with bipolar disorder rises to 67% in monozigotic twins and 19% in dizigotic.[28] The relatively low concordance between dizygotic twins brought up together suggests that shared family environmental effects are limited, although the ability to detect them has been limited by small sample sizes.[27]

Genetic

Genetic studies have suggested many chromosomal regions and candidate genes appearing to relate to bipolar disorder's development, but the results are not consistent and often not replicated.[29]

Although the first genetic linkage finding for mania was in 1969,[30] the linkage studies have been inconsistent.[31] Meta-analyses of linkage studies detected either no significant genome-wide findings or, using a different methodology, only two genome-wide significant peaks, on chromosome 6q and on 8q21.[citation needed] Neither have genome-wide association studies brought a consistent focus — each has identified new loci.[31]

Findings point strongly to heterogeneity, with different genes being implicated in different families.[32] A review seeking to identify the more consistent findings suggested several genes related to serotonin (SLC6A4 and TPH2), dopamine (DRD4 and SLC6A3), glutamate (DAOA and DTNBP1), and cell growth and/or maintenance pathways (NRG1, DISC1 and BDNF), although noting a high risk of false positives in the published literature. It was also suggested that individual genes are likely to have only a small effect and to be involved in some aspect related to the disorder (and a broad range of "normal" human behavior) rather than the disorder per se.[33]

Advanced paternal age has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new genetic mutations.[34]

Physiological

Abnormalities in the structure and/or function of certain brain circuits could underlie bipolar. Two meta-analyses of MRI studies in bipolar disorder report an increase in the volume of the lateral ventricles, globus pallidus and increase in the rates of deep white matter hyperintensities.[35][36]

The "kindling" theory asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events,[37] each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and become recurrent) by itself. There is evidence of hypothalamic-pituitary-adrenal axis (HPA axis) abnormalities in bipolar disorder due to stress.[38]

Other brain components which have been proposed to play a role are the mitochondria,[39] and a sodium ATPase pump,[40] causing cyclical periods of poor neuron firing (depression) and hypersensitive neuron firing (mania). This may only apply for type one, but type two apparently results from a large confluence of factors.[citation needed]Circadian rhythms and melatonin activity also seem to be altered.[41]

Environmental

Evidence suggests that environmental factors play a significant role in the development and course of bipolar disorder, and that individual psychosocial variables may interact with genetic dispositions.[33] There is fairly consistent evidence from prospective studies that recent life events and interpersonal relationships contribute to the likelihood of onsets and recurrences of bipolar mood episodes, as they do for onsets and recurrences of unipolar depression.[42] There have been repeated findings that between a third and a half of adults diagnosed with bipolar disorder report traumatic/abusive experiences in childhood, which is associated on average with earlier onset, a worse course, and more co-occurring disorders such as PTSD.[43] The total number of reported stressful events in childhood is higher in those with an adult diagnosis of bipolar spectrum disorder compared to those without, particularly events stemming from a harsh environment rather than from the child's own behavior.[44]

Diagnosis

Diagnosis is based on the self-reported experiences of an individual as well as abnormalities in behavior reported by family members, friends or co-workers, followed by secondary signs observed by a psychiatrist, nurse, social worker, clinical psychologist or other clinician in a clinical assessment. There are lists of criteria for someone to be so diagnosed. These depend on both the presence and duration of certain signs and symptoms. Assessment is usually done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to oneself or others. The most widely used criteria for diagnosing bipolar disorder are from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, the current version being DSM-IV-TR, and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, currently the ICD-10. The latter criteria are typically used in Europe and other regions while the DSM criteria are used in the USA and other regions, as well as prevailing in research studies. The DSM-V, to be published in 2013, will likely include further and more accurate sub-typing.[45]

An initial assessment may include a physical exam by a physician. Although there are no biological tests which confirm bipolar disorder, tests may be carried out to exclude medical illnesses such as hypo- or hyperthyroidism, metabolic disturbance, a systemic infection or chronic disease, and syphilis or HIV infection. An EEG may be used to exclude epilepsy, and a CT scan of the head to exclude brain lesions. Investigations are not generally repeated for relapse unless there is a specific medical indication.

Several rating scales for the screening and evaluation of bipolar disorder exist, such as the Bipolar spectrum diagnostic scale.[46] The use of evaluation scales can not substitute a full clinical interview but they serve to systematize the recollection of symptoms.[46] On the other hand instruments for the screening of bipolar disorder have low sensitivity[disambiguation needed ] and limited diagnostic validity.[46]

Criteria and subtypes

There is no clear consensus as to how many types of bipolar disorder exist.[47] In DSM-IV-TR and ICD-10, bipolar disorder is conceptualized as a spectrum of disorders occurring on a continuum. The DSM-IV-TR lists three specific subtypes and one for non-specified:[48]

Bipolar I disorder

One or more manic episodes. Subcategories specify whether there has been more than one episode, and the type of the most recent episode.[49] A depressive or hypomanic episode is not required for diagnosis, but it frequently occurs.

Bipolar II disorder

No manic episodes, but one or more hypomanic episodes and one or more major depressive episode.[50] However, a bipolar II diagnosis is not a guarantee that they will not eventually suffer from such an episode in the future.[citation needed] Hypomanic episodes do not go to the full extremes of mania (i.e., do not usually cause severe social or occupational impairment, and are without psychosis), and this can make bipolar II more difficult to diagnose, since the hypomanic episodes may simply appear as a period of successful high productivity and is reported less frequently than a distressing, crippling depression.

Cyclothymia

A history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes.[51] There is a low-grade cycling of mood which appears to the observer as a personality trait, and interferes with functioning.

Bipolar Disorder NOS (Not Otherwise Specified)

This is a catchall category, diagnosed when the disorder does not fall within a specific subtype.[52]Bipolar NOS can still significantly impair and adversely affect the quality of life of the patient.

The bipolar I and II categories have specifiers that indicate the presentation and course of the disorder. For example, the "with full interepisode recovery" specifier applies if there was full remission between the two most recent episodes.[53]

Rapid cycling

Most people who meet criteria for bipolar disorder experience a number of episodes, on average 0.4 to 0.7 per year, lasting three to six months.[54]Rapid cycling, however, is a course specifier that may be applied to any of the above subtypes. It is defined as having four or more episodes per year and is found in a significant fraction of individuals with bipolar disorder. The definition of rapid cycling most frequently cited in the literature (including the DSM) is that of Dunner and Fieve: at least four major depressive, manic, hypomanic or mixed episodes are required to have occurred during a 12-month period.[55] Ultra-rapid (days) and ultra-ultra rapid or ultradian (within a day) cycling have also been described.[56]

Differential diagnosis

There are several other mental disorders which may involve similar symptoms to bipolar disorder. These include schizophrenia,[57]

Challenges

The experiences and behaviors involved in bipolar disorder are often not understood by individuals or recognized by mental health professionals, so diagnosis may sometimes be delayed for over 10 years.[58] The treatment lag is apparently not decreasing, even though there is increased public awareness of the condition.

Individuals are commonly misdiagnosed.[59][60]

It has been noted that the bipolar disorder diagnosis is officially characterised in historical terms such that, technically, anyone with a history of (hypo)mania and depression has bipolar disorder whatever their current or future functioning and vulnerability. This has been described as "an ethical and methodological issue", as it means no one can be considered as being recovered (only "in remission") from bipolar disorder according to the official criteria. This is considered especially problematic given that brief hypomanic episodes are widespread among people generally and not necessarily associated with dysfunction.[22]

Comorbid conditions

The diagnosis of bipolar disorder can be complicated by coexisting (comorbid) psychiatric conditions such as obsessive-compulsive disorder, social phobia, panic disorder and attention-deficit hyperactivity disorder. Substance abuse may predate the appearance of bipolar symptoms, further complicating the diagnosis. A careful longitudinal analysis of symptoms and episodes, enriched if possible by discussions with friends and family members, is crucial to establishing a treatment plan where these comorbidities exist.[61]

Management

There are a number of pharmacological and psychotherapeutic techniques used to treat bipolar disorder. Individuals may use self-help and pursue recovery.

Hospitalization may be required especially with the manic episodes present in bipolar I. This can be voluntary or (if mental health legislation allows and varying state-to-state regulations in the USA) involuntary (called civil or involuntary commitment). Long-term inpatient stays are now less common due to deinstitutionalization, although these can still occur.[62] Following (or in lieu of) a hospital admission, support services available can include drop-in centers, visits from members of a community mental health team or Assertive Community Treatment team, supported employment and patient-led support groups, intensive outpatient programs. These are sometimes referred to partial-inpatient programs.[63]

Psychosocial

Psychotherapy is aimed at alleviating core symptoms, recognizing episode triggers, reducing negative expressed emotion in relationships, recognizing prodromal symptoms before full-blown recurrence, and, practicing the factors that lead to maintenance of remission[64]Cognitive behavioural therapy, family-focused therapy, and psychoeducation have the most evidence for efficacy in regard to relapse prevention, while interpersonal and social rhythm therapy and cognitive-behavioural therapy appear the most effective in regard to residual depressive symptoms. Most studies have been based only on bipolar I, however, and treatment during the acute phase can be a particular challenge.[65] Some clinicians emphasize the need to talk with individuals experiencing mania, to develop a therapeutic alliance in support of recovery.[66]

Medication

Medications used to treat bipolar disorder are known as mood stabilizers; these work by reversing manic or depressive episodes and preventing relapses.[67] The first known and "gold standard" mood stabilizer is lithium carbonate, which is effective in treating acute manic episodes,[68] and preventing relapses, more so for manic than for depressive episodes.[69] Treatment with lithium carbonate has been strongly linked to a reduced risk of suicide, self-harm, and death in people with bipolar disorder.[70] Initially used as an anticonvulsant, sodium valproate has become a commonly prescribed treatment, and is effective in treating manic episodes.[71] Three other anticonvulsants are used in to treat bipolar disorder. Carbamazepine became widely used to treat bipolar disorder in the late 1980s and early 1990s, but was displaced by sodium valproate in the 1990s. Carbamazepine is effective in treating manic episodes, with some evidence it has greater benefit in rapid-cycling bipolar disorder, or those with more psychotic manic symptoms or a more schizoaffective clinical picture. It is less effective in preventing relapse than lithium.[72]Lamotrigine has been shown to have some efficacy in treating bipolar depression, and this benefit is greatest in more severe depression.[73] It has also been shown to have some benefit in preventing further episodes, though there are concerns about the studies done, and is of no benefit in rapid cycling disorder.[74] The effectiveness of topiramate is unknown.[75] Depending on the severity of the case, anti-convulsants may be used in combination with lithium-based products or on their own.[76]

Atypical antipsychotics have been found to be effective in managing mania associated with bipolar disorder.[77] Olanzapine is effective in preventing relapses, although the evidence is not as solid as for lithium.[78]Antidepressants have not been found to be of any benefit over that found with mood stabilizers.[77]

Omega 3 fatty acids, in addition to normal pharmacological treatment, may have beneficial effects on depressive symptoms, although studies have been scarce and of variable quality.[79]

Prognosis

For many individuals with bipolar disorder a good prognosis results from good treatment, which, in turn, results from an accurate diagnosis. Because bipolar disorder can have a high rate of both under-diagnosis and misdiagnosis,[6] it is often difficult for individuals with the condition to receive timely and competent treatment.

Bipolar disorder can be a severely disabling medical condition. However, many individuals with bipolar disorder can live full and satisfying lives. Quite often, medication is needed to enable this. Persons with bipolar disorder may have periods of normal or near normal functioning between episodes.[80]

Prognosis depends on many factors such as the right medicines and dosage, comprehensive knowledge of the disease and its effects; a positive relationship with a competent medical doctor and therapist; and good physical health, which includes exercise, nutrition, and a regulated stress level. There are other factors that lead to a good prognosis, such as being very aware of small changes in a person's energy, mood, sleep and eating behaviors.[81]

Functioning

A recent 20-year prospective study on bipolar I and II found that functioning varied over time along a spectrum from good to fair to poor. During periods of major depression or mania (in BPI), functioning was on average poor, with depression being more persistently associated with disability than mania. Functioning between episodes was on average good — more or less normal. Subthreshold symptoms were generally still substantially impairing, however, except for hypomania (below or above threshold) which was associated with improved functioning.[82]

Another study confirmed the seriousness of the disorder as "the standardized all-cause mortality ratio among patients with bipolar disorder is increased approximately two-fold." Bipolar disorder is currently regarded "as possibly the most costly category of mental disorders in the United States." Episodes of abnormality are associated with distress and disruption, and an elevated risk of suicide, especially during depressive episodes.[83]

Recovery and recurrence

A naturalistic study from first admission for mania or mixed episode (representing the hospitalized and therefore most severe cases) found that 50% achieved syndromal recovery (no longer meeting criteria for the diagnosis) within six weeks and 98% within two years. Within two years, 72% achieved symptomatic recovery (no symptoms at all) and 43% achieved functional recovery (regaining of prior occupational and residential status). However, 40% went on to experience a new episode of mania or depression within 2 years of syndromal recovery, and 19% switched phases without recovery.[84]

Symptoms preceding a relapse (prodromal), specially those related to mania, can be reliably identified by people with bipolar disorder.[85] There have been intents to teach patients coping strategies when noticing such symptoms with encouraging results.[86]

Mortality

Bipolar disorder can cause suicidal ideation that leads to suicidal attempts. One out of three people with bipolar disorder report past attempts of suicide or complete it,[87] and the annual average suicide rate is 0.4%, which is 10 to 20 times that of the general population.[88] The standardized mortality ratio from suicide in bipolar disorder is between 18 and 25.[89]

Epidemiology

Disability-adjusted life year for bipolar disorder per 100,000 inhabitants in 2002.

  no data

  less than 180

  180–186

  186–190

  190–195

  195–200

  200–205

  205–210

  210–215

  215–220

  220–225

  225–230

  230–235

When broadly defined 4% of people experience bipolar at some point in their life.[90] The lifetime prevalence of bipolar disorder type I, which includes at least a lifetime manic episode, has generally been estimated at 2%.[91] It is equally prevalent in men and women and is found across all cultures and ethnic groups.

A reanalysis of data from the National Epidemiological Catchment Area survey in the United States, however, suggested that 0.8 percent experience a manic episode at least once (the diagnostic threshold for bipolar I) and 0.5 a hypomanic episode (the diagnostic threshold for bipolar II or cyclothymia). Including sub-threshold diagnostic criteria, such as one or two symptoms over a short time-period, an additional 5.1 percent of the population, adding up to a total of 6.4 percent, were classed as having a bipolar spectrum disorder.[93] A more recent analysis of data from a second US National Comorbidity Survey found that 1% met lifetime prevalence criteria for bipolar I, 1.1% for bipolar II, and 2.4% for subthreshold symptoms.[94] There are conceptual and methodological limitations and variations in the findings. Prevalence studies of bipolar disorder are typically carried out by lay interviewers who follow fully structured/fixed interview schemes; responses to single items from such interviews may suffer limited validity. In addition, diagnosis and prevalence rates are dependent on whether a categorical or spectrum approach is used. Concerns have arisen about the potential for both underdiagnosis and overdiagnosis.[95]

Late adolescence and early adulthood are peak years for the onset of bipolar disorder.[96]</ref> One study also found that in 10% of bi-polar cases, the onset of mania had happened after the patient had turned 50.[98]

History

Variations in moods and energy levels have been observed as part of the human experience since time immemorial. The words "melancholia" (an old word for depression) and "mania" have their etymologies in Ancient Greek. The word melancholia is derived from melas/μελας, meaning "black", and chole/χολη, meaning "bile" or "gall",[99] indicative of the term's origins in pre-Hippocratic humoral theories. Within the humoral theories, mania was viewed as arising from an excess of yellow bile, or a mixture of black and yellow bile. The linguistic origins of mania, however, are not so clear-cut. Several etymologies are proposed by the Roman physician Caelius Aurelianus, including the Greek word ania, meaning "to produce great mental anguish", and manos, meaning "relaxed" or "loose", which would contextually approximate to an excessive relaxing of the mind or soul (Angst and Marneros 2001[Full citation needed]). There are at least five other candidates, and part of the confusion surrounding the exact etymology of the word mania is its varied usage in the pre-Hippocratic poetry and mythologies (Angst and Marneros 2001[Full citation needed]).

The basis of the current conceptualisation of manic-depressive illness can be traced back to the 1850s; on January 31, 1854, Jules Baillarger described to the French Imperial Academy of Medicine a biphasic mental illness causing recurrent oscillations between mania and depression, which he termed folie à double forme ("dual-form insanity").[100] Two weeks later, on February 14, 1854, Jean-Pierre Falret presented a description to the Academy on what was essentially the same disorder, and designated folie circulaire ("circular insanity") by him (Sedler 1983[Full citation needed]). The two bitterly disputed as to who had been the first to conceptualise the condition.

These concepts were developed by the German psychiatrist Emil Kraepelin (1856–1926), who, using Kahlbaum's concept of cyclothymia,[101] categorized and studied the natural course of untreated bipolar patients. He coined the term manic depressive psychosis, after noting that periods of acute illness, manic or depressive, were generally punctuated by relatively symptom-free intervals where the patient was able to function normally.[102]

The term "manic-depressive reaction" appeared in the first American Psychiatric Association Diagnostic Manual in 1952, influenced by the legacy of Adolf Meyer who had introduced the paradigm illness as a reaction of biogenetic factors to psychological and social influences. Subclassification of bipolar disorder was first proposed by German psychiatrist Karl Leonhard in 1957; he was also the first to introduce the terms bipolar (for those with mania) and unipolar (for those with depressive episodes only).

Society and culture

There are widespread problems with social stigma, stereotypes, and prejudice against individuals with a diagnosis of bipolar disorder.[4]Kay Redfield Jamison, a clinical psychologist and Professor of Psychiatry at the Johns Hopkins University School of Medicine, profiled her own bipolar disorder in her memoir An Unquiet Mind (1995).[105]

Several dramatic works have portrayed characters with traits suggestive of the diagnosis that has been the subject of discussion by psychiatrists and film experts alike. A notable example is Mr. Jones (1993), in which Mr. Jones (Richard Gere) swings from a manic episode into a depressive phase and back again, spending time in a psychiatric hospital and displaying many of the features of the syndrome. In The Mosquito Coast (1986), Allie Fox (Harrison Ford) displays some features including recklessness, grandiosity, increased goal-directed activity and mood lability, as well as some paranoia.. Psychiatrists have suggested that Willy Loman, the main character in Arthur Miller's classic play Death of a Salesman, suffers from bipolar disorder,[108] though the term did not exist when the play was written.

TV specials, for example the BBC's The Secret Life of the Manic Depressive,[109] MTV's True Life: I'm Bipolar, talk shows, and public radio shows, and the greater willingness of public figures to discuss their own bipolar disorder, have focused on psychiatric conditions, thereby, raising public awareness.

On April 7, 2009, the nighttime drama 90210 on the CW network, aired a special episode where the character Silver was diagnosed with bipolar disorder.[110]Stacey Slater, a character from the BBC soap EastEnders, has been diagnosed with the disorder. The storyline was developed as part of the BBC's Headroom campaign.[111] The Channel 4 soap Brookside had earlier featured a story about bipolar disorder when the character Jimmy Corkhill was diagnosed with the condition.[112]

Specific populations

In children

Emil Kraepelin in the 1920s noted that mania episodes were rare before puberty.[113] In general, bipolar disorder in children was not recognized in the first half of the twentieth century. This issue diminished with an increased following of the DSM criteria in the last part of the twentieth century.[113][114]

While in adults the course of bipolar disorder is characterized by discrete episodes of depression and mania with no clear symptomatology between them, in chidren and adolescents very fast mood changes or even chronic symptoms are the norm.[115] On the other hand pediactric bipolar disorder instead of euphoric mania commonly develops with outbursts of anger, irritability and psychosis, less common in adults.[113][115]

The diagnosis of childhood bipolar disorder is controversial,[115] although it is not under discussion that bipolar disorder typical symptoms have negative consequences for minors suffering them.[113] Main discussion is centered on whether what is called bipolar disorder in children refers to the same disorder than when diagnosing adults,[113] and the related question on whether adults criteria for diagnosis are useful and accurate when applied to children.[115] Regarding diagnosis of children some experts recommend to follow the DSM criteria.[115] Others believe that these criteria do not separate correctly children with bipolar disorder from other problems such as ADHD, and emphasize fast mood cycles.[115] Still others argue that what accurately differentiates children with bipolar disorder is irritability.[115] The practice parameters of the AACAP encourage the first strategy.[113][115] American children and adolescents diagnosed of bipolar disorder in community hospitals increased 4-fold reaching rates of up to 40% in 10 years around the beginning of the current century, while in outpatient clinics it doubled reaching the 6%.[115] Studies using DSM criteria show that up to 1% of youth may have bipolar disorder.[113]

Treatment involves medication and psychotherapy.[115] Drug prescription usually consists in mood stabilizers and atypical antipsychotics.[115] Among the formers lithium is the only compound approved by the FDA for children.[113] Psychological treatment combines normally education on the disease, group therapy and cognitive behavioral therapy.[115]Chronic medication is often needed.[115]

Current research directions for bipolar disorder in children include optimizing treatments, increasing the knowledge of the genetic and neurobiological basis of the pediatric disorder and improving diagnostic criteria.[115] The DSM-V has proposed a new diagnosis which is considered to cover some presentations currently thought of as childhood-onset bipolar.[116]

In the elderly

There is a relative lack of knowledge about bipolar disorder in late life. There is evidence that it becomes less prevalent with age but nevertheless accounts for a similar percentage of psychiatric admissions; that older bipolar patients had first experienced symptoms at a later age; that later onset of mania is associated with more neurologic impairment; that substance abuse is considerably less common in older groups; and that there is probably a greater degree of variation in presentation and course, for instance individuals may develop new-onset mania associated with vascular changes, or become manic only after recurrent depressive episodes, or may have been diagnosed with bipolar disorder at an early age and still meet criteria. There is also some weak evidence that mania is less intense and there is a higher prevalence of mixed episodes, although there may be a reduced response to treatment. Overall there are likely more similarities than differences from younger adults.[117] In the elderly, recognition and treatment of bipolar disorder may be complicated by the presence of dementia or the side effects of medications being taken for other conditions.[118]

See also

References

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Citations

Further reading

Contemporary first-person accounts

Managing bipolar disorder

Bipolar disorder in children

• Greenberg, Rosalie (2008). Bipolar Kids: Helping Your Child Find Calm in the Mood Storm. ISBN 978-0-7382-1113-8
• Papolos, Demetri; Papolos, Janice (2007). The Bipolar Child: The Definitive and Reassuring Guide to Childhood's Most Misunderstood Disorder 3rd ed. New York: Broadway. ISBN 978-0-7679-2860-1.
• Raeburn, Paul (2004). Acquainted with the Night: A Parent's Quest to Understand Depression and Bipolar Disorder in His Children. ISBN 978-0-7679-1437-6.
• Earley, Pete (2006). Crazy. New York: G. P. Putnam. ISBN 978-0-399-15313-6. A father's account of his son's bipolar disorder.

Classic works on bipolar disorder

• Kraepelin, Emil (1921). Manic-depressive Insanity and Paranoia ISBN 978-0-405-07441-7. English translation of the original German from the earlier eighth edition of Kraepelin's textbook – now outdated, but a work of major historical importance.
• Padesky, Christine; Greenberger, Dennis (1995). Mind Over Mood: Cognitive Treatment Therapy Manual for Clients. New York: Guilford. ISBN 978-0-89862-128-0.

External links

History Symptoms Spectrum Treatment Related

Schizophrenia (/ˌskɪtsɵˈfrɛniə/ or /ˌskɪtsɵˈfriːniə/) is a mental disorder characterized by a breakdown of thought processes and by poor emotional responsiveness.[1] It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3–0.7%.[2] Diagnosis is based on observed behavior and the patient's reported experiences.

Genetics, early environment, neurobiology, and psychological and social processes appear to be important contributory factors; some recreational and prescription drugs appear to cause or worsen symptoms. Current research is focused on the role of neurobiology, although no single isolated organic cause has been found. The many possible combinations of symptoms have triggered debate about whether the diagnosis represents a single disorder or a number of discrete syndromes. Despite the etymology of the term from the Greek roots skhizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-; "mind"), schizophrenia does not imply a "split mind" and it is not the same as dissociative identity disorder—also known as "multiple personality disorder" or "split personality"—a condition with which it is often confused in public perception.[3]

The mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine (and sometimes serotonin) receptor activity. Psychotherapy and vocational and social rehabilitation are also important in treatment. In more serious cases—where there is risk to self and others—involuntary hospitalization may be necessary, although hospital stays are now shorter and less frequent than they once were.[4]

The disorder is thought mainly to affect cognition, but it also usually contributes to chronic problems with behavior and emotion. People with schizophrenia are likely to have additional (comorbid) conditions, including major depression and anxiety disorders; the lifetime occurrence of substance abuse is almost 50%.[5] Social problems, such as long-term unemployment, poverty and homelessness, are common. The average life expectancy of people with the disorder is 12 to 15 years less than those without, the result of increased physical health problems and a higher suicide rate (about 5%).[2]

Symptoms

A person diagnosed with schizophrenia may experience hallucinations (most reported are hearing voices), delusions (often bizarre or persecutory in nature), and disorganized thinking and speech. The latter may range from loss of train of thought, to sentences only loosely connected in meaning, to incoherence known as word salad in severe cases. Social withdrawal, sloppiness of dress and hygiene, and loss of motivation and judgment are all common in schizophrenia.[6] There is often an observable pattern of emotional difficulty, for example lack of responsiveness.[7] Impairment in social cognition is associated with schizophrenia,[8] as are symptoms of paranoia; social isolation commonly occurs.[9] Difficulties in working and long-term memory, attention, executive functioning, and speed of processing also commonly occur.[2] In one uncommon subtype, the person may be largely mute, remain motionless in bizarre postures, or exhibit purposeless agitation, all signs of catatonia.[10]

Late adolescence and early adulthood are peak periods for the onset of schizophrenia,[2] critical years in a young adult's social and vocational development.[11] In 40% of men and 23% of women diagnosed with schizophrenia, the condition manifested itself before the age of 19.[12] To minimize the developmental disruption associated with schizophrenia, much work has recently been done to identify and treat the prodromal (pre-onset) phase of the illness, which has been detected up to 30 months before the onset of symptoms.[11] Those who go on to develop schizophrenia may experience transient or self-limiting psychotic symptoms[13] and the non-specific symptoms of social withdrawal, irritability, dysphoria,[14] and clumsiness[15] during the prodromal phase.

Schneiderian classification

In the early 20th century, the psychiatrist Kurt Schneider listed the forms of psychotic symptoms that he thought distinguished schizophrenia from other psychotic disorders. These are called first-rank symptoms or Schneider's first-rank symptoms. They include delusions of being controlled by an external force; the belief that thoughts are being inserted into or withdrawn from one's conscious mind; the belief that one's thoughts are being broadcast to other people; and hearing hallucinatory voices that comment on one's thoughts or actions or that have a conversation with other hallucinated voices.[16] Although they have significantly contributed to the current diagnostic criteria, the specificity of first-rank symptoms has been questioned. A review of the diagnostic studies conducted between 1970 and 2005 found that they allow neither a reconfirmation nor a rejection of Schneider's claims, and suggested that first-rank symptoms should be de-emphasized in future revisions of diagnostic systems.[17]

Positive and negative symptoms

Schizophrenia is often described in terms of positive and negative (or deficit) symptoms.[18] Positive symptoms are those that most individuals do not normally experience but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis.[19] Hallucinations are also typically related to the content of the delusional theme.[20] Positive symptoms generally respond well to medication.[20] Negative symptoms are deficits of normal emotional responses or of other thought processes, and respond less well to medication.[6] They commonly include flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), lack of desire to form relationships (asociality), and lack of motivation (avolition). Research suggests that negative symptoms contribute more to poor quality of life, functional disability, and the burden on others than do positive symptoms.[21] People with prominent negative symptoms often have a history of poor adjustment before the onset of illness, and response to medication is often limited.[6][22]

Causes

A combination of genetic and environmental factors play a role in the development of schizophrenia.[2][3] People with a family history of schizophrenia who suffer a transient or self-limiting psychosis have a 20–40% chance of being diagnosed one year later.[23]

Genetic

Estimates of heritability vary because of the difficulty in separating the effects of genetics and the environment.[24] The greatest risk for developing schizophrenia is having a first-degree relative with the disease (risk is 6.5%); more than 40% of monozygotic twins of those with schizophrenia are also affected.[3] It is likely that many genes are involved, each of small effect and unknown transmission and expression.[3] Many possible candidates have been proposed, including specific copy number variations, NOTCH4, and histone protein loci.[25] A number of genome-wide associations such as zinc finger protein 804A have also been linked.[26] There appears to be significant overlap in the genetics of schizophrenia and bipolar disorder.[27]

Assuming a hereditary basis, one question from evolutionary psychology is why genes that increase the likelihood of psychosis evolved, assuming the condition would have been maladaptive from an evolutionary point of view. One theory implicates genes involved in the evolution of language and human nature, but to date such ideas remain little more than theoretical in nature. [28][29]

Environment

Environmental factors associated with the development of schizophrenia include the living environment, drug use and prenatal stressors.[2] Parenting style seems to have no major effect, although people with supportive parents do better than those with critical or hostile parents.[3] Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two,[2][3] even after taking into account drug use, ethnic group, and size of social group.[30] Other factors that play an important role include social isolation and immigration related to social adversity, racial discrimination, family dysfunction, unemployment, and poor housing conditions.[3][31]

Substance misuse

A number of drugs have been associated with the development of schizophrenia, including cannabis, cocaine, and amphetamines.[3] About half of those with schizophrenia use drugs and/or alcohol excessively.[32] The role of cannabis could be causal,[33] but other drugs may be used only as coping mechanisms to deal with depression, anxiety, boredom, and loneliness.[32][34]

Cannabis is associated with a dose-dependent increase in the risk of developing a psychotic disorder[35] with frequent use being correlated with twice the risk of psychosis and schizophrenia.[34][36] While cannabis use is accepted as a contributory cause of schizophrenia by many,[37] it remains controversial.[25][38] Amphetamine, cocaine, and to a lesser extent alcohol, can result in psychosis that presents very similarly to schizophrenia.[3][39] Although not generally believed to be a cause of the illness, people with schizophrenia use nicotine at much greater rates than the general population.[40]

Developmental factors

Factors such as hypoxia and infection, or stress and malnutrition in the mother during fetal development, may result in a slight increase in the risk of schizophrenia later in life.[2] People diagnosed with schizophrenia are more likely to have been born in winter or spring (at least in the northern hemisphere), which may be a result of increased rates of viral exposures in utero.[3] This difference is about 5 to 8%.[41]

Mechanisms

A number of attempts have been made to explain the link between altered brain function and schizophrenia.[2] One of the most common is the dopamine hypothesis, which attributes psychosis to the mind's faulty interpretation of the misfiring of dopaminergic neurons.[2]

Psychological

Many psychological mechanisms have been implicated in the development and maintenance of schizophrenia. Cognitive biases have been identified in those with the diagnosis or those at risk, especially when under stress or in confusing situations.[42] Some cognitive features may reflect global neurocognitive deficits such as memory loss, while others may be related to particular issues and experiences.[43][44]

Despite a demonstrated appearance of blunted affect, recent findings indicate that many individuals diagnosed with schizophrenia are emotionally responsive, particularly to stressful or negative stimuli, and that such sensitivity may cause vulnerability to symptoms or to the disorder.[45][46] Some evidence suggests that the content of delusional beliefs and psychotic experiences can reflect emotional causes of the disorder, and that how a person interprets such experiences can influence symptomatology.[47][48][49] The use of "safety behaviors" to avoid imagined threats may contribute to the chronicity of delusions.[50] Further evidence for the role of psychological mechanisms comes from the effects of psychotherapies on symptoms of schizophrenia.[51]

Neurological

Schizophrenia is associated with subtle differences in brain structures, found in 40 to 50% of cases, and in brain chemistry during acute psychotic states.[2] Studies using neuropsychological tests and brain imaging technologies such as fMRI and PET to examine functional differences in brain activity have shown that differences seem to most commonly occur in the frontal lobes, hippocampus and temporal lobes.[52] Reductions in brain volume, smaller than those found in Alzheimer's disease, have been reported in areas of the frontal cortex and temporal lobes. It is uncertain whether these volumetric changes are progressive or preexist prior to the onset of the disease.[53] These differences have been linked to the neurocognitive deficits often associated with schizophrenia.[54] Because neural circuits are altered, it has alternatively been suggested that schizophrenia should be thought of as a collection of neurodevelopmental disorders.[55]

Particular attention has been paid to the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that phenothiazine drugs, which block dopamine function, could reduce psychotic symptoms. It is also supported by the fact that amphetamines, which trigger the release of dopamine, may exacerbate the psychotic symptoms in schizophrenia.[56] The influential dopamine hypothesis of schizophrenia proposed that excessive activation of D2 receptors was the cause of (the positive symptoms of) schizophrenia. Although postulated for about 20 years based on the D2 blockade effect common to all antipsychotics, it was not until the mid-1990s that PET and SPET imaging studies provided supporting evidence. The dopamine hypothesis is now thought to be simplistic, partly because newer antipsychotic medication (atypical antipsychotic medication) can be just as effective as older medication (typical antipsychotic medication), but also affects serotonin function and may have slightly less of a dopamine blocking effect.[57]

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia, largely because of the abnormally low levels of glutamate receptors found in the postmortem brains of those diagnosed with schizophrenia,[58] and the discovery that glutamate-blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.[59] Reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function, and glutamate can affect dopamine function, both of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in the condition.[60] But positive symptoms fail to respond to glutamatergic medication.[61]

Diagnosis

Schizophrenia is diagnosed based on criteria in either the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, version DSM-IV-TR, or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, the ICD-10.[2] These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a clinical assessment by a mental health professional. Symptoms associated with schizophrenia occur along a continuum in the population and must reach a certain severity before a diagnosis is made.[3] As of 2009 there is no objective test.[2]

Criteria

The ICD-10 criteria are typically used in European countries, while the DSM-IV-TR criteria are used in the United States and the rest of the world, and are prevailing in research studies. The ICD-10 criteria put more emphasis on Schneiderian first-rank symptoms. In practice, agreement between the two systems is high.[62]

According to the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), to be diagnosed with schizophrenia, three diagnostic criteria must be met:[63]

1. Characteristic symptoms: Two or more of the following, each present for much of the time during a one-month period (or less, if symptoms remitted with treatment).
   • Delusions
   • Hallucinations
   • Disorganized speech, which is a manifestation of formal thought disorder
   • Grossly disorganized behavior (e.g. dressing inappropriately, crying frequently) or catatonic behavior
   • Negative symptoms: Blunted affect (lack or decline in emotional response), alogia (lack or decline in speech), or avolition (lack or decline in motivation)

   If the delusions are judged to be bizarre, or hallucinations consist of hearing one voice participating in a running commentary of the patient's actions or of hearing two or more voices conversing with each other, only that symptom is required above. The speech disorganization criterion is only met if it is severe enough to substantially impair communication.

2. Social or occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care, are markedly below the level achieved prior to the onset.
3. Significant duration: Continuous signs of the disturbance persist for at least six months. This six-month period must include at least one month of symptoms (or less, if symptoms remitted with treatment).

If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied.[63] Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, and various conditions may be classed as psychotic disorder not otherwise specified. Schizophrenia cannot be diagnosed if symptoms of mood disorder are substantially present (although schizoaffective disorder could be diagnosed), or if symptoms of pervasive developmental disorder are present unless prominent delusions or hallucinations are also present, or if the symptoms are the direct physiological result of a general medical condition or a substance, such as abuse of a drug or medication.

Subtypes

The DSM-IV-TR contains five sub-classifications of schizophrenia, although the developers of DSM-5 are recommending they be dropped from the new classification:[64][65]

• Paranoid type: Delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not. Delusions are persecutory and/or grandiose, but in addition to these, other themes such as jealousy, religiosity, or somatization may also be present. (DSM code 295.3/ICD code F20.0)
• Disorganized type: Named hebephrenic schizophrenia in the ICD. Where thought disorder and flat affect are present together. (DSM code 295.1/ICD code F20.1)
• Catatonic type: The subject may be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility. (DSM code 295.2/ICD code F20.2)
• Undifferentiated type: Psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met. (DSM code 295.9/ICD code F20.3)
• Residual type: Where positive symptoms are present at a low intensity only. (DSM code 295.6/ICD code F20.5)

The ICD-10 defines two additional subtypes:[65]

• Post-schizophrenic depression: A depressive episode arising in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present. (ICD code F20.4)
• Simple schizophrenia: Insidious and progressive development of prominent negative symptoms with no history of psychotic episodes. (ICD code F20.6)

Differential

Psychotic symptoms may be present in several other mental disorders, including bipolar disorder,[66]borderline personality disorder,[67] drug intoxication and drug-induced psychosis. Delusions ("non-bizarre") are also present in delusional disorder, and social withdrawal in social anxiety disorder, avoidant personality disorder and schizotypal personality disorder. Schizophrenia is comorbid with obsessive-compulsive disorder (OCD) considerably more often than could be explained by pure chance, although it can be difficult to distinguish obsessions that occur in OCD from the delusions of schizophrenia.[68]

A more general medical and neurological examination may be needed to rule out medical illnesses which may rarely produce psychotic schizophrenia-like symptoms,[63] such as metabolic disturbance, systemic infection, syphilis, HIV infection, epilepsy, and brain lesions. It may be necessary to rule out a delirium, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, and indicates an underlying medical illness. Investigations are not generally repeated for relapse unless there is a specific medical indication or possible adverse effects from antipsychotic medication.

Prevention

Currently the evidence for the effectiveness of early interventions to prevent schizophrenia is inconclusive.[69] While there is some evidence that early intervention in those with a psychotic episode may improve short term outcomes, there is little benefit from these measures after five years.[2] Attempting to prevent schizophrenia in the prodrome phase is of uncertain benefit and therefore as of 2009 is not recommended.[70] Prevention is difficult as there are no reliable markers for the later development of the disease.[71]

Theoretical research continues into strategies that might lower the incidence of schizophrenia. One approach seeks to understand what happens on a genetic and neurological level to account for the illness, so that biomedical interventions can be developed. However, multiple and varied genetic effects each of small size, interacting with the environment, makes this difficult. Alternatively, public health strategies could selectively address socioeconomic factors that have been linked to higher rates of schizophrenia in certain groups, for example in relation to immigration, ethnicity or poverty. Population-wide strategies could promote services to ensure safe pregnancies and healthy growth, including in areas of psychological development such as social cognition. However, there is not enough evidence to implement such ideas at the current time, and a number of the broader issues are not specific to schizophrenia.[72][73]

Management

The primary treatment of schizophrenia is antipsychotic medications, often in combination with psychological and social supports.[2] Hospitalization may occur for severe episodes either voluntarily or (if mental health legislation allows it) involuntarily. Long-term hospitalization is uncommon since deinstitutionalization beginning in the 1950s, although still occurs.[4] Community support services including drop-in centers, visits by members of a community mental health team, supported employment[74] and support groups are common. Some evidence indicates that regular exercise has a positive effect on the physical and mental health of those with schizophrenia.[75]

Medication

The first-line psychiatric treatment for schizophrenia is antipsychotic medication,[76] which can reduce the positive symptoms of psychosis in about 7–14 days. Antipsychotics, however, fail to significantly ameliorate the negative symptoms and cognitive dysfunction.[22][77] Long term use decreases the risk of relapse.[78]

The choice of which antipsychotic to use is based on benefits, risks, and costs.[2] It is debatable whether, as a class, typical or atypical antipsychotics are better.[79] Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages.[80] There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people.[22]Clozapine is an effective treatment for those who respond poorly to other drugs, but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in 1–4%.[2][3][81]

With respect to side effects typical antipsychotics are associated with a higher rate of extrapyramidal side effects while atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome.[80] While atypicals have fewer extrapyramidal side effects these differences are modest.[82] Some atypicals such as quetiapine and risperidone are associated with a higher risk of death compared to the typical antipsychotic perphenazine, while clozapine is associated with the lowest risk of death.[83] It remains unclear whether the newer antipsychotics reduce the chances of developing neuroleptic malignant syndrome, a rare but serious neurological disorder.[84]

For people who are unwilling or unable to take medication regularly, long-acting depot preparations of antipsychotics may be used to achieve control.[85] They reduce the risk of relate to a greater degree than oral medications.[78] When used in combination with psychosocial interventions they may improve long-term adherence to treatment.[85]

Psychosocial

A number of psychosocial interventions may be useful in the treatment of schizophrenia including: family therapy,[86]assertive community treatment, supported employment, cognitive remediation,[87] skills training, cognitive behavioral therapy (CBT), token economic interventions, and psychosocial interventions for substance use and weight management.[88] Family therapy or education, which addresses the whole family system of an individual, may reduce relapses and hospitalizations.[86] The evidence for CBT's effectiveness in either reducing symptoms or preventing relapse is minimal.[89][90] Art or drama therapy have not been well-researched.[91][92]

Prognosis

Schizophrenia has great human and economic costs.[2] It results in a decreased life expectancy of 12–15 years, primarily because of its association with obesity, sedentary lifestyles, and smoking, with an increased rate of suicide playing a lesser role.[2] These differences in life expectancy increased between the 1970s and 1990s,[93] and between the 1990s and first decade of the 21st century did not change substantially in a health system with open access to care (Finland).[83]

Schizophrenia is a major cause of disability, with active psychosis ranked as the third-most-disabling condition after quadriplegia and dementia and ahead of paraplegia and blindness.[94] Approximately three-fourths of people with schizophrenia have ongoing disability with relapses.[22] Some people do recover completely and others function well in society.[95] Most people with schizophrenia live independently with community support.[2] In people with a first episode of psychosis a good long-term outcome occurs in 42%, an intermediate outcome in 35% and a poor outcome in 27%.[96] Outcomes for schizophrenia appear better in the developing than the developed world.[97] These conclusions, however, have been questioned.[98][99]

There is a higher than average suicide rate associated with schizophrenia. This has been cited at 10%, but a more recent analysis of studies and statistics revises the estimate to 4.9%, most often occurring in the period following onset or first hospital admission.[100] Several times more (20 to 40%) attempt suicide at least once.[101][102] There are a variety of risk factors, including male gender, depression, and a high intelligence quotient.[101]

Schizophrenia and smoking have shown a strong association in studies world-wide.[103][104] Use of cigarettes is especially high in individuals diagnosed with schizophrenia, with estimates ranging from 80% to 90% being regular smokers, as compared to 20% of the general population.[104] Those who smoke tend to smoke heavily, and additionally smoke cigarettes with high nicotine content.[102] Some evidence suggests that paranoid schizophrenia may have a better prospect than other types of schizophrenia for independent living and occupational functioning.[105]

Epidemiology

Disability-adjusted life year for schizophrenia per 100,000 inhabitants in 2004.

no data   ≤ 185   185–197   197–207   207–218   218–229   229–240

240–251   251–262   262–273   273–284   284–295   ≥ 295

Schizophrenia affects around 0.3–0.7% of people at some point in their life,[2] or 24 million people worldwide as of 2011.[106] It occurs 1.4 times more frequently in males than females and typically appears earlier in men[3]—the peak ages of onset are 20–28 years for males and 26–32 years for females.[107]Onset in childhood is much rarer,[108] as is onset in middle- or old age.[109] Despite the received wisdom that schizophrenia occurs at similar rates worldwide, its prevalence varies across the world,[110] within countries,[111] and at the local and neighborhood level.[112] It causes approximately 1% of worldwide disability adjusted life years.[3] The rate of schizophrenia varies up to threefold depending on how it is defined.[2]

History

Accounts of a schizophrenia-like syndrome are thought to be rare in the historical record before the 19th century, although reports of irrational, unintelligible, or uncontrolled behavior were common. A detailed case report in 1797 concerning James Tilly Matthews, and accounts by Phillipe Pinel published in 1809, are often regarded as the earliest cases of the illness in the medical and psychiatric literature.[113] Schizophrenia was first described as a distinct syndrome affecting teenagers and young adults by Bénédict Morel in 1853, termed démence précoce (literally 'early dementia'). The term dementia praecox was used in 1891 by Arnold Pick in a case report of a psychotic disorder. In 1893 Emil Kraepelin introduced a broad new distinction in the classification of mental disorders between dementia praecox and mood disorder (termed manic depression and including both unipolar and bipolar depression). Kraepelin believed that dementia praecox was primarily a disease of the brain,[114] and particularly a form of dementia, distinguished from other forms of dementia such as Alzheimer's disease which typically occur later in life.[115]

The word schizophrenia—which translates roughly as "splitting of the mind" and comes from the Greek roots schizein (σχίζειν, "to split") and phrēn, phren- (φρήν, φρεν-, "mind")[116]—was coined by Eugen Bleuler in 1908 and was intended to describe the separation of function between personality, thinking, memory, and perception. Bleuler described the main symptoms as 4 A's: flattened Affect, Autism, impaired Association of ideas and Ambivalence.[117] Bleuler realized that the illness was not a dementia, as some of his patients improved rather than deteriorated, and thus proposed the term schizophrenia instead. Treatment was revolutionized in the mid-1950s with the development and introduction of chlorpromazine.[118]

In the early 1970s, the diagnostic criteria for schizophrenia was the subject of a number of controversies which eventually led to the operational criteria used today. It became clear after the 1971 US-UK Diagnostic Study that schizophrenia was diagnosed to a far greater extent in America than in Europe.[119] This was partly due to looser diagnostic criteria in the US, which used the DSM-II manual, contrasting with Europe and its ICD-9. David Rosenhan's 1972 study, published in the journal Science under the title "On being sane in insane places", concluded that the diagnosis of schizophrenia in the US was often subjective and unreliable.[120] These were some of the factors leading to the revision not only of the diagnosis of schizophrenia, but the revision of the whole DSM manual, resulting in the publication of the DSM-III in 1980.[121] The term schizophrenia is commonly misunderstood to mean that affected persons have a "split personality". Although some people diagnosed with schizophrenia may hear voices and may experience the voices as distinct personalities, schizophrenia does not involve a person changing among distinct multiple personalities. The confusion arises in part due to the literal interpretation of Bleuler's term schizophrenia (Bleuler originally associated Schizophrenia with dissociation and included split personality in his category of Schizophrenia[122][123]). Dissociative identity disorder (having a "split personality") was also often misdiagnosed as Schizophrenia based on the loose criteria in the DSM-II[123][124]. The first known misuse of the term to mean "split personality" was in an article by the poet T. S. Eliot in 1933.[125]

Society and culture

In 2002 the term for schizophrenia in Japan was changed from Seishin-Bunretsu-Byō　精神分裂病 (mind-split-disease) to Tōgō-shitchō-shō　統合失調症 (integration disorder) to reduce stigma.[126] The new name was inspired by the biopsychosocial model; it increased the percentage of patients who were informed of the diagnosis from 37% to 70% over three years.[127]

In the United States, the cost of schizophrenia—including direct costs (outpatient, inpatient, drugs, and long-term care) and non-health care costs (law enforcement, reduced workplace productivity, and unemployment)—was estimated to be $62.7 billion in 2002.[128] The book and film A Beautiful Mind chronicles the life of John Forbes Nash, a Nobel Prize-winning mathematician who was diagnosed with schizophrenia.

Social stigma has been identified as a major obstacle in the recovery of patients with schizophrenia.[129]

Violence

Individuals with severe mental illness including schizophrenia are at a significantly greater risk of being victims of both violent and non violent crime.[130] On the other hand, schizophrenia has sometimes been associated with a higher rate of violent acts, although this is primarily due to higher rates of drug use.[131] Rates of homicide linked to psychosis are similar to those linked to substance misuse, and parallel the overall rate in a region.[132] What role schizophrenia has on violence independent of drug misuse is controversial, but certain aspects of individual histories or mental states may be factors.[133]

Media coverage relating to schizophrenia tends to revolve around rare but unusual acts of violence. Furthermore, in a large, representative sample from a 1999 study, 12.8% of Americans believed that individuals with schizophrenia were "very likely" to do something violent against others, and 48.1% said that they were "somewhat likely" to. Over 74% said that people with schizophrenia were either "not very able" or "not able at all" to make decisions concerning their treatment, and 70.2% said the same of money management decisions.[134] The perception of individuals with psychosis as violent has more than doubled in prevalence since the 1950s, according to one meta-analysis.[135]

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External links

The Rosenhan experiment was a famous experiment into the validity of psychiatric diagnosis conducted by psychologist David Rosenhan in 1973. It was published in the journal Science under the title "On being sane in insane places."[1] The study is considered an important and influential criticism of psychiatric diagnosis.[2]

Rosenhan's study was done in two parts. The first part involved the use of healthy associates or "pseudopatients" (three women and five men) who briefly simulated auditory hallucinations in an attempt to gain admission to 12 different psychiatric hospitals in five different states in various locations in the United States. All were admitted and diagnosed with psychiatric disorders. After admission, the pseudopatients acted normally and told staff that they felt fine and had not experienced any more hallucinations. Hospital staff failed to detect a single pseudopatient, and instead believed that all of the pseudopatients exhibited symptoms of ongoing mental illness. Several were confined for months. All were forced to admit to having a mental illness and agree to take antipsychotic drugs as a condition of their release. The second part involved an offended hospital challenging Rosenhan to send pseudopatients to its facility, whom its staff would then detect. Rosenhan agreed and in the following weeks out of 193 new patients the staff identified 41 as potential pseudopatients, with 19 of these receiving suspicion from at least 1 psychiatrist and 1 other staff member. In fact Rosenhan had sent no-one to the hospital.

The study concluded, "It is clear that we cannot distinguish the sane from the insane in psychiatric hospitals" and also illustrated the dangers of dehumanization and labeling in psychiatric institutions. It suggested that the use of community mental health facilities which concentrated on specific problems and behaviors rather than psychiatric labels might be a solution and recommended education to make psychiatric workers more aware of the social psychology of their facilities.

[edit] The pseudopatient experiment

Rosenhan himself and seven mentally healthy associates, called "pseudopatients", attempted to gain admission to psychiatric hospitals by calling for an appointment and feigning auditory hallucinations. The hospital staffs were not informed of the experiment. The pseudopatients included a psychology graduate student in his twenties, three psychologists, a pediatrician, a psychiatrist, a painter and a housewife. None had a history of mental illness. Pseudopatients used pseudonyms, and those who worked in the mental health field were given false jobs in a different sector to avoid invoking any special treatment or scrutiny. Apart from giving false names and employment details, further biographical details were truthfully reported.

During their initial psychiatric assessment, they claimed to be hearing voices of the same sex as the patient which were often unclear, but which seemed to pronounce the words "empty", "hollow", "thud" and nothing else. These words were chosen as they vaguely suggest some sort of existential crisis and for the lack of any published literature referencing them as psychotic symptoms. No other psychiatric symptoms were claimed. If admitted, the pseudopatients were instructed to "act normally," reporting that they felt fine and no longer heard voices. Hospital records obtained after the experiment indicate that all pseudopatients were characterized as friendly and cooperative by staff.

All were admitted, to 12 different psychiatric hospitals across the United States, including rundown and underfunded public hospitals in rural areas, urban university-run hospitals with excellent reputations, and one expensive private hospital. Though presented with identical symptoms, 7 were diagnosed with schizophrenia at public hospitals, and one with manic-depressive psychosis, a more optimistic diagnosis with better clinical outcomes, at the private hospital. Their stays ranged from 7 to 52 days, and the average was 19 days. All were discharged with a diagnosis of schizophrenia "in remission," which Rosenhan takes as evidence that mental illness is perceived as an irreversible condition creating a lifelong stigma rather than a curable illness.

Despite constantly and openly taking extensive notes on the behavior of the staff and other patients, none of the pseudopatients were identified as impostors by the hospital staff, although many of the other psychiatric patients seemed to be able to correctly identify them as impostors. In the first three hospitalizations, 35 of the total of 118 patients expressed a suspicion that the pseudopatients were sane, with some suggesting that the patients were researchers or journalists investigating the hospital.

Hospital notes indicated that staff interpreted much of the pseudopatients' behavior in terms of mental illness. For example, one nurse labeled the note-taking of one pseudopatient as "writing behavior" and considered it pathological. The patients' normal biographies were recast in hospital records along the lines of what was expected of schizophrenics by the then-dominant theories of its etiology.

The pseudopatients were required to get out of the hospital on their own by getting the hospital to release them, though a lawyer was retained to be on call for emergencies when it became clear that the pseudopatients would not ever be voluntarily released on short notice. Once admitted and diagnosed, the pseudopatients were not able to obtain their release until they agreed with the psychiatrists that they were mentally ill and began taking antipsychotic medications, which they flushed down the toilet. No staff member noticed that the pseudopatients were flushing their medication down the toilets and did not report patients doing this.

Rosenhan and the other pseudopatients reported an overwhelming sense of dehumanization, severe invasion of privacy, and boredom while hospitalized. Their possessions were searched randomly, and they were sometimes observed while using the toilet. They reported that though the staff seemed to be well-meaning, they generally objectified and dehumanized the patients, often discussing patients at length in their presence as though they were not there, and avoiding direct interaction with patients except as strictly necessary to perform official duties. Some attendants were prone to verbal and physical abuse of patients when other staff were not present. A group of bored patients waiting outside the cafeteria for lunch early were said by a doctor to his students to be experiencing "oral-acquisitive" psychiatric symptoms. Contact with doctors averaged 6.8 minutes per day.

"I told friends, I told my family, 'I can get out when I can get out. That's all. I'll be there for a couple of days and I'll get out.' Nobody knew I'd be there for two months … The only way out was to point out that they're [the psychiatrists] correct. They had said I was insane, 'I am insane; but I am getting better.' That was an affirmation of their view of me." — David Rosenhan in the BBC program "The Trap."[3]

[edit] The non-existent impostor experiment

For this experiment, Rosenhan used a well-known research and teaching hospital, whose staff had heard of the results of the initial study but claimed that similar errors could not be made at their institution. Rosenhan arranged with them that during a three month period, one or more pseudopatients would attempt to gain admission and the staff would rate every incoming patient as to the likelihood they were an impostor. Out of 193 patients, 41 were considered to be impostors and a further 42 were considered suspect. In reality, Rosenhan had sent no pseudopatients and all patients suspected as impostors by the hospital staff were ordinary patients. This led to a conclusion that "any diagnostic process that lends itself too readily to massive errors of this sort cannot be a very reliable one". Studies by others found similarly problematic diagnostic results.[citation needed]

[edit] Impact and controversy

Rosenhan published his findings in Science, criticizing the reliability of psychiatric diagnosis and the disempowering and demeaning nature of patient care experienced by the associates in the study. His article generated an explosion of controversy.

Many defended psychiatry, arguing that as psychiatric diagnosis relies largely on the patient's report of their experiences, faking their presence no more demonstrates problems with psychiatric diagnosis than lying about other medical symptoms. In this vein, psychiatrist Robert Spitzer quoted Kety in a 1975 criticism of Rosenhan's study:

If I were to drink a quart of blood and, concealing what I had done, come to the emergency room of any hospital vomiting blood, the behavior of the staff would be quite predictable. If they labeled and treated me as having a bleeding peptic ulcer, I doubt that I could argue convincingly that medical science does not know how to diagnose that condition.[4]

Rosenhan replied that if they continue thinking that you still have an ulcer during x weeks despite having no other symptoms of ulcer, that makes for a big problem.[citation needed]

Kety also argued that psychiatrists should not necessarily be expected to assume that a patient is pretending to have mental illness, thus the study lacked realism.[5] Rosenhan called this the "experimenter effect" or "expectation bias," something indicative of the problems he uncovered rather than a problem in his methodology.[6]

The experiment "accelerated the movement to reform mental institutions and to deinstitutionalize as many mental patients as possible."[7]

[edit] Related experiments

American investigative journalist Nellie Bly feigned symptoms of mental illness to gain admission to a lunatic asylum in 1887 and report on the terrible conditions therein. The results were published as Ten Days in a Mad-House.

Maurice K. Temerlin split 25 psychiatrists into two groups and had them listen to an actor portraying a character of normal mental health. One group was told that the actor "was a very interesting man because he looked neurotic, but actually was quite psychotic" while the other was told nothing. Sixty percent of the former group diagnosed psychoses, most often schizophrenia, while none of the control group did so.[8]

In 1988, Loring and Powell gave 290 psychiatrists a transcript of a patient interview and told half of them that the patient was black and the other half white; they concluded of the results that "Clinicians appear to ascribe violence, suspiciousness, and dangerousness to black clients even though the case studies are the same as the case studies for the white clients".[9]

The science writer Lauren Slater may have conducted a very similar experiment for her 2004 book Opening Skinner's Box.[2] She claims to have presented herself at 9 different psychiatric emergency rooms with auditory hallucinations, resulting in being diagnosed "almost every time" with psychotic depression. However, when challenged to provide evidence of actually conducting her experiment, she could not.[10]

In 2008, the BBC's Horizon science program performed a somewhat related experiment over two episodes entitled "How Mad Are You?". The experiment involved ten subjects, five living with previously-diagnosed mental health conditions, and five with no such diagnosis. They were observed by three experts in mental health diagnoses and their challenge was to identify the five with mental health problems.[11] The experts correctly diagnosed two of the ten patients, misdiagnosed one patient, and incorrectly identified two healthy patients as having mental health problems.[12]

[edit] See also

[edit] References

• Slater, Lauren (2004). Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century. W. W. Norton. pp. 64–94. ISBN 0-393-05095-5. 

Notes

1. ^ Rosenhan DL (January 1973). "On being sane in insane places". Science 179 (4070): 250–8. DOI:10.1126/science.179.4070.250. PMID 4683124. Archived from the original on 2004-11-17. http://web.archive.org/web/20041117175255/http://web.cocc.edu/lminorevans/on_being_sane_in_insane_places.htm. 
2. ^ a b Slater, Lauren (2004). Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century. W. W. Norton. ISBN 0-393-05095-5. 
3. ^ An excerpt from the BBC program with this statement by David Rosen can be viewed here.
4. ^ Spitzer, Robert L. (October 1975). "On pseudoscience in science, logic in remission, and psychiatric diagnosis: a critique of Rosenhan's "On being sane in insane places"". Journal of Abnormal Psychology 84 (5): 442–52. DOI:10.1037/h0077124. PMID 1194504. 
5. ^ http://www.integratedsociopsychology.net/sane_insane-place.html
6. ^ "The Rosenhan experiment examined", Frontier Psychiatrist
7. ^ Kornblum, William (2011). Mitchell, Erin; Jucha, Robert; Chell, John. eds (Google Books). Sociology in a Changing World (9th ed.). Cengage learning. p. 195. ISBN 978-1-111-30157-6. http://books.google.ca/books?id=DtKcG6qoY5AC&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false. 
8. ^ Temerlin, 1968. "Suggestion Effects in Psychiatric Diagnosis"; Journal of Nervous & Mental Disease: October 1968 - Volume 147 - Issue 4 - ppg 349-353.
9. ^ Loring M, Powell B (March 1988). "Gender, race, and DSM-III: a study of the objectivity of psychiatric diagnostic behavior". Journal of health and social behavior 29 (1): 1–22. DOI:10.2307/2137177. JSTOR 2137177. PMID 3367027. 
10. ^ Moran, Mark (April 7, 2006). "Writer Ignites Firestorm With Misdiagnosis Claims". Psychiatric News (American Psychiatric Association) 41 (7): 10–12. ISSN 1559-1255, Print 0033-2704 Online 1559-1255, Print 0033-2704. http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=109856. Retrieved 2009-12-30. ,
11. ^ BBC Headroom Horizon: How Mad Are You?
12. ^ How Mad Are You? - Spotlight

[edit] External links

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder.[1] It is characterized primarily by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.[2]

ADHD is the most commonly studied and diagnosed psychiatric disorder in children, affecting about 3 to 5 percent of children globally[3][4] and diagnosed in about 2 to 16 percent of school-aged children.[5] It is a chronic disorder[6] with 30 to 50 percent of those individuals diagnosed in childhood continuing to have symptoms into adulthood.[7][8] Adolescents and adults with ADHD tend to develop coping mechanisms to compensate for some or all of their impairments.[9] It is estimated that 4.7 percent of American adults live with ADHD.[10] Standardized rating scales such as the World Health Organization's Adult ADHD Self-Report Scale can be used for ADHD screening and assessment of the disorder's symptoms' severity.[11]

ADHD is diagnosed two to four times more frequently in boys than in girls,[12][13] though studies suggest this discrepancy may be partially due to subjective bias of referring teachers.[14]ADHD management usually involves some combination of medications, behavior modifications, lifestyle changes, and counseling. Its symptoms can be difficult to differentiate from other disorders, increasing the likelihood that the diagnosis of ADHD will be missed.[15] In addition, most clinicians have not received formal training in the assessment and treatment of ADHD, in particular in adult patients.[15]

ADHD and its diagnosis and treatment have been considered controversial since the 1970s.[16] The controversies have involved clinicians, teachers, policymakers, parents and the media. Topics include ADHD's causes, and the use of stimulant medications in its treatment.[17][18][19] Most healthcare providers accept that ADHD is a genuine disorder with debate in the scientific community centering mainly around how it is diagnosed and treated.[20][21][22] The American Medical Association concluded in 1998 that the diagnostic criteria for ADHD are based on extensive research and, if applied appropriately, lead to the diagnosis with high reliability.[23]

Classification

ADHD may be seen as one or more continuous traits found normally throughout the general population.[24] It is a developmental disorder in which certain traits such as impulse control lag in development. Using magnetic resonance imaging of the prefrontal cortex, this developmental lag has been estimated to range from 3 to 5 years.[25] However, the definition of ADHD is based on behaviour and it does not imply a neurological disease.[24] ADHD is classified as a disruptive behavior disorder along with oppositional defiant disorder, conduct disorder and antisocial personality disorder.[26]

ADHD has three subtypes:[27]

• Predominantly hyperactive-impulsive
  • Most symptoms (six or more) are in the hyperactivity-impulsivity categories.
  • Fewer than six symptoms of inattention are present, although inattention may still be present to some degree.
• Predominantly inattentive
  • The majority of symptoms (six or more) are in the inattention category and fewer than six symptoms of hyperactivity-impulsivity are present, although hyperactivity-impulsivity may still be present to some degree.
  • Children with this subtype are less likely to act out or have difficulties getting along with other children. They may sit quietly, but they are not paying attention to what they are doing. Therefore, the child may be overlooked, and parents and teachers may not notice symptoms of ADHD.
• Combined hyperactive-impulsive and inattentive
  • Six or more symptoms of inattention and six or more symptoms of hyperactivity-impulsivity are present.
  • Most children with ADHD have the combined type.

Signs and symptoms

Inattention, hyperactivity, and impulsivity are the key behaviors of ADHD. The symptoms of ADHD are especially difficult to define because it is hard to draw the line at where normal levels of inattention, hyperactivity, and impulsivity end and clinically significant levels requiring intervention begin.[15] To be diagnosed with ADHD, symptoms must be observed in two different settings for six months or more and to a degree that is greater than other children of the same age.[28]

The symptom categories of ADHD in children yield three potential classifications of ADHD—predominantly inattentive type, predominantly hyperactive-impulsive type, or combined type if criteria for both subtypes are met:[15]:p.4

Predominantly inattentive type symptoms may include:[29]

• Be easily distracted, miss details, forget things, and frequently switch from one activity to another
• Have difficulty maintaining focus on one task
• Become bored with a task after only a few minutes, unless doing something enjoyable
• Have difficulty focusing attention on organizing and completing a task or learning something new or trouble completing or turning in homework assignments, often losing things (e.g., pencils, toys, assignments) needed to complete tasks or activities
• Not seem to listen when spoken to
• Daydream, become easily confused, and move slowly
• Have difficulty processing information as quickly and accurately as others
• Struggle to follow instructions.

Predominantly hyperactive-impulsive type symptoms may include:[29]

• Fidget and squirm in their seats
• Talk nonstop
• Dash around, touching or playing with anything and everything in sight
• Have trouble sitting still during dinner, school, and story time
• Be constantly in motion
• Have difficulty doing quiet tasks or activities.

and also these manifestations primarily of impulsivity:[29]

• Be very impatient
• Blurt out inappropriate comments, show their emotions without restraint, and act without regard for consequences
• Have difficulty waiting for things they want or waiting their turns in games

Most people exhibit some of these behaviors, but not to the degree where such behaviors significantly interfere with a person's work, relationships, or studies—and in the absence of significant interference or impairment, a diagnosis of ADHD is normally not appropriate. The core impairments are consistent even in different cultural contexts.[30]

Symptoms may persist into adulthood for up to half of children diagnosed with ADHD. This rate is difficult to estimate, as there are no official diagnostic criteria for ADHD in adults.[15] ADHD in adults remains a clinical diagnosis. The signs and symptoms may differ from those during childhood and adolescence due to the adaptive processes and avoidance mechanisms learned during the process of socialisation.[31]

A 2009 study found that children with ADHD move around a lot because it helps them stay alert enough to complete challenging tasks.[32][33]

Comorbid disorders

Inattention and "hyperactive" behavior are not necessarily the only problems in children with ADHD. ADHD exists alone in only about 1/3 of the children diagnosed with it. The combination of ADHD with other conditions can greatly complicate diagnosis and treatment. Many co-existing conditions require other courses of treatment and should be diagnosed separately instead of being grouped in the ADHD diagnosis.

There is a strong association between persistent bed wetting and ADHD[34] Multiple research studies have also found a significant association between ADHD and language delay.[35]Anxiety and depression are some of the disorders that can accompany ADHD. Academic studies, and research in private practice suggest that depression in ADHD appears to be increasingly prevalent in children as they get older, with a higher rate of increase in girls than in boys, and to vary in prevalence with the subtype of ADHD. Where a mood disorder complicates ADHD, it would be prudent to treat the mood disorder first, but parents of children with ADHD often wish to have the ADHD treated first, because the response to treatment is quicker.[36]

Some of the associated conditions are:

• Oppositional defiant disorder and conduct disorder, both of which characterized by antisocial behaviors such as stubbornness, aggression, frequent temper tantrums, deceitfulness, lying, or stealing,[37] inevitably linking these comorbid disorders with antisocial personality disorder (ASPD); about half of those with hyperactivity and ODD or CD develop ASPD in adulthood.[38]
• Borderline personality disorder, which was according to a study on 120 female psychiatric patients diagnosed and treated for BPD associated with ADHD in 70 percent of those cases.[39]
• Primary disorder of vigilance, which is characterized by poor attention and concentration, as well as difficulties staying awake. These children tend to fidget, yawn and stretch and appear to be hyperactive in order to remain alert and active.[37]
• Mood disorders. Boys diagnosed with the combined subtype have been shown likely to suffer from a mood disorder.[40]
• Bipolar disorder. As many as 25 percent of children with ADHD have bipolar disorder. Children with this combination may demonstrate more aggression and behavioral problems than those with ADHD alone.[37]
• Anxiety disorder, which has been found to be common in girls diagnosed with the inattentive subtype of ADHD.[41]
• Obsessive-compulsive disorder. OCD can co-occur with ADHD and shares many of its characteristics.[37]

In adults

Researchers found that 60 percent of the children diagnosed with ADHD continue having symptoms well into adulthood.[42][43] Many adults, however, remain untreated.[42] Untreated adults with ADHD often have chaotic lifestyles, may appear to be disorganized and may rely on non-prescribed drugs and alcohol to get by.[44] They often have such associated psychiatric comorbidities as depression, anxiety disorder, substance abuse, or a learning disability.[44] A diagnosis of ADHD may offer adults insight into their behaviors and allow patients to become more aware and seek help with coping and treatment strategies.[43] Recognized as occurring in adults in 1978, it is currently not addressed separately from ADHD in childhood. Obstacles that clinicians face when assessing adults who may have ADHD include developmentally inappropriate diagnostic criteria, age-related changes, comorbidities and the possibility that high intelligence or situational factors can mask ADHD.

Cause

The specific causes of ADHD are not known.[45] There are, however, a number of factors that may contribute to, or exacerbate ADHD. They include genetics, diet and the social and physical environments.

Genetics

Twin studies indicate that the disorder is highly heritable and that genetics are a factor in about 75 percent of all cases.[24] Hyperactivity also seems to be primarily a genetic condition; however, other causes have been identified.[46]

Researchers believe that a large majority of ADHD cases arise from a combination of various genes, many of which affect dopamine transporters. Candidate genes include α2A adrenergic receptor, dopamine transporter, dopamine receptors D2/D3,[47]dopamine beta-hydroxylase monoamine oxidase A, catecholamine-methyl transferase, serotonin transporter promoter (SLC6A4), 5HT2A receptor, 5HT1B receptor,[48] the 10-repeat allele of the DAT1 gene,[49] the 7-repeat allele of the DRD4 gene,[49] and the dopamine beta hydroxylase gene (DBH TaqI).[50] A common variant of a gene called LPHN3 is estimated to be responsible for about 9% of the incidence of ADHD, and ADHD cases where this gene is present are particularly responsive to stimulant medication.[51]

Evolutionary theories

The hunter vs. farmer theory is a hypothesis proposed by author Thom Hartmann about the origins of ADHD. The theory proposes that hyperactivity may be an adaptive behavior in pre-modern humans[52] and that those with ADHD retain some of the older "hunter" characteristics associated with early pre-agricultural human society. According to this theory, individuals with ADHD may be more adept at searching and seeking and less adept at staying put and managing complex tasks over time.[53] Further evidence showing hyperactivity may be evolutionarily beneficial was put forth in 2006 in a study that found it may carry specific benefits for certain forms of society. In these societies, those with ADHD are hypothesized to have been more proficient in tasks involving risk or competition (i.e., hunting, mating rituals, etc.).[54] A genetic variant associated with ADHD (DRD4 48bp VNTR 7R allele) has been found to be at higher frequency in more nomadic populations and those with more of a history of migration.[55] Consistent with this, another group of researchers observed that the health status of nomadic Ariaal men was higher if they had the ADHD associated genetic variant (7R alleles). However in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly worse health.[56]

Environmental

Twin studies to date have suggested that approximately 9 to 20 percent of the variance in hyperactive-impulsive-inattentive behavior or ADHD symptoms can be attributed to nonshared environmental (nongenetic) factors.[57][58][59][60] Environmental factors implicated include alcohol and tobacco smoke exposure during pregnancy and environmental exposure to lead in very early life.[61] The relation of smoking to ADHD could be due to nicotine causing hypoxia (lack of oxygen) to the fetus in utero.[62] It could also be that women with ADHD are more likely to smoke[63] and therefore, due to the strong genetic component of ADHD, are more likely to have children with ADHD.[64] Complications during pregnancy and birth—including premature birth—might also play a role.[65] ADHD patients have been observed to have higher than average rates of head injuries;[66] however, current evidence does not indicate that head injuries are the cause of ADHD in the patients observed.[67] Infections during pregnancy, at birth, and in early childhood are linked to an increased risk of developing ADHD. These include various viruses (measles, varicella, rubella, enterovirus 71) and streptococcal bacterial infection.[68][69]

A 2007 study linked the organophosphate insecticide chlorpyrifos, which is used on some fruits and vegetables, with delays in learning rates, reduced physical coordination, and behavioral problems in children, especially ADHD.[70]

A 2010 study found that pesticide exposure is strongly associated with an increased risk of ADHD in children. Researchers analyzed the levels of organophosphate residues in the urine of more than 1,100 children aged 8 to 15 years old, and found that those with the highest levels of dialkyl phosphates, which are the breakdown products of organophosphate pesticides, also had the highest incidence of ADHD. Overall, they found a 35 percent increase in the odds of developing ADHD with every 10-fold increase in urinary concentration of the pesticide residues. The effect was seen even at the low end of exposure: children who had any detectable, above-average level of pesticide metabolite in their urine were twice as likely as those with undetectable levels to record symptoms of ADHD.[71][72]

Three government-funded longitudinal studies from 2010 and 2011 examined environmental exposure to organophosphate pesticides between pregnancy and grade school. Although the studies varied in techniques to measure pesticide exposure, they reached similar conclusions. Children exposed to higher levels of organophosphates during pregnancy were more likely to have lower IQs and problems focusing or solving problems. One study suggested that genetics play a strong role in whether exposure to organophosphates causes damage. Two studies found higher rates of ADHD diagnosis among children exposed to higher levels of organophosphate pesticides.[73]

Diet

A study[74] published in The Lancet in 2007 found a link between children’s ingestion of many commonly used artificial food colors, the preservative sodium benzoate and hyperactivity. In response to these findings, the British government took prompt action. According to the Food Standards Agency, the food regulatory agency in the UK, food manufacturers are being encouraged to voluntarily phase out the use of most artificial food colors by the end of 2009. Following the FSA’s actions, the European Commission ruled that any food products containing the “Southampton Six” (The contentious colourings are: sunset yellow FCF (E110), quinoline yellow (E104), carmoisine (E122), allura red (E129), tartrazine (E102) and ponceau 4R (E124)) must display warning labels on their packaging by 2010.[75] In the US, little has been done[clarification needed] to curb food manufacturer’s use of specific food colors, despite the new evidence presented by the Southampton study. However, the existing US Food Drug and Cosmetic Act[76] had already required that artificial food colors be approved for use, that they must be given FD&C numbers by the FDA, and the use of these colors must be indicated on the package.[77] This is why food packaging in the USA may state something like: "Contains FD&C Red #40." As of March 2011, the FDA was evaluating the scientific evidence of a link between dyes and ADHD; a preliminary analysis found there was no link.[78]

Social

The World Health Organization states that the diagnosis of ADHD can represent family dysfunction or inadequacies in the educational system rather than individual psychopathology.[79] Other researchers believe that relationships with caregivers have a profound effect on attentional and self-regulatory abilities. A study of foster children found that a high number of them had symptoms closely resembling ADHD.[80] Researchers have found behavior typical of ADHD in children who have suffered violence and emotional abuse.[24][81] Furthermore, Complex Post Traumatic Stress Disorder can result in attention problems that can look like ADHD.[82] ADHD is also considered to be related to sensory integration dysfunction.[83]

A 2010 article by CNN suggests that there is an increased risk for internationally adopted children to develop mental health disorders, such as ADHD and ODD.[84] The risk may be related to the length of time the children spent in an orphanage, especially if they were neglected or abused. Many of these families who adopted the affected children feel overwhelmed and frustrated, since managing their children may entail more responsibilities than originally anticipated. The adoption agencies may be aware of the child's behavioral history, but decide to withhold the information prior to the adoption. This in turn has resulted in some parents suing adoption agencies, in the abuse of children, and even in the relinquishment of the child.

Neurodiversity

Main article: Neurodiversity

Proponents of the neurodiversity theory assert that atypical (neurodivergent) neurological development is a normal human difference that is to be tolerated and respected just like any other human difference. Social critics argue that while biological factors may play a large role in difficulties with sitting still in class and/or concentrating on schoolwork in some children, these children could have failed to integrate others' social expectations of their behavior for a variety of other reasons.[85] As genetic research into ADHD proceeds, it may become possible to integrate this information with the neurobiology in order to distinguish disability from varieties of normal or even exceptional functioning in people along the same spectrum of attention differences.[86]

Social construct theory of ADHD

Social construction theory states that it is societies that determine where the line between normal and abnormal behavior is drawn. Thus society members including physicians, parents, teachers, and others are the ones who determine which diagnostic criteria are applied and, thus, determine the number of people affected.[87] This is exemplified in the fact that the DSM IV arrives at levels of ADHD three to four times higher than those obtained with use of the ICD 10.[13]Thomas Szasz, a proponent of this theory, has argued that ADHD was "invented and not discovered."[88][89]

Low arousal theory

According to the low arousal theory, people with ADHD need excessive activity as self-stimulation because of their state of abnormally low arousal.[90] The theory states that those with ADHD cannot self-moderate, and their attention can be gained only by means of environmental stimuli, which in turn results in disruption of attentional capacity and an increase in hyperactive behaviour.[91]

Without enough stimulation coming from the environment, an ADHD child will create it him or herself by walking around, fidgeting, talking, etc. This theory also explains why stimulant medications have high success rates and can induce a calming effect at therapeutic dosages among children with ADHD. It establishes a strong link with scientific data that ADHD is connected to abnormalities with the neurochemical dopamine and a powerful link with low-stimulation PET scan results in ADHD subjects.

Pathophysiology

The pathophysiology of ADHD is unclear and there are a number of competing theories.[92] Research on children with ADHD has shown a general reduction of brain volume, but with a proportionally greater reduction in the volume of the left-sided prefrontal cortex. These findings suggest that the core ADHD features of inattention, hyperactivity, and impulsivity may reflect frontal lobe dysfunction, but other brain regions in particular the cerebellum have also been implicated.[93] Neuroimaging studies in ADHD have not always given consistent results and as of 2008 are used only for research and not diagnostic purposes.[94] A 2005 review of published studies involving neuroimaging, neuropsychological genetics, and neurochemistry found converging lines of evidence to suggest that four connected frontostriatal regions play a role in the pathophysiology of ADHD: The lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen.[95]

In one study a delay in development of certain brain structures by an average of three years occurred in ADHD elementary school-aged patients. The delay was most prominent in the frontal cortex and temporal lobe, which are believed to be responsible for the ability to control and focus thinking. In contrast, the motor cortex in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might be required for the fidgetiness that characterizes ADHD.[96] It should be noted that stimulant medication itself may affect growth factors of the central nervous system.[97]

The same laboratory had previously found involvement of the "7-repeat" variant of the dopamine D4 receptor gene, which accounts for about 30 percent of the genetic risk for ADHD, in unusual thinness of the cortex of the right side of the brain; however, in contrast to other variants of the gene found in ADHD patients, the region normalized in thickness during the teen years in these children, coinciding with clinical improvement.[98]

In addition, SPECT scans found people with ADHD to have reduced blood circulation (indicating low neural activity),[99] and a significantly higher concentration of dopamine transporters in the striatum, which is in charge of planning ahead.[100][101] A study by the U.S. Department of Energy’s Brookhaven National Laboratory in collaboration with Mount Sinai School of Medicine in New York suggest that it is not the dopamine transporter levels that indicate ADHD, but the brain's ability to produce neurotransmitters like dopamine itself. The study was done by injecting 20 ADHD subjects and 25 control subjects with a radiotracer that attaches itself to dopamine transporters. The study found that it was not the transporter levels that indicated ADHD, but the dopamine itself. ADHD subjects showed lower levels of dopamine (hypodopaminergia) across the board. They speculated that since ADHD subjects had lower levels of dopamine to begin with, the number of transporters in the brain was not the telling factor. In support of this notion, plasma homovanillic acid, an index of dopamine levels, was found to be inversely related not only to childhood ADHD symptoms in adult psychiatric patients but to "childhood learning problems" in healthy subjects as well.[102] One interpretation of dopamine pathway tracers is that the biochemical "reward" mechanism works for those with ADHD only when the task performed is inherently motivating; low levels of dopamine raise the threshold at which someone can maintain focus on a task that is otherwise boring.[103] Neuroimaging studies also found that neurotransmitters level (e.g. dopamine and serotonin) in the synaptic cleft goes down during depression.[104][105]

A 1990 PET scan study by Alan J. Zametkin et al. found that global cerebral glucose metabolism was 8 percent lower in medication-naive adults who had been hyperactive since childhood.[106] Further studies found that chronic stimulant treatment had little effect on global glucose metabolism,[107] a 1993 study in girls failed to find a decreased global glucose metabolism, but found significant differences in glucose metabolism in 6 specific regions of the brains of ADHD girls as compared to control subjects. The study also found that differences in one specific region of the frontal lobe were statistically correlated with symptom severity.[108] A further study in 1997 also failed to find global differences in glucose metabolism, but, likewise, found differences in glucose normalization in specific regions of the brain. The 1997 study also noted that their findings were somewhat different than those in the 1993 study, and concluded that sexual maturation may have played a role in this discrepancy.[109] The significance of the research by Zametkin has not been determined and neither his group nor any other has been able to replicate the 1990 results.[110][111][112]

Critics, such as Jonathan Leo and David Cohen, who reject the characterization of ADHD as a disorder, contend that the controls for stimulant medication usage were inadequate in some lobar volumetric studies, which makes it impossible to determine whether ADHD itself or psychotropic medication used to treat ADHD is responsible for the decreased thickness observed[113] in certain brain regions. While the main study in question used age-matched controls, it did not provide information on height and weight of the subjects. These variables it has been argued could account for the regional brain size differences rather than ADHD itself.[114][115] They believe many neuroimaging studies are oversimplified in both popular and scientific discourse and given undue weight despite deficiencies in experimental methodology.[114][116]

Diagnosis

ADHD is diagnosed via a psychiatric assessment; to rule out other potential causes or comorbidities, physical examination, radiological imaging, and laboratory tests may be used.[117]

In North America, the DSM-IV criteria are often the basis for a diagnosis, while European countries usually use the ICD-10. If the DSM-IV criteria are used, rather than the ICD-10, a diagnosis of ADHD is 3–4 times more likely.[13] Factors other than those within the DSM or ICD however have been found to affect the diagnosis in clinical practice. A child's social and school environment as well as academic pressures at school are likely to be of influence.[118]

Many of the symptoms of ADHD occur from time to time in everyone; in patients with ADHD, the frequency of these symptoms is greater and patients' lives are significantly impaired. Impairment must occur in multiple settings to be classified as ADHD.[28] As with many other psychiatric and medical disorders, the formal diagnosis is made by a qualified professional in the field based on a set number of criteria. In the USA these criteria are laid down by the American Psychiatric Association in their Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edition. Based on the DSM-IV criteria listed below, three types of ADHD are classified:

1. ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months
2. ADHD Predominantly Inattentive Type: if criterion 1A is met but criterion 1B is not met for the past six months
3. ADHD, Predominantly Hyperactive-Impulsive Type: if criterion 1B is met but criterion 1A is not met for the past six months.[119]

The previously used term ADD expired with the most recent revision of the DSM. As a consequence, ADHD is the current nomenclature used to describe the disorder as one distinct disorder that can manifest itself as being a primary deficit resulting in hyperactivity/impulsivity (ADHD, predominately hyperactive-impulsive type) or inattention (ADHD, predominately inattentive type) or both (ADHD combined type).

DSM-IV

The diagnostic criteria outlined in DSM-IV assume that attention deficits (1) are a distinct, differentiated condition; (2) can be reliably measured using objective, behavioral measures; and (3)are abnormalities resulting from organic/biological origins.[120]

IA. Six or more of the following signs of inattention have been present for at least 6 months to a point that is disruptive and inappropriate for developmental level:

1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities.
2. Often has trouble keeping attention on tasks or play activities.
3. Often does not seem to listen when spoken to directly.
4. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions).
5. Often has trouble organizing activities.
6. Often avoids, dislikes, or does not want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework).
7. Often loses things needed for tasks and activities (such as toys, school assignments, pencils, books, or tools).
8. Is often easily distracted.
9. Often forgetful in daily activities.

IB. Six or more of the following signs of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level:

1. Often fidgets with hands or feet or squirms in seat.
2. Often gets up from seat when remaining in seat is expected.
3. Often runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless).
4. Often has trouble playing or enjoying leisure activities quietly.
5. Is often "on the go" or often acts as if "driven by a motor".
6. Often talks excessively.

1. Often blurts out answers before questions have been finished.
2. Often has trouble waiting one's turn.
3. Often interrupts or intrudes on others (example: butts into conversations or games).

II. Some signs that cause impairment were present before age 7 years.

III. Some impairment from the signs is present in two or more settings (such as at school/work and at home).

IV. There must be clear evidence of significant impairment in social, school, or work functioning.

V. The signs do not happen only during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The signs are not better accounted for by another mental disorder (such as Mood Disorder, Anxiety Disorder, Dissociative Identity Disorder, or a Personality Disorder).[121]

ICD-10

In the tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) the signs of ADHD are given the name "Hyperkinetic disorders". When a conduct disorder (as defined by ICD-10[122]) is present, the condition is referred to as "Hyperkinetic conduct disorder". Otherwise the disorder is classified as "Disturbance of Activity and Attention", "Other Hyperkinetic Disorders" or "Hyperkinetic Disorders, Unspecified". The latter is sometimes referred to as, "Hyperkinetic Syndrome".[122]

Other guidelines

The American Academy of Pediatrics Clinical Practice Guideline for children with ADHD emphasizes that a reliable diagnosis is dependent upon the fulfillment of three criteria:[123]

• The use of explicit criteria for the diagnosis using the DSM-IV-TR.
• The importance of obtaining information about the child’s signs in more than one setting.
• The search for coexisting conditions that may make the diagnosis more difficult or complicate treatment planning.

All three criteria are determined using the patient's history given by the parents, teachers and/or the patient.

Adults often continue to be impaired by ADHD. Adults with ADHD are diagnosed under the same criteria, including the stipulation that their signs must have been present prior to the age of seven.[124] Adults face some of their greatest challenges in the areas of self-control and self-motivation, as well as executive functioning, usually having more signs of inattention and fewer of hyperactivity or impulsiveness than children do.[125]

The American Academy of Child Adolescent Psychiatry (AACAP) considers it necessary that the following be present before attaching the label of ADHD to a child:

• The behaviors must appear before age 7.
• They must continue for at least six months.
• The symptoms must also create a real handicap in at least two of the following areas of the child’s life:
  • in the classroom,
  • on the playground,
  • at home,
  • in the community, or
  • in social settings.[126]

If a child seems too active on the playground but not elsewhere, the problem might not be ADHD. It might also not be ADHD if the behaviors occur in the classroom but nowhere else. A child who shows some symptoms would not be diagnosed with ADHD if his or her schoolwork or friendships are not impaired by the behaviors.[126]

Differential

To make the diagnosis of ADHD, a number of other possible medical and psychological conditions must be excluded.

Medical conditions

Medical conditions that must be excluded include: hypothyroidism, anemia, lead poisoning, chronic illness, hearing or vision impairment, substance abuse, medication side-effects, sleep impairment and child abuse,[127] and cluttering (tachyphemia) among others.

Sleep conditions

As with other psychological and neurological issues, the relationship between ADHD and sleep is complex. In addition to clinical observations, there is substantial empirical evidence from a neuroanatomic standpoint to suggest that there is considerable overlap in the central nervous system centers that regulate sleep and those that regulate attention/arousal.[128] Primary sleep disorders play a role in the clinical presentation of symptoms of inattention and behavioral dysregulation. There are multilevel and bidirectional relationships among sleep, neurobehavioral functioning and the clinical syndrome of ADHD.[129]

Behavioral manifestations of sleepiness in children range from the classic ones (yawning, rubbing eyes), to externalizing behaviors (impulsivity, hyperactivity, aggressiveness), to mood lability and inattentiveness.[128][130][131] Many sleep disorders are important causes of symptoms that may overlap with the cardinal symptoms of ADHD; children with ADHD should be regularly and systematically assessed for sleep problems.[128][132]

From a clinical standpoint, mechanisms that account for the phenomenon of excessive daytime sleepiness include:

• Chronic sleep deprivation, that is insufficient sleep for physiologic sleep needs,
• Fragmented or disrupted sleep, caused by, for example, obstructive sleep apnea (OSA) or periodic limb movement disorder (PLMD),
• Primary clinical disorders of excessive daytime sleepiness, such as narcolepsy and
• Circadian rhythm disorders, such as delayed sleep phase syndrome (DSPS). A study in the Netherlands compared two groups of unmedicated 6-12-year-olds, all of them with "rigorously diagnosed ADHD". 87 of them had problems getting to sleep, 33 had no sleep problems. The larger group had a significantly later dim light melatonin onset (DLMO) than did the children with no sleep problems.[133]

Management

Methods of treatment often involve some combination of behavior modification, life-style changes, counseling, and medication. A 2005 study found that medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment.[134] While medication has been shown to improve behavior when taken over the short term, they have not been shown to alter long-term outcomes.[135] Medications have at least some effect in about 80% of people.[136]

Psychosocial

The evidence is strong for the effectiveness of behavioral treatments in ADHD.[137] It is recommended first line in those who have mild symptoms and in preschool-aged children.[138] Psychological therapies used include psychoeducational input, behavior therapy, cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), family therapy, school-based interventions, social skills training, parent management training,[24]neurofeedback,[139] and nature exposure.[140][141] Parent training and education have been found to have short-term benefits.[142] There is a deficiency of good research on the effectiveness of family therapy for ADHD, but the evidence that exists shows that it is comparable in effectiveness to treatment as usual in the community and is superior to medication placebo.[143] Several ADHD specific support groups exist as informational sources and to help families cope with challenges associated with dealing with ADHD.

Medication

Stimulant medications are the medical treatment of choice.[144] There are a number of non-stimulant medications, such as atomoxetine, that may be used as alternatives.[144] There are no good studies of comparative effectiveness between various medications, and there is a lack of evidence on their effects on academic performance and social behaviors.[145] While stimulants and atomoxetine are generally safe, there are side-effects and contraindications to their use.[144] Medications are not recommended for preschool children, as their long-term effects in such young people are unknown.[24][146] There is very little data on the long-term benefits or adverse effects of stimulants for ADHD.[147] Any drug used for ADHD may have adverse drug reactions such as psychosis and mania,[148] though methylphenidate-induced psychosis is uncommon.[149] People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk.[150][151] Stimulant medications in and of themselves however have the potential for abuse and dependence.[152]Guidelines on when to use medications vary internationally, with the UK's National Institute of Clinical Excellence, for example, recommending use only in severe cases, while most United States guidelines recommend medications in nearly all cases.[153]

Prognosis

Children diagnosed with ADHD have significant difficulties in adolescence, regardless of treatment.[154][155] In the United States, 37 percent of those with ADHD do not get a high school diploma even though many of them will receive special education services.[156] A 1995 briefing citing a 1994 book review says the combined outcomes of the expulsion and dropout rates indicate that almost half of all ADHD students never finish high school.[157] Also in the US, less than 5 percent of individuals with ADHD get a college degree[158] compared to 28 percent of the general population.[159] The proportion of children meeting the diagnostic criteria for ADHD drops by about 50 percent over three years after the diagnosis. This occurs regardless of the treatments used and also occurs in untreated children with ADHD.[127][160][161] ADHD persists into adulthood in about 30 to 50 percent of cases.[7] Those affected are likely to develop coping mechanisms as they mature, thus compensating for their previous ADHD.[9]

Epidemiology

Percent of United States youth 4–17 ever diagnosed with ADHD as of 2007

ADHD's global prevalence is estimated at 3 to 5 percent in people under the age of 19. There is, however, both geographical and local variability among studies. Children in North America appear to have a higher rate of ADHD than children in Africa and the Middle East.[163] Published studies have found rates of ADHD as low as 2 percent and as high as 14 percent among school-aged children.[164] The rates of diagnosis and treatment of ADHD are also much higher on the East Coast of the USA than on the West Coast.[165] The frequency of the diagnosis differs between male children (10%) and female children (4%) in the United States.[166] This difference between genders may reflect either a difference in susceptibility or that females with ADHD are less likely to be diagnosed than males.[167]

Rates of ADHD diagnosis and treatment have increased in both the UK and the USA since the 1970s. In the UK an estimated 0.5 per 1,000 children had ADHD in the 1970s, while 3 per 1,000 received ADHD medications in the late 1990s. In the USA in the 1970s 12 per 1,000 children had the diagnosis, while in the late 1990s 34 per 1,000 had the diagnosis and the numbers continue to increase.[24]

In the UK in 2003 a prevalence of 3.6 percent is reported in male children and less than 1 percent is reported in female children.[168]

History

Hyperactivity has long been part of the human condition. Sir Alexander Crichton describes "mental restlessness" in his book An Inquiry Into the Nature and Origin of Mental Derangement written in 1798.[169][170] The terminology used to describe the symptoms of ADHD has gone through many changes over history including: "minimal brain damage", "minimal brain dysfunction" (or disorder),[171] "learning/behavioral disabilities" and "hyperactivity". In the DSM-II (1968) it was the "Hyperkinetic Reaction of Childhood". In the DSM-III "ADD (Attention-Deficit Disorder) with or without hyperactivity" was introduced. In 1987 this was changed to ADHD in the DSM-III-R and subsequent editions.[172] The use of stimulants to treat ADHD was first described in 1937.[173]

Society and culture

The media have reported on many issues related to ADHD. In 2001 PBS's Frontline aired a one-hour program about the effects of the diagnosis and treatment of ADHD in minors, entitled "Medicating Kids."[174] The program included a selection of interviews with representatives of various points of view. In one segment, entitled Backlash, retired neurologist Fred Baughman and Peter Breggin whom PBS described as "outspoken critics who insist [ADHD is] a fraud perpetrated by the psychiatric and pharmaceutical industries on families anxious to understand their children's behavior"[175] were interviewed on the legitimacy of the disorder. Russell Barkley and Xavier Castellanos, then head of ADHD research at the National Institute of Mental Health (NIMH), defended the viability of the disorder. In the interview with Castellanos, he stated that little is scientifically understood.[176] Lawrence Diller was interviewed on the business of ADHD along with a representative from Shire Plc (then known as Shire-Richwood).[citation needed]

A number of notable individuals have given controversial opinions on ADHD. Scientologist Tom Cruise's interview with Matt Lauer was widely watched by the public in 2005. In this interview he spoke about postpartum depression and also referred to Ritalin and Adderall as being "street drugs" rather than as ADHD medication.[177] In England Baroness Susan Greenfield, a leading neuroscientist, spoke out publicly in 2007 in the House of Lords about the need for a wide-ranging inquiry into the dramatic increase in the diagnosis of ADHD in the UK and possible causes following a BBC Panorama programme that highlighted US research (The Multimodal Treatment Study of Children with ADHD by the University of Buffalo) suggesting drugs are no better than other forms of therapy for ADHD in the long term.[178] However, in 2010 the BBC Trust criticized the 2007 BBC Panorama programme for summarizing the US research as showing "no demonstrable improvement in children's behaviour after staying on ADHD medication for three years" when in actuality "the study found that medication did offer a significant improvement over time."[179]

As of 2009[update], eight percent of all Major League Baseball players have been diagnosed with ADHD, making the disorder epidemic among this population. The increase coincided with the League's 2006 ban on stimulants (q.v. Major League Baseball drug policy).[180]

Legal status of medications

Stimulants legal status was recently reviewed by several international organizations:

• Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[181]
• In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high likelihood for abuse because of their addictive potential.
• In the United Kingdom, methylphenidate is a controlled 'Class B' substance, and possession without prescription is illegal, with a sentence up to 14 years and/or an unlimited fine.[182]
• In New Zealand, it is a 'class B2 controlled substance'. unlawful possession is punishable by 6-month prison sentence and distribution of it is punishable by a 14-year sentence.

Controversies

ADHD and its diagnosis and treatment have been considered controversial since the 1970s.[16][18][183] The controversies have involved clinicians, teachers, policymakers, parents and the media. Opinions regarding ADHD range from not believing it exists at all[17] to believing there are genetic and physiological bases for the condition as well as disagreement about the use of stimulant medications in treatment.[17][18][19] Some sociologists consider ADHD to be a "classic example of the medicalization of deviant behavior, defining a previously nonmedical problem as a medical one".[16] Most healthcare providers in U.S. accept that ADHD is a genuine disorder with debate in centering mainly around how it is diagnosed and treated.[20][21][22] However, The British Psychological Society said in a 1997 report that physicians and psychiatrists should not follow the American example of applying medical labels to such a wide variety of attention-related disorders: "The idea that children who don’t attend or who don’t sit still in school have a mental disorder is not entertained by most British clinicians."[184][185] In 2009, the British Psychological Society, in collaboration with the Royal College of Psychiatrists, released a set of guidelines for the diagnosis and treatment of ADHD.[186] In its guideline, it state that available evidence indicate that ADHD is a valid diagnosis. However, it states that the diagnosis lack any biological basis and that "[c]ontroversial issues surround changing thresholds applied to the definition of illness as new knowledge and treatments are developed and the extent to which it is acknowledged that clinical thresholds are socially and culturally influenced and determine how an individual's level of functioning within the 'normal cultural environment' is assessed". It further states that "the acceptable thresholds for impairment are partly driven by the contemporary societal view of what is an acceptable level of deviation from the norm."

Others have included that it may stem from a misunderstanding of the diagnostic criteria and how they are utilized by clinicians,[15]:p.3 teachers, policymakers, parents and the media.[17] Debates center around key controversial issues; whether ADHD is a disability or merely a neurological description, the cause of the disorder, the changing of the diagnostic criteria, the rapid increase in diagnosis of ADHD, and the use of stimulants to treat the disorder.[187] Possible long-term side-effects of stimulants and their usefulness are largely unknown because of a lack of long-term studies.[188] Some research raises questions about the long-term effectiveness and side-effects of medications used to treat ADHD.[189]

In 1998, the US National Institutes of Health (NIH) released a consensus statement on the diagnosis and treatment of ADHD. The statement, while recognizing that stimulant treatment is controversial, supports the validity of the ADHD diagnosis and the efficacy of stimulant treatment. It found controversy only in the lack of sufficient data on long-term use of medications, and in the need for more research in many areas.[190]

With a "wide variation in diagnosis across states, races, and ethnicities"[191] some investigators[who?] suspect that factors other than neurological conditions play a role when the diagnosis of ADHD is made.[191][192] Two studies published in 2010 suggest that the diagnosis is more likely to be made in the younger children within a grade; the authors propose that such a misdiagnosis of ADHD within a grade may be due to different states of maturity and may lead to potentially inappropriate treatment.[191][192] A further study involving a million children in British Columbia (Canada) published in 2012 using data from 1997 to 2008 unambiguously confirmed the phenomenon, finding children born in December (the youngest) 39% more likely to be diagnosed with ADHD than those born in January (the oldest).[193]

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180. ^ Saletan, William (2009-01-12). "Doping Deficit Disorder. Need performance-enhancing drugs? Claim ADHD". Slate. http://www.slate.com/id/2208429/. Retrieved 2009-05-02. 
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Bibliography

• Dr Jennifer Erkulwater; Dr Rick Mayes; Dr Catherine Bagwell (2009). Medicating Children: ADHD and Pediatric Mental Health. Cambridge: Harvard University Press. p. 5. ISBN 0-674-03163-6. 

Further reading

• Faraone Stephen V (2005). "The scientific foundation for understanding attention-deficit/hyperactivity disorder as a valid psychiatric disorder". Eur Child Adolesc Psychiatry 14 (1): 1–10. DOI:10.1007/s00787-005-0429-z. PMID 15756510. 
• Faraone, Stephen, V.Straight Talk about Your Child's Mental Health: What to Do When Something Seems Wrong (2003) New York:Guilford Press
• Hartmann, Thom (2003). The Edison gene: ADHD and the gift of the hunter child. Rochester, Vt: Park Street Press. ISBN 0-89281-128-5. 
• Matlen, Terry. (2005) "Survival Tips for Women with AD/HD". ISBN 1-886941-59-9
• Millichap, J. Gordon, MD, FRCP Attention Deficit Hyperactivity Disorder Handbook: A Physician’s Guide to ADHD. New York: Springer, 2010 ISBN 978-1-4419-1396-8
• Southall, Angela (2007). The Other Side of ADHD:Attention Deficit Hyperactivity Disorder Exposed and Explained. Radcliffe Publishing Ltd. ISBN 1-84619-068-1. http://books.google.com/?id=AKXhThWgvyYC&pg=PA41&lpg=PA41&dq=barkley+drug+company+funding. Retrieved 2009-05-02. 

External links

Attention deficit hyperactivity disorder (F90, 314) Main articles Sub-types Notable publications Notable experts Relevant drugs Other

Emotional and behavioral

Adderall is a brand name of amphetamine salts-based medication used for attention deficit hyperactivity disorder and narcolepsy,[1] legal only in the United States and Canada[citation needed] It is a brand-name psychostimulant medication composed of racemic amphetamine aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine saccharide, and dextroamphetamine sulfate, which are all amphetamine salts. It is thought to work by increasing the amount of dopamine and norepinephrine in between synapses in the brain because the drug is a potent dopamine reuptake inhibitor and norepinephrine reuptake inhibitor.[2] It is available in two formulations: IR (Instant Release) and XR (Extended Release). The immediate release formulation is indicated for use in attention deficit hyperactivity disorder (ADHD) and narcolepsy,[3] while the XR formulation is approved for use only with ADHD.[2]

Like other stimulant prescription drugs, Adderall directly affects the mesolimbic reward pathway in the brain. Amphetamine salts preparations are considered to have high abuse potential, and it is classified as Schedule II by the US DEA.

[edit] Medical uses

Adderall is used for attention-deficit hyperactivity disorder and narcolepsy.[1] It has been used to treat obesity, but The American Society of Health-System Pharmacists does not recommend this use.[1]

[edit] Attention deficit hyperactivity disorder

Adderall, has been shown to significantly reduce symptoms associated with attention-deficit hyperactivity disorder (ADHD), and in many patients it presents minimal side-effects. Depending on dosage, the beneficial effects of stimulant medications can last several hours, allowing improved performance throughout the day.[4] Compared to the similar medication methylphenidate (sold under the brand name Ritalin and others), studies have suggested that Adderall is slightly more potent and has a longer period of efficacy, especially at lower doses.[5] For those who experience adverse side-effects to Ritalin or for whom Ritalin has become ineffective, Adderall is often recommended as a substitute.[6][7] A typical adult dosing is between 30–40 mg for Adderall XR.[8]

Apart from the FDA-approved indications for the treatment of ADHD and narcolepsy, Adderall has also been used off-label to manage cases of treatment-resistant depression, exogenous obesity, and alternate sleep cycle disorders.[9]

[edit] Dosing and administration

Adderall is marketed as either an immediate-release tablet Adderall, or an extended-release capsule Adderall XR.[3]

Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves slowly, releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, mean plasma concentration is prolonged by 2.5 hours (using a 900-calorie standard high-fat meal as the control). Medications that alter urinary pH will cause variations in the amount and method of excretion, and usage should be monitored when taken concurrently with Adderall.[10]

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall[11] was a pharmaceutical composition patent listing a rapid immediate-release oral dosage form. No claim of increased or smooth drug delivery was made. A recent double-blind, placebo-controlled crossover study conducted among 35 children ages 5–12 indicated that patients behaved similarly to those having taken other immediate-release amphetamines. The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, however D-amphetamine was less effective in the first few hours.[12]

[edit] Adverse effects

Studies of long-term use of Adderall and methylphenidate in children have shown a temporary decrease in growth rate that does not affect final adult height.[13] Stimulant medications also decrease appetite in some people, leading to weight loss, and this effect is more common with mixed amphetamine salts than methylphenidate[13] or atomoxetine. Changes in vision have been reported with both Adderall and methylphenidate.[2][14] Women who are pregnant should avoid taking Adderall, especially during early pregnancy. Studies on rats show long-term neurological and behavioral changes resulting from prenatal and early postnatal exposure to amphetamines.[2] Other potential side effects in adults include insomnia, headaches, increased muscle tension, irritability, and anxiety.[15]

[edit] Contraindications, interactions, and precautions

The following provides only general guidelines and is not comprehensive. Please refer to a more comprehensive list for further information regarding co-administration of amphetamine with other substances.

• MAOIs (monoamine oxidase inhibitors, e.g., phenelzine, selegiline, iproniazid, etc.) — Do not administer amphetamine for a minimum of two weeks after last use of MAOI type drug. High risk for hypertensive crisis. Preliminary trials of low-dose amphetamine and MAOIs being administered together are in progress. However, this is to be done only under strict supervision of the prescribing parties.
• SSRIs (selective serotonin reuptake inhibitors, e.g., fluvoxamine, citalopram, paroxetine, etc.) — While a common combination, and although rare, the risk for serotonin syndrome exists. (Use only when directed)
• NRIs (norepinephrine reuptake inhibitors, e.g., atomoxetine, etc.) — NRI medications and amphetamine both enhance noradrenergic activity. Possible augmentation/potentiation of effects. (Use only when directed)
• SNRIs (selective serotonin-norepinephrine reuptake inhibitors) — See SSRIs and NRIs.
• Bupropion  — Both bupropion and amphetamine have noradrenergic and dopaminergic activity. Possible augmentation/potentiation of effects. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine.[16] (Use only when directed)
• Tricyclics and related compounds (tricyclic antidepressant)  — See SNRIs and SSRIs. Possible potentiation of serotonin-, dopamine-, and norepinephrine-related drug effects. The combination of tricyclic and amphetamine compounds/other direct-acting sympathomimetics has been associated with increased sympathetic action. Adjustments to dose may be required. Concurrent use not generally recommended due to interaction between direct-acting sympathomimetics such as amphetamine and tricyclics. Indirect-acting sympathomimetics may have decreased efficacy when combined with tricyclics (tricyclic blockade may inhibit the action of some indirect-acting sympathomimetics).
• CYP2D6 (liver enzyme) inhibitors, e.g., most SSRIs such as fluoxetine, citalopram, paroxetine, etc. Some anti-psychotics such as thioridazine, haloperidol, and levomepromazine, as well as cocaine, the opioid agonist methadone, and others. It is important to determine if any medication or drug taken is a CYP2D6 inhibitor. Taking a CYP2D6-inhibiting drug along with amphetamine will lead to an elevated level of amphetamine in the system, resulting in the drug's remaining in the body for a longer period, which can lead to undesirable and possibly serious side effects.

[edit] Pregnancy

FDA pregnancy category C. It is not known whether Adderall will harm a developing embryo or fetus. It could cause premature birth, low birth weight, or withdrawal symptoms in a newborn if the mother takes this medication during pregnancy.[17]

[edit] Government warnings

On February 9, 2005, Health Canada suspended all sales of Adderall XR after data collected by manufacturer Shire Pharmaceuticals linked the drug to 12 sudden deaths in American children.[18] Further research found data suggesting use of Adderall resulted in an increased risk of cardiac defect and it is known that amphetamine class drugs like Adderall present a marked increase in heart rate and blood pressure.[19] Although more than 37 million prescriptions for Adderall were filled during the four years prior, the U.S. Food and Drug Administration could find no increased risk of sudden death among Adderall users.[18][20] In August 2005, Health Canada followed the committee report of three independent physicians and lifted the ban on Adderall XR.[21][22] Given that persons with ADHD are more likely to engage in risky or dangerous behavior, it has been suggested that stimulant medications for persons with ADHD may actually result in lower incidence of premature death.[23] The use of Adderall is generally not advised in those persons with pre-existing cardiac or mental illnesses. It is also not advised in persons who have a history of drug abuse.[3] Although FDA safety advisors voted 8 to 7 to issue a black box warning, the FDA's pediatric advisory committee refused to give the drug its most severe black box warning in March 2006.[24] A Black Box Warning regarding amphetamine abuse potential is in place, however. In September 2008, Britain's National Institute for Health and Clinical Excellence urged physicians not to prescribe Adderall or similar drugs to children under 5, and to exhaustively consider other approaches to behavioral modification before prescribing such drugs to children 5 and up.[25]

[edit] Prolonged use

Prolonged high doses of amphetamines followed by an abrupt cessation can result in extreme fatigue, insomnia, irritability, and mental depression. Chronic abuse of amphetamines can result in the manifestation of amphetamine psychosis.[2]

[edit] Chemistry

Adderall's effects are similar to other CNS stimulants of the same class and preparation. (See amphetamine for details.)

Urinary and stomach pH levels can have a strong effect on DL-amphetamine excretion and absorption.[26] An acidic stomach and GI pH will decrease the absorption of Adderall,[10] and acidic urine levels will decrease the reabsorption of the drug through the renal system.[27] Co-administration of acidic substances (e.g., citric acid) causes decreased renal reabsorption of DL-amphetamine; whereas, alkaline agents (e.g., antacids) may cause a marked increase in renal tubular reabsorption. The increased reabsorption can increase the retention of amphetamines, with potential to result in dangerously high serum levels.[27]

[edit] Adderall XR

Adderall XR consists of the following amphetamine compounds in equal proportions: dextroamphetamine saccharate, dextroamphetamine sulfate, racemic amphetamine aspartate monohydrate, and racemic amphetamine sulfate.[2] Breakdown rates are affected by many factors including urinary and stomach pH,[10][26] weight, gender, other medications being taken, and age. Alkalinity increases bioavailability, while acidity causes the drug to be excreted more quickly. Manufacturers claim that the mixture of salts in Adderall XR makes its effects smoother (that is, makes softer highs and lows).[28] The mixture of salts and their ratios are as follows:

• 1/4 dextroamphetamine saccharate
• 1/4 dextroamphetamine sulfate, USP
• 1/4 (racemic) amphetamine aspartate monohydrate
• 1/4 (racemic) amphetamine sulfate, USP

[edit] Metabolism

"The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13–17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis children have a higher clearance than adolescents or adults."[29](p2)

[edit] Generic forms

Both Adderall IR and Adderall XR are available in generic forms.[30][31][32] The generic version of Adderall IR is available as generic drugs but the generic version of Adderall XR is only available as authorized generics.[33][34] Authorized generics are still manufactured by the brand name manufacturer but marketed and sold by a different company. Authorized generics are exactly the same as the brand name product both in active and inactive ingredients—they go through exactly the same brand manufacturing line, yet different labels are put on at the end of the manufacturing process.

[edit] Mechanism of action

With respect to central stimulant actions, the S(+) isomer (i.e., dextroamphetamine) is several times more potent than its R(-)enantiomer (i.e., levoamphetamine); this is not necessarily the case with other actions produced by amphetamine, in particular those produced in the periphery such as its cardiovascular actions.[35] Dextroamphetamine induces more euphoria, whereas levoamphetamine induces more depression. The overall greater potency of the dextro form to central actions suggests that this form may have a higher potential for abuse.[36]

Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals formulated exclusively of dextroamphetamine.[37] Although it seems the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.[38] Amphetamines are believed to exert their effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine, and serotonin[citation needed] .

It is hypothesized that D-amphetamine acts primarily on the dopaminergic (DA) systems, while L-amphetamine is comparatively norepinephrinergic (NE)[citation needed]. The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic dopaminergic pathway. Amphetamine binds to the dopamine transporter (DAT) and blocks the transporter's ability to clear DA from the synaptic space. In addition, amphetamine is transported into the cell, which leads to dopamine efflux (DA is transported out of the cell and into the synaptic space via reverse transport of the DAT).

Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase-A and -B (MAO-A and MAO-B) in high doses[citation needed]. MAO-A is responsible for the breakdown of serotonin, dopamine, norepinephrine, and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to those of amphetamine itself, and is thought to be involved in feelings of lust, confidence, obsession, and sexuality. Some of the first antidepressants successfully marketed are, in fact, Monoamine-Oxidase inhibitors. However, MAO inhibition seen with amphetamine is not substantial enough in duration and quantity to entail the need for a tyramine-limited diet, unlike the more potent and long-lived MAO-inhibiting antidepressants.

Amphetamine's ability to cause the inhibition of MAO results in the accumulation of monoamines: Amphetamine directly stimulates the release of these neurochemicals, resulting in a potent elevation in monoamine neurotransmission. In sum, the effect of amphetamines is to increase neurotransmitter availability in the synapse, by both releasing more neurotransmitters and prolonging their availability in the synapse by slowing their removal.

[edit] Performance-enhancing use

Adderall is widely used as a "study drug" at many universities,[39] due to Adderall's reported ability to help focus energy and concentration to a much higher level than normal.[citation needed] It enables the user to focus and stay awake. Stories of students writing papers continuously for an unusually long time or "cramming" all night for an exam with no loss of energy or concentration are common.[39] College campuses known to be highly competitive or have a high rate of binge drinking had up to 25% of students use an ADHD medication within one year, a survey of students at 119 colleges across the country concluded.[citation needed]

Adderall use as an academic advantage has become increasingly more common amongst college students. Illegal Adderall use is highest among white fraternity members, students from the northeastern region of the United States and students from colleges with more competitive admission standards. [40] Students with ADHD sell Adderall on college campuses for anywhere from $5 to $25 a pill depending on the time of the academic year. [41] The legal consequences for selling Adderall include prison time because it is classified as a controlled substance. [42] It is often difficult to catch illegal Adderall sales because the pills are “easily concealed, odorless, and can be perceived as prescribed drugs” Of these sales, 62% of buyers report to using Adderall for concentration and study help. [43]

Many athletic organizations have restricted the usage of Adderall by athletes. The NCAA has banned the use of Adderall for its collegiate athletes without a prescription and adequate records of evaluation and diagnosis of ADHD.[44]Nevada State Athletic Commission has also banned athletes in the state from using Adderall. Tim Credeur was removed from a UFC fight on the finale of The Ultimate Fighter 7 because of a positive drug test due to his use of it. In the National Football League, New Orleans Saints kicker Garrett Hartley served a four-game suspension when the 2009 NFL regular season began because he tested positive for the banned stimulant. The Arizona Cardinals tight end Ben Patrick received a four-game suspension as a result of using Adderall.[45]

The New York Giants running back Andre Brown is facing a four-game suspension for violating NFL's performance-enhancing substance ban. Brown said: “It was something that I've been on since I've been in the league, which was Adderall. I just forgot to fill out some paperwork and that was it.” [46]

[edit] Recreational Use

Adderall, as an amphetamine product, is used recreationally for its euphoric and stimulant properties.[47] Prescription amphetamines are often obtained by those with a prescription and diverted and sold to those who do not have a prescription.[48] As a Schedule II drug, Adderall is considered to have a high potential for misuse and a high liability for dependence.[49][50] Amphetamine has the potential to cause withdrawal (mainly psychological) symptoms when ceasing use.[51]

[edit] Detection of use

Amphetamine is frequently measured in hair, oral fluid, sweat, or urine as part of a drug abuse testing program. Techniques such as immunoassay may cross-react with a number of sympathomimetics drugs, so chromatographic methods specific for amphetamine should be employed to prevent false-positive results. Chiral techniques may be employed to help distinguish the source of the drug, whether obtained legally (by prescription) or illegally or possibly as a result of formation from a prodrug such as lisdexamfetamine or selegiline. Chiral separation can be used to differentiate Adderall use from use of another prescription form of amphetamine or from use of illicit amphetamine, since Adderall is unique in having a 3:1 mixture of the d- and l-isomers.[52][53][54]

[edit] History

Adderall is available as an instant-release (IR) and an extended-release (XR) drug. Adderall instant-release is manufactured today by Teva and Barr Pharmaceuticals. Shire Pharmaceuticals, the creator of Adderall IR, no longer produces it. However, Shire does continue to manufacture the extended-release version of Adderall ("Adderall XR"). Shire introduced the Adderall brand in 1996 in the form of a multi-dose, instant-release tablet derived from an original formula of the weight management drug Obetrol. In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals[55] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals (including Barr's Duramed division).[56] Therefore, following its acquisition of Duramed, Teva is in the somewhat unusual position of manufacturing both a generic formulation of Adderall instant-release (under its Barr Division) as well as "brand name" Adderall (under its DuraMed division.)

Reflecting the change in manufacturers from Shire Pharmaceuticals to Teva's DuraMed Pharmaceuticals, the "imprint" on Adderall instant-release tablets has changed. One side of the instant-release tablets now bears the DuraMed Pharmaceuticals imprint, a lowercase letter "d" over a lowercase letter "p". This is a change from the previous uppercase "AD" imprint on the tablets.

The active ingredients of Adderall include a combination of dextroamphetamine and racemic DL-amphetamine salts.[57] In 2001, Shire introduced an extended-release preparation of these ingredients in a variety of dosages under the brand name "Adderall XR," on which Shire retains exclusive patent rights until the patent expires, expected in 2018.[58] However, due to issues with Shire's inability to evergreen (extend the patent life by obtaining either a new FDA indication or application of other patent life) the patent for Adderall XR, the drug has become available in a generic form.[59] In 2009, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning April 1, 2009.[60]

[edit] Legal status

• Canada: In March of 2012, Canada passed the "Safe Streets and Communities Act" into law, which (in part) rescheduled amphetamines from Schedule III to Schedule I.
• Japan: Any medicine containing Methamphetamine or Amphetamine is defined as one of “Prohibited Stimulants” and strictly restricted in Japan. Nobody can bring any medicine containing Methamphetamine or Amphetamine (including Adderall) into Japan.[61]
• South Korea: Non-prescribed Amphetamine-based medications are banned in South Korea. They are illegal to import without a doctor's prescription.[62] Adderall is not currently prescribed inside Korea, but other stimulant medications such as Ritalin are.
• Thailand: Amphetamine and dextroamphetamine are classified as Type 1 Narcotics.[63]
• United Nations: The United Nations Office on Drugs and Crime has recommended that Adderall should only be administered to those with a valid prescription and valid diagnosis. The UN believes that stimulant abuse is a problem and is trying to find a way to decrease the amount of people who abuse stimulants.[64]
• United States: The United States Drug Enforcement Agency classifies Adderall as a Schedule II substance. According to the US DEA, these are substances with a high potential for abuse, but with legitimate and accepted medical uses. This makes it a criminal offense to possess Adderall without a valid prescription and limits the amount a medical provider can prescribe to a 90 day supply, which must be three separate prescriptions, each for a 30 day supply and with instructions to the pharmacy for when the prescription may be filled.[65][66]

[edit] References

1. ^ a b c "Adderall". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/adderall.html. Retrieved 3 April 2011. 
2. ^ a b c d e f "Adderall XR prescribing information". Shire US. March 2009. http://pi.shirecontent.com/PI/PDFs/AdderallXR_USA_ENG.PDF. Retrieved 2009-06-23. 
3. ^ a b c "ADDERALL (CII)" (PDF). Food and Drug Administration. March 2007. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf. Retrieved 2009-06-23. 
4. ^ Biederman J, Lopez FA, Boellner SW, Chandler MC (August 2002). "A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder". Pediatricsa 110 (2 Pt 1): 258–66. DOI:10.1542/peds.110.2.258. PMID 12165576. http://pediatrics.aappublications.org/cgi/content/full/110/2/258. Retrieved 2009-06-23. 
5. ^ "Adderall compared to methylphenidate; Efficacy and safety
6. ^ Pelham WE, Aronoff HR, Midlam JK, et al. (April 1999). "A comparison of Ritalin and Adderall: efficacy and time-course in children with attention-deficit/hyperactivity disorder". Pediatrics 103 (4): e43. DOI:10.1542/peds.103.4.e43. PMID 10103335. Archived from the original on 15 May 2009. http://pediatrics.aappublications.org/cgi/content/full/103/4/e43. Retrieved 2009-06-23. 
7. ^ Pliszka SR, Browne RG, Olvera RL, Wynne SK (May 2000). "A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry 39 (5): 619–26. DOI:10.1097/00004583-200005000-00016. PMID 10802980. 
8. ^ "Adult ADHD: Drug Choice Typically Includes Timing Issues". Clinical Psychiatry News. http://psych.imng.com/fileadmin/content_pdf/cpn/archive_pdf/vol33iss6/70422_main.pdf. 
9. ^ Fernstrom, Madelyn (2006-10-26). "Quick-fix diet drugs: Effective or harmful?". Today (Msnbc). http://www.msnbc.msn.com/id/15385195/. Retrieved 2009-06-23. 
10. ^ a b c Aschenbrenner, Diane S.; Samantha J. Venable (2008). Drug Therapy in Nursing. Lippincott Williams & Wilkins. p. 359. ISBN 0-7817-6587-0. 
11. ^ US patent 6384020, Flanner, Henry H., et al., "A pharmaceutical composition comprising lactitol and one or more amphetamine salts in a rapid-release formulation", issued 2002-05-07 
12. ^ Buck, ML (March 2002). "Amphetamines in the Treatment of Attention-Deficit/Hyperactivity Disorder" (PDF). Pediatric Pharmacotherapy 8 (3). http://www.healthsystem.virginia.edu/alive/pediatrics/PharmNews/200203.pdf. Retrieved 2009-06-23. 
13. ^ a b Pliszka SR, Matthews TL, Braslow KJ, Watson MA (May 2006). "Comparative effects of methylphenidate and mixed salts amphetamine on height and weight in children with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry 45 (5): 520–6. DOI:10.1097/01.chi.0000205702.48324.fd. PMID 16670648. 
14. ^ "ADHD Medications - Actions and Side Effects". Healthcenter.pterrywave.com. http://healthcenter.pterrywave.com/ADHD/Drugs.aspx. Retrieved 2011-10-31. 
15. ^ Barkley, Russell (2010). Taking Charge of Adult ADD. 72 Spring Street, New York, NY: The Guilford Press. p. 122. ISBN 978-1-60623-710-6. 
16. ^ "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor". Ncbi. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514842/. Retrieved 2011-10-31. 
17. ^ "Adderall, Prescription Marketed Drugs, www.drugsdb.eu". http://drugsdb.eu/drug.php?d=Adderall&m=Barr%20Laboratories%20Inc.&id=d16d512f-48e9-400e-8ac1-7cbd8dd61dc1.xml. 
18. ^ a b "Public Health Advisory for Adderall and Adderall XR". Food and Drug Administration. 2009-04-30. Archived from the original on 10 July 2009. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051672.htm. Retrieved 2009-06-23. [dead link]
19. ^ Nissen, Steven E (April 6, 2006). "ADHD Drugs and Cardiovascular Risk". New England Journal of Medicine. pp. April 6, 2006. http://www.nejm.org/doi/full/10.1056/NEJMp068049. Retrieved March 29, 2012. 
20. ^ DeNoon, Daniel (2005-02-10). "Sudden Death in 12 Kids on ADHD Drug Adderall". WebMD. Archived from the original on 22 June 2009. http://www.webmd.com/add-adhd/news/20050210/sudden-death-in-12-kids-on-adhd-drug-adderall-news. Retrieved 2009-06-23. 
21. ^ "Report of the Adderall XR New Drug Committee". Health Canada. 2005-08-26. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/new-drug-com-nouvelle-drogue/ndca_rep_cnma_rap_2005-08-25-eng.php. Retrieved 2009-06-23. 
22. ^ Rosack, J (7 October 2005). "Canada reverses ban on ADHD medication". Psychiatric News (American Psychiatric Association) 40 (19): 2. ISSN 1559-1255. Archived from the original on 28 June 2009. http://pn.psychiatryonline.org/cgi/content/full/40/19/2. Retrieved 2009-06-23. 
23. ^ Brown, Thomas (May 2006). "Excessive Fears about Stimulant Medications for ADHD". The BrownLetter on ADD. http://www.drthomasebrown.com/resources/newsletters/may06.html. Retrieved 2009-06-23. 
24. ^ "Dire warning not urged for ADHD drugs". Washington Post. 2006-03-23. http://www.washingtonpost.com/wp-dyn/content/article/2006/03/22/AR2006032202079.html. Retrieved 2009-06-23. 
25. ^ Cummings, Denis (2008-09-26). "British Health Agency Discourages Ritalin Use". FindingDulcinea. Archived from the original on 22 June 2009. http://www.findingdulcinea.com/news/health/September-October-08/British-Health-Agency-Discourages-Ritalin-Use.html. Retrieved 2009-06-23. 
26. ^ a b Washington, Neena (1991). Antacids and Anti-reflux Agents. CRC Press. p. 175. ISBN 0-8493-5444-7. http://books.google.com/?id=MKxtXgtt5SIC. 
27. ^ a b Nobles, Sylvia Tindell (2001). Delmar's Drug Reference for Health Care Professionals. Cengage Learning. p. 10. ISBN 0-7668-2523-X. 
28. ^ Reynolds, Cecil R; Fletcher-Janzen, Elaine (2009). Handbook of Clinical Child Neuropsychology (3rd, revised ed.). Springer. p. 531. ISBN 978-0-387-70708-2. http://books.google.com/?id=Cm86pbWGVj8C. Retrieved 2009-06-23. 
29. ^ FDA (2007). Medication guide adderall xr. pp. 1–14. Archived from the original on 30 January 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021303s015lbl.pdf. Retrieved 2011-02-04. 
30. ^ "Adderall IR; Adderall XR: Are they from Shire, Barr, Teva, or Ranbaxy?". Armand Rossetti. InjuryBoard.com. 2009-08-17. http://westpalmbeach.injuryboard.com/fda-and-prescription-drugs/adderall-ir-adderall-xr-are-they-from-shire-barr-teva-or-ranbaxy.aspx?googleid=269158. Retrieved 2009-10-01. 
31. ^ "Has anyone noticed change in Adderall (brand, not generic) formula?". addforums. 2009-08-26. http://www.addforums.com/forums/showthread.php?t=56460. Retrieved 2009-10-01. 
32. ^ "Why has brand-name Adderall changed formula, and now has 'dp' imprint, rather than 'AD'?". healthcentral.com. 2009-08-17. http://www.healthcentral.com/adhd/c/question/513341/59075. Retrieved 2009-02-11. 
33. ^ http://blue.regence.com/trgmedpol/drugs/dru179.pdf
34. ^ "FDA Listing of Authorized Generics" (PDF). http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM183605.pdf. Retrieved 2011-10-31. 
35. ^ Williams, David A; Lemke, Thomas L; Foye, William O, eds. (2002). "Hallucinogens, stimulants, and related drugs of abuse". Foye's principles of medicinal chemistry (5th, illustrated ed.). Lippincott Williams & Wilkins. p. 445. ISBN 978-0-683-30737-5. http://books.google.com.au/books?id=KGLF4ZudTyAC&pg=PA445&lpg=PA445&dq=caffiene+is+works+in+the+same+way+as+amphetamine+only+less+potent&source=bl&ots=6y9FDsWGPB&sig=v9HY-NwUzxzbEqs30oBkcemDipU&hl=en&ei=b2_IScTmMNeGkAXuu-joAg&sa=X&oi=book_result&resnum=1&ct=result. Retrieved 2009-06-23. 
36. ^ edited by Alan F. Schatzberg, Charles B. Nemeroff. (2004). Schatzberg, Alan F; Nemeroff, Charles B. eds. The American Psychiatric Publishing textbook of psychopharmacology (3rd ed.). American Psychiatric Publishing. ISBN 978-1-58562-060-9. http://books.google.com/?id=5QfL19H5nVkC. Retrieved 2009-06-23. 
37. ^ Glaser PE, Thomas TC, Joyce BM, Castellanos FX, Gerhardt GA (March 2005). "Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core". Psychopharmacology 178 (2–3): 250–8. DOI:10.1007/s00213-004-2012-6. PMID 15719230. 
38. ^ Arnold (2000). "Methylphenidate vs Amphetamine: Comparative Review". Journal of Attention Disorders 3 (4): 200–211. DOI:10.1177/108705470000300403. 
39. ^ a b Kristina M. Hall et al., "Illicit Use of Prescribed Stimulant Medication Among College Students," Journal of American College Health, Vol. 53, No. 4 (2005).
40. ^ DeSantis and Hane, 2010, pg.31-46
41. ^ Teter, 2006, pg. 1501-1510
42. ^ Trudeau, 2009
43. ^ Drown, 2010
44. ^ "NCAA Banned Drugs and Medical Exceptions Policy". http://www.ncaa.org/wps/portal/ncaahome/ncaa/NCAA/Legislation+and+Governance/Eligibility+and+Recruiting/Drug+Testing/Medical+Exceptions+Policy+Video. Retrieved 27 June 2011. 
45. ^ "Patrick tests positive for amphetamine". Associated Press. ESPN. 2009-06-15. Archived from the original on 21 June 2009. http://sports.espn.go.com/nfl/news/story?id=4261608. Retrieved 2009-06-23. 
46. ^ "Brown believes PED suspension due to Adderall prescription". CBSSports. Chris Adamski. 2012-05-23. http://www.cbssports.com/nfl/rapid-reports/post/19134152. Retrieved 2012-05-23. 
47. ^ "Erowid Amphetamine Vault". Erowid.org. http://www.erowid.org/chemicals/amphetamines/amphetamines.shtml. Retrieved 2012-05-07. 
48. ^ "Erowid Amphetamine Basics". Erowid.org. http://www.erowid.org/chemicals/amphetamines/amphetamines_basics.shtml. Retrieved 2012-05-07. 
49. ^ "Commonly Abused Prescription Drugs Chart". National Institute on Drug Abuse. http://www.drugabuse.gov/drugs-abuse/commonly-abused-drugs/commonly-abused-prescription-drugs-chart. Retrieved 2012-05-07. 
50. ^ "Stimulant ADHD Medications - Methylphenidate and Amphetamines". National Institute on Drug Abuse. http://www.drugabuse.gov/publications/infofacts/stimulant-adhd-medications-methylphenidate-amphetamines. Retrieved 2012-05-07. 
51. ^ "Erowid Amphetamine Effects". Erowid.org. http://www.erowid.org/chemicals/amphetamines/amphetamines_effects.shtml. Retrieved 2012-05-07. 
52. ^ JT Cody, S Valtier, SL Nelson. Amphetamine excretion profile following multidose administration of mixed salt amphetamine preparation. J. Anal. Toxicol. 28: 563–573, 2004.
53. ^ Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA. Enantiomeric separation and quantitation of (+/-)-amphetamine, (+/-)-methamphetamine, (+/-)-MDA, (+/-)-MDMA, and (+/-)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(-)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA). J. Anal. Toxicol. 28: 449–455, 2004.
54. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 85–88.
55. ^ "Barr and Shire Sign Three Agreements" (Press release). Barr Pharmaceuticals. 2006-08-14. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/08-14-2006/0004416042. Retrieved 2009-06-23. 
56. ^ "Teva Completes Acquisition of Barr". Drugs.com. http://www.drugs.com/news/teva-completes-acquisition-barr-15356.html. Retrieved 2011-10-31. 
57. ^ Adderall (Amphetamine Mixed Salts) drug description – U.S. Food and Drug Administration (FDA) approved labeling for prescription drugs and medications at RxList
58. ^ "Shire’s Adderall XRTM receives patent protection" (PDF) (Press release). Shire Pharmaceuticals. 2001-11-28. http://www.shire.com/shire/uploads/press/shire/28112001B.pdf. Retrieved 2009-06-23. [dead link]
59. ^ Foley, Stephen (2006-08-16). "Shire in deal with Barr to delay launch of rival to its ADHD drug". London: The Independent. http://www.independent.co.uk/news/business/news/shire-in-deal-with-barr-to-delay-launch-of-rival-to-its-adhd-drug-412102.html. Retrieved 2006-06-23. 
60. ^ "Teva sells 1st generic of Adderall XL in US". Associated Press. Forbes Magazine. 2009-04-02. Archived from the original on 9 April 2009. http://www.forbes.com/feeds/ap/2009/04/02/ap6248888.html. Retrieved 2009-04-22. [dead link]
61. ^ http://kouseikyoku.mhlw.go.jp/kantoshinetsu/gyomu/bu_ka/shido_kansa/documents/qa_bringmedicines_070618.pdf
62. ^ "Korean Customs Service : Restricted Items". English.customs.go.kr. http://english.customs.go.kr/kcsweb/user.tdf?a=common.HtmlApp&c=1501&page=/english/html/kor/personal/personal_01_04.html&mc=ENGLISH_PERSONAL_TRAVELERS_040. Retrieved 2011-10-31. 
63. ^ "Erowid Psychoactive Vaults : Thailand Law". Erowid.org. 2009-03-27. http://www.erowid.org/psychoactives/law/countries/law_thailand.shtml. Retrieved 2011-10-31. 
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• DeSantis, Alan D, and Audrey Curtis Hane. “‘Adderall is Definitely Not a Drug’: Justifications for the Illegal Use of ADHD Stimulants.” Medical Stimulant Misuse: Justifications Jan. 2010: 31-46. EBSCOhost. Web. 18 Mar. 2012.
• Drown, Britton. “Adderall Use Increases on College Campuses.” Kansas State Collegian. 7 Jul. 2010. Web. 17 Mar. 2012.
• Teter, Christian J. “Illicit Use of Specific Prescription Stimulants Among College Students.” Pharmacotherapy Oct. 2006: 1501-1510. PubMed. Web. 17 Mar. 2012.
• Trudeau, Michelle. “More Students Turning Illegally To ‘Smart’ Drugs.” National Public Radio. 5 Feb. 2009. Web. 17 Mar. 2012.

Centrally acting sympathomimetics Xanthine derivatives Glutamate receptor Eugeroics / Benzhydryl compounds Histamine H3 receptor antagonists GABAA α5 inverse agonists Dopamine D1 receptor agonists α7 nicotinic agonists / PAMs Prolyl endopeptidase inhibitors Alpha-adrenergic agonists Plants Antioxidants Other psychostimulants and nootropics

Adamantanes Adenosine antagonists Alkylamines Arylcyclohexylamines Benzazepines Cholinergics Convulsants Eugeroics Oxazolines Phenethylamines Piperazines Piperidines Pyrrolidines Tropanes Others

The trait of extraversion–introversion is a central dimension of human personality theories.

The terms introversion and extraversion were first popularized by Carl Jung.[1] Virtually all comprehensive models of personality include these concepts in various forms. Examples include the Big Five model, Jung's analytical psychology, Hans Eysenck's three-factor model, Raymond Cattell's 16 personality factors, the Minnesota Multiphasic Personality Inventory, and the Myers Briggs Type Indicator.

Extraversion and introversion are typically viewed as a single continuum. Thus, to be high on one it is necessary to be low on the other. Carl Jung and the authors of the Myers-Briggs provide a different perspective and suggest that everyone has both an extraverted side and an introverted side, with one being more dominant than the other. Rather than focusing on interpersonal behavior, however, Jung defined introversion as an "attitude-type characterised by orientation in life through subjective psychic contents" (focus on one's inner psychic activity); and extraversion as "an attitude type characterised by concentration of interest on the external object", (the outside world).[2]

In any case, people fluctuate in their behavior all the time, and even extreme introverts and extraverts do not always act according to their type.

[edit] Varieties

Extraversion is "the act, state, or habit of being predominantly concerned with and obtaining gratification from what is outside the self".[3] Extraverts tend to enjoy human interactions and to be enthusiastic, talkative, assertive, and gregarious. They take pleasure in activities that involve large social gatherings, such as parties, community activities, public demonstrations, and business or political groups. Politics, teaching, sales, managing and brokering are fields that favor extraversion. An extroverted person is likely to enjoy time spent with people and find less reward in time spent alone. They tend to be energized when around other people, and they are more prone to boredom when they are by themselves.

[edit] Introversion

Introversion is "the state of or tendency toward being wholly or predominantly concerned with and interested in one's own mental life".[3] Some popular writers have characterized introverts as people whose energy tends to expand through reflection and dwindle during interaction.[4] This is similar to Jung's view, although he focused on psychic energy rather than physical energy. Few modern conceptions make this distinction.

The common modern perception is that introverts tend to be more reserved and less outspoken in groups. They often take pleasure in solitary activities such as reading, writing, using computers, hiking and fishing. The archetypal artist, writer, sculptor, engineer, composer, and inventor are all highly introverted. An introvert is likely to enjoy time spent alone and find less reward in time spent with large groups of people, though he or she may enjoy interactions with close friends. Trust is usually an issue of significance: a virtue of utmost importance to an introvert choosing a worthy companion. They prefer to concentrate on a single activity at a time and like to observe situations before they participate, especially observed in developing children and adolescents.[5] They are more analytical before speaking.[6] Introverts are easily overwhelmed by too much stimulation from social gatherings and engagement, introversion having even been defined by some in terms of a preference for a quiet, more minimally stimulating environment.[7]

Introversion is not seen as being identical to shy or to being a social outcast. Introverts prefer solitary activities over social ones, whereas shy people (who may be extroverts at heart) avoid social encounters out of fear,[8] and the social outcast has little choice in the matter of his or her solitude.

[edit] Ambiversion

Although many people view being introverted or extroverted as a question with only two possible answers, most contemporary trait theories measure levels of extraversion-introversion as part of a single, continuous dimension of personality, with some scores near one end, and others near the half-way mark.[9]Ambiversion is a term used to describe people who fall more or less directly in the middle and exhibit tendencies of both groups.[3][10] An ambivert is normally comfortable with groups and enjoys social interaction, but also relishes time alone and away from the crowd.

[edit] Measurement

Assessing extraversion and introversion is normally accomplished through self-reporting.[citation needed] A questionnaire might ask if the test-taker agrees or disagrees with statements such as I am the life of the party or I think before I talk.

The following is an example of such a questionnaire. It consists of ten "agree or disagree" statements. For the first five statements, agreement indicates a tendency towards extraversion. For the last five statements, agreement indicates introversion. Included in the table are hypothetical responses from five different people:

	Nathan	Beatrice	Dave	Spencer	Anne
I am the life of the party.	Agree	Agree	Agree	Disagree	Disagree
I enjoy being the center of attention.	Agree	Disagree	Agree	Disagree	Disagree
I am skilled in handling social situations.	Agree	Agree	Agree	Disagree	Disagree
I like to be where the action is.	Agree	Agree	Disagree	Agree	Disagree
I make new friends easily.	Agree	Agree	Disagree	Agree	Disagree
I am quiet around strangers.	Disagree	Disagree	Agree	Disagree	Agree
I don't like to draw attention to myself.	Disagree	Agree	Agree	Agree	Agree
I don't like to party.	Disagree	Disagree	Disagree	Agree	Agree
I like to work independently.	Disagree	Agree	Agree	Agree	Agree
I often enjoy spending time by myself.	Disagree	Disagree	Disagree	Agree	Agree
Score	100% Extravert	70% Extravert	50% Extravert 50% Introvert (Ambivert)	70% Introvert	100% Introvert

In this example, Nathan and Beatrice are extroverted, Spencer and Anne are introverted, and Dave is ambiverted.

Self-report questionnaires have obvious limitations in that people may misrepresent themselves either intentionally or through lack of self-knowledge. As such, it is also common to use peer reporting or third-party observation.

Another approach is to present test takers with various sets of adjectives (e.g., thoughtful, talkative, energetic, independent) and ask which describes them most and least. Psychological measures of this trait may break it down into subfactors including warmth, affiliation, positive affect, excitement seeking, and assertiveness/dominance seeking.

[edit] Eysenck's theory

Hans Eysenck described extraversion-introversion as the degree to which a person is outgoing and interactive with other people. These behavioral differences are presumed to be the result of underlying differences in brain physiology.[11] Extroverts seek excitement and social activity in an effort to heighten their arousal level, whereas introverts tend to avoid social situations in an effort to keep such arousal to a minimum. Eysenck designated extraversion as one of three major traits in his P-E-N model of personality, which also includes psychoticism and neuroticism.

Eysenck originally suggested that extraversion was a combination of two major tendencies, impulsiveness and sociability. He later added several other more specific traits, namely liveliness, activity level, and excitability. These traits are further linked in his personality hierarchy to even more specific habitual responses, such as partying on the weekend.

Eysenck compared this trait to the four temperaments of ancient medicine, with choleric and sanguine temperaments equating to extraversion, and melancholic and phlegmatic temperaments equating to introversion.[12]

[edit] Biological factors

The relative importance of nature versus environment in determining the level of extraversion is controversial and the focus of many studies. Twin studies find a genetic component of 39% to 58%. In terms of the environmental component, the shared family environment appears to be far less important than individual environmental factors that are not shared between siblings.[13]

Eysenck proposed that extraversion was caused by variability in cortical arousal. He hypothesized that introverts are characterized by higher levels of activity than extroverts and so are chronically more cortically aroused than extroverts. The fact that extroverts require more external stimulation than introverts has been interpreted as evidence for this hypothesis. Other evidence of the "stimulation" hypothesis is that introverts salivate more than extroverts in response to a drop of lemon juice.[14]

Extraversion has been linked to higher sensitivity of the mesolimbic dopamine system to potentially rewarding stimuli.[15] This in part explains the high levels of positive affect found in extroverts, since they will more intensely feel the excitement of a potential reward. One consequence of this is that extroverts can more easily learn the contingencies for positive reinforcement, since the reward itself is experienced as greater.

One study found that introverts have more blood flow in the frontal lobes of their brain and the anterior or frontal thalamus, which are areas dealing with internal processing, such as planning and problem solving. Extroverts have more blood flow in the anterior cingulate gyrus, temporal lobes, and posterior thalamus, which are involved in sensory and emotional experience.[16] This study and other research indicates that introversion-extraversion is related to individual differences in brain function.

Extraversion has also been linked to physiological factors such as respiration, through its association with surgency.[17]

[edit] Behavior

Extraverts and introverts have a variety of behavioral differences. According to one study, extraverts tend to wear more decorative clothing, whereas introverts prefer practical, comfortable clothes.[18] Extraverts are likely to prefer more upbeat, conventional, and energetic music than introverts.[19] Personality also influences how people arrange their work areas. In general, extraverts decorate their offices more, keep their doors open, keep extra chairs nearby, and are more likely to put dishes of candy on their desks. These are attempts to invite co-workers and encourage interaction. Introverts, in contrast, decorate less and tend to arrange their workspace to discourage social interaction.[20]

Although extraverts and introverts have real personality and behavior differences, it is important to avoid pigeonholing or stereotyping by personality. Humans are complex and unique, and because extraversion varies along a continuum, they may have a mixture of both orientations. A person who acts introverted in one scenario may act extraverted in another, and people can learn to act “against type” in certain situations. Jung's theory states that when someone's primary function is extraverted, his secondary function is always introverted (and vice versa).[1]

[edit] Implications

Acknowledging that introversion and extraversion are normal variants of behavior can help in self-acceptance and understanding of others. For example, an extravert can accept her introverted partner’s need for space, while an introvert can acknowledge his extraverted partner’s need for social interaction.

Researchers have found a correlation between extraversion and happiness. That is, more extraverted people tend to report higher levels of happiness than introverts.[21][22] Other research has shown that being instructed to act in an extraverted manner leads to increases in positive affect, even for people who are trait-level introverts.[23]

This does not mean that introverts are unhappy. Extroverts simply report experiencing more positive emotions, whereas introverts tend to be closer to neutral. This may be due to the fact that extraversion is socially preferable in Western culture and thus introverts feel less desirable. In addition to the research on happiness, other studies have found that extroverts tend to report higher levels of self-esteem than introverts.[24][25] Others suggest that such results reflect socio-cultural bias in the survey itself.[26][27][dead link] Dr. David Meyers has claimed that happiness is a matter of possessing three traits: self-esteem, optimism and extraversion. Meyers bases his conclusions on studies that report extraverts to be happier; these findings have been questioned in light of the fact that the "happiness" prompts given to the studies' subjects, such as "I like to be with others" and "I'm fun to be with," only measure happiness among extroverts.[28] Also, according to Carl Jung, introverts acknowledge more readily their psychological needs and problems, whereas extroverts tend to be oblivious to them because they focus more on the outer world.[1]

Extraversion is perceived as socially desirable in Western culture, but it is not always an advantage. For example, extroverted youths are more likely to engage in delinquent behavior.[29] Conversely, while introversion is perceived as less socially desirable, it is strongly associated with positive traits such as intelligence[30] and "giftedness."[31][32] For many years, researchers have found that introverts tend to be more successful in academic environments, which extroverts may find boring.[33]Career counselors often use personality traits, along with other factors such as skill and interest, to advise their clients.[34] Some careers such as computer programming may be more satisfying for an introverted temperament, while other areas such as sales may be more agreeable to the extroverted type.

Although neither introversion nor extraversion is pathological, psychotherapists can take temperament into account when treating clients. Clients may respond better to different types of treatment depending on where they fall on the introversion/extraversion spectrum. Teachers can also consider temperament when dealing with their pupils, for example acknowledging that introverted children need more encouragement to speak in class while extroverted children may grow restless during long periods of quiet study.

[edit] Regional Variation

It is asserted that Americans live in an "extraverted society"[35] that rewards extravert behavior and rejects introversion.[36] Other cultures, such as Central Europe, Japan or regions where Buddhism, Sufism etc. prevail, prize introversion.[6] These cultural differences predict individuals' happiness such that people who score higher in extraversion are happier, on average, in particularly extroverted cultures and vice versa.[37]

Researchers have found that people who live on islands tend to be less extroverted (more introverted) than those living on the mainland, and that people whose ancestors had inhabited the island for twenty generations tend to be less extroverted than more recent arrivals. Furthermore, people who emigrate from islands to the mainland tend to be more extroverted than people that stay on islands, and those that immigrate to islands.[38]

In the United States, researchers have found that people living in the midwestern states of North Dakota, South Dakota, Nebraska, Minnesota, Wisconsin, and Illinois score higher than the U.S. average on extraversion. Utah and the southeastern states of Florida and Georgia also score high on this personality trait. The most introverted states in the United States are Maryland, New Hampshire, Alaska, Washington, Oregon and Vermont. People who live in the northwestern states of Idaho, Montana, and Wyoming are also relatively introverted.[39]

[edit] Extraversion, Introversion and Happiness

Extraverts are found to have higher levels of happiness and positive affect than introverts.[40][41][42] An influential review article concluded that personality, specifically extraversion and emotional stability, was the best predictor of subjective well-being.[43] As examples, Argyle and Lu (1990)[44] found that the trait of extraversion, as measured by Extraversion Scale of the Eysenck Personality Questionnaire (EPQ), was positively and significantly correlated with happiness, as measured by the Oxford Happiness Inventory. Using the same happiness and extraversion scales, Hills and Argyle (2001)[45] found that happiness was again significantly correlated with extraversion. Also, the study by Emmons and Diener (1986)[46] showed that extraversion correlates positively and significantly with positive affect but not with negative affect. Similar results were found in a large longitudinal study by Diener, Sandvik, Pavot, and Fujita (1992)[47], which assessed 14,407 participants from 100 areas of continental United States. Using the abbreviated General Well-Being Schedule, which tapped positive and negative affects, and Costa and McCrae's (1986)[48] short version of the NE0's Extraversion scale, the authors reported that extraverts experienced greater well-being at two points in time, during which data were collected: first between 1971 and 1975, and later between 1981 and 1984. Furthermore, Larsen and Ketelaar (1991)[49] showed that extraverts respond more to positive affect than to negative affect, since they exhibit more positive-affect reactivity to the positive-affect induction, yet they do not react more negatively to the negative-affect induction.[50]

[edit] Possible reasons

[edit] Instrumental View

The instrumental view proposes that personality traits give rise to conditions and actions, which have affective consequences, and thus generate individual differences in emotionality.[51][50]

• Personality trait as a cause of higher sociability

According to the instrumental view, one explanation for greater subjective well-being among extraverts could be the fact that extraversion helps in the creation of life circumstances, which promote high levels of positive affect. Specifically, the personality trait of extraversion is seen as a facilitator of more social interactions[52][40][50], since the low cortical arousal among extraverts results in them seeking more social situations in order to increase their arousal.[53]

• The social participation theory

According to the social participation theory, more frequent participation in social situations creates more frequent, and higher levels, of positive affect. Therefore, it is believed that since extraverts are characterized as more sociable than introverts, they also possess higher levels of positive affect brought on by social interactions.[54][55][56] Specifically, the results of Furnham and Brewin's study (1990)[42] suggest that extraverts enjoy and participate more in social activities than introverts, and as a result extraverts report higher level of happiness. Also, in the study of Argyle and Lu (1990)[44] extraverts were found to be less likely to avoid participation in noisy social activities, and to be more likely to participate in social activities such as: party games, jokes, or going to the cinema. Similar results were reported by Diener, Larsen, and Emmons (1984)[57] who found that extraverts seek social situations more often than introverts, especially when engaging in recreational activities.

However, a variety of findings contradict the claims of the social participation theory. Firstly, it was found that extraverts were happier than introverts even when alone. Specifically, extraverts tend to be happier regardless of whether they live alone or with others, or whether they live in a vibrant city or quiet rural environment.[41] Similarly, a study by Diener, Sandvik, Pavot, and Fujita (1992)[47] showed that although extraverts chose social jobs relatively more frequently (51%) than nonsocial jobs compared to introverts (38%), they were happier than introverts regardless of whether their occupations had social or nonsocial character. Secondly, it was found that extraverts only sometimes reported greater amounts of social activity than introverts[57], but in general extraverts and introverts do not differ in the quantity of their socialization.[41] Similar finding was reported by Srivastava, Angelo, and Vallereux (2008)[58], who found that extraverts and introverts both enjoy participating in social interactions, but extraverts participate socially more. Thirdly, studies have shown that both extraverts and introverts participate in social relations, but that the quality of this participation differs. The more frequent social participation among extraverts could be explained by the fact that extraverts know more people, but those people are not necessarily their close friends, while introverts, when participating in social interactions, are more selective and have only few close friends with whom they have special relationships.[45]

• The social attention theory

Yet another explanation of the high correlation between extraversion and happiness comes from the study by Ashton, Lee, and Paunonen (2002)[59]. They suggested that the core element of extraversion is a tendency to behave in ways that attract, hold, and enjoy social attention, and not reward sensitivity. They claimed that one of the fundamental qualities of social attention is its potential of being rewarding. Therefore, if a person shows positive emotions of enthusiasm, energy, and excitement, that person is seen favorably by others and he or she gains others’ attention. This favorable reaction from others likely encourages extraverts to engage in further extravted behavior.[60]Ashton, Lee, and Paunonen’s (2002)[61] study showed that their measure of social attention, the Social Attention Scale, was much more highly correlated with extraversion than were measures of reward sensitivity.

[edit] Temperamental View

Temperamental view is based on the notion that there is a direct link between people's personality traits and their sensitivity to positive and negative affects.[49][40][50]

• The affective reactivity model

The affective reactivity model states that the strength of a person's reactions to affect-relevant events are caused by people's differences in affect.[62][49] This model is based on the reinforcement sensitivity theory by Jeffrey Alan Gray, which states that people with stronger behavioral activation system (BAS) are high in reward responsiveness and are predisposed to the personality trait of extraversion, while people with a stronger behavioral inhibition system (BIS) are lower in reward responsiveness and are more predisposed to personality trait of neuroticism and introversion.[63] Therefore, extraverts are seen as having a temperamental predisposition to positive affect since positive mood induction has a greater effect on them than on introverts, thus extraverts are more prone to react to pleasant effects.[64][65][49][66][62] For example, Gable, Reis, and Elliot (2000).[67] found in two consecutive studies that people with more sensitive BIS reported higher levels of average negative affect, while people with more sensitive BAS reported higher higher levels of positive affect. Also Zelenski and Larsen (1999)[50] found that people with more sensitive BAS reported more positive emotions during the positive mood induction, while people with more sensitive BIS reported more negative emotions during the negative mood induction.

• The social reactivity theory

The social reactivity theory alleges that all humans, whether they like it or not, are required to participate in social situations. Since extraverts prefer engaging in social interactions more than introverts, they also derive more positive affect from such situations than introverts do.[44][57][41] The support for this theory comes from work of Brian R. Little, who popularized concept of "restorative niches". Little claimed that life often requires people to participate in social situations, and since acting social is out of character for introverts, it was shown to harm their well-being. Therefore, one way to preserve introverts' well-being is for them to recharge as often as possible in places where they can return to their true selves - places Little calls "restorative niches".[68]

However, it was also found that extraverts did not respond stronger to social situations than introverts, nor did they report bigger boosts of positive affect during such interactions.[52][58]

Another possible explanation for more happiness among extraverts comes from the fact that extraverts are able to better regulate their affective states. This means that in ambiguous situations (situations where positive and negative moods are introduced and mixed in similar proportions) extraverts show a slower decrease of positive affect, and, as a result, they maintained a more positive affect balance than introverts.[69] Extraverts may also choose activities that facilitate happiness (e.g., recalling pleasant vs. unpleasant memories) more than introverts when anticipating difficult tasks.[70]

• The set-point model aka affect-level model

According to the set-point model, levels of positive and negative affects are more or less fixed within each individual, hence, after a positive or negative event, people's moods tend to go back to the pre-set level. According to the set-point model, extraverts' experience more happiness because their pre-set level of positive affect is set higher than the pre-set point of positive affect in introverts, therefore extraverts require less positive reinforcement in order to feel happy.[66]

• Pleasure-arousal relation

A study by Kuppens (2008)[71] showed that extraverts and introverts engage in different behaviors when feeling pleasant, which could be a potential explanation for underestimating the frequency and intensity of happiness exhibited by introverts. Specifically, Kuppens (2008)[71] found that arousal and pleasantness are positively correlated for extraverts, which means that pleasant feelings are more likely to be accompanied by high arousal for extraverts. On the other hand, arousal and pleasantness are negatively correlated for introverts, resulting in introverts exhibiting low arousal when feeling pleasant. In other words, if everything is going well in an extravt's life, which is a source of pleasant feelings, extraverts see such situation as an opportunity to engage in active behavior and goal pursuit, which brings about an active, aroused pleasant state. Yet, when everything is going good for introverts, they see it as an opportunity to let down their guards, resulting in them feeling relaxed and content.[71]

[edit] References

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[edit] See also

[edit] External links

Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor[1] (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders.

SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the noradrenaline and dopamine transporter.

The efficacy of SSRIs in mild or moderate cases has been disputed. A 2010 meta-analysis states that "The magnitude of benefit of antidepressant medication compared with placebo ... may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial."[2] This analysis discarded a great majority of FDA-approved antidepressant studies[citation needed], including those that used placebo washout periods typically used as controls.[3]

SSRIs are the first class of psychotropic drugs discovered using the process called rational drug design, a process that starts with a specific biological target and then creates a molecule designed to affect it.[4] They are the most widely prescribed antidepressants in many countries.[4]

[edit] Medical uses

The main indication for SSRIs is clinical depression. SSRIs are frequently prescribed for anxiety disorders, such as social anxiety, panic disorders, obsessive–compulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder, although generally with poor results.[5]

[edit] Depression

Efficacy of SSRIs for the treatment of depression in mild and moderate cases has been disputed.[citation needed]

Two meta-analyses of clinical trials found that in mild and moderate depression, which constitute the vast majority of depression cases, the effect of SSRI is small or none compared to placebo, while in very severe depression the effect of SSRIs is clinically significant.[2][6] Second generation antidepressents appeared equally effective/ineffective.[7]

A widely reported 2008 meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the SNRI (serotonin and norepinephrine reuptake inhibitor) venlafaxine). The authors found that although the effect of antidepressants vs placebos was statistically significant, it did not exceed the NICE criteria for a clinically significant effect. In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.[6][8][9][10][11][12] Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants but even when they re-analyse the data they find that this is still below the NICE threshold for 'clinical significance' when all results are combined (although individually paroxetine and venflafaxine exceed this threshold).[13][14]

A 2010 review reached similar conclusions: in mild and moderate depression, specifically that the effect of SSRI is very small or none compared to placebo, while it is clinically significant in very severe depression.[2][15]

[edit] Premature ejaculation

A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly.[16] For the occasional "on-demand" treatment, a few hours before coitus, clomipramine gave better results than paroxetine in one study,[17] while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.[18] The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,[19] with on-demand sertraline, paroxetine or clomipramine,[18] and with the pause–squeeze technique.[18][19]

[edit] List of agents

Drugs in this class include (trade names in parentheses):

• citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)
• dapoxetine (Priligy)
• escitalopram (Lexapro, Cipralex, Seroplex, Esertia)
• fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND))
• fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)
• indalpine (Upstene) (discontinued)
• paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)
• sertraline (Zoloft, Lustral, Serlain, Asentra)
• zimelidine (Zelmid, Normud) (discontinued)

[edit] Related agents

SSRIs form a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors as well. Serotonin-norepinephrine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors and selective serotonin reuptake enhancers are also serotonergic antidepressants.

[edit] Adverse effects

General side effects are mostly present during the first 1–4 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 6–8 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:

Many side effects disappear after the adaptation phase, when the antidepressant effects begin to come to prominence. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (e.g. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove ineffective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI.[22]

Mania or hypomania is a possible side effect. Users with some type of bipolar disorder are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar episode; however, according to DSM IV-TR, the diagnosis of bipolar disorder requires that the individuals symptoms must not stem from medication side effects, toxins, drug abuse, or another general medical condition.

[edit] Sexual dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido. Initial studies found sexual side effects not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41%[23][24] of patients, although the lack of placebo control in these studies means they are likely overestimates. This is because release of extracellular concentrations of serotonin in the brain decreases dopamine and norepinephrine leading to erectile and/or sexual dysfunction.

Release of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine and norepinephrine release from the substantia nigra. A number of drugs are not associated with sexual side effects (such as bupropion, mirtazapine and maprotiline,[25][26] some of which are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be treated by several different medications. These include:

On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation.[27] The Andean herbaceous biennial plant Lepidium meyenii (also known as "maca") was found to be effective for alleviating SSRI-induced sexual dysfunction on a small double-blind, randomized, parallel group dose-finding pilot study.[28]

[edit] Cardiovascular side effects

Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0.0003 percent.[29] SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals.[30] However, a number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use.[31] In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.[32]

[edit] Discontinuation syndrome

Antidepressants such as SSRIs have some dependence producing effects, most notably a withdrawal syndrome. Their dependence producing properties (depending on the antidepressant) may not be as significant as other psychotropic drugs such as benzodiazepines; however, withdrawal symptoms nonetheless may be quite severe and even debilitating. SSRIs have little abuse potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness.[33] Since physical dependence is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.

When discontinuing an SSRI or SNRI some doctors may switch the patient to fluoxetine due to its much longer half-life. This may avoid many of the severe withdrawal symptoms associated with SSRI/SNRI discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Any SSRI or SNRI may be requested in liquid form, which allows very gradual tapering. Alternatively, a patient wishing to stop taking an SSRI/SNRI may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. For example the lowest dose of cymbalta that can normally be prescribed is 20 mg in gel capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5 mg so that a proper tapered reduction may take place.

[edit] Post-SSRI sexual dysfunction

According to one source, Post-SSRI sexual dysfunction (PSSD) is an iatrogenic type of sexual dysfunction caused directly by the previous use of SSRI antidepressants.[34]

While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs.[35]

One or more of the following sexual symptoms may persist or begin after the discontinuation of SSRIs:

[edit] Suicide risk

[edit] Children and adolescents

Several studies have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.[36][37][38] For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%.[39] More infrequently, studies have been inconclusive.[40] There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear.[41]

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation.[42] Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of obsessive–compulsive disorder. Fluoxetine, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.[43]

[edit] Adults

It is unclear whether or not SSRIs affect the risk of suicidal behavior for adults.

• A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide; however, important protective or hazardous effects could not be excluded.[44] Also among high-risk adult patients, antidepressant drug treatment does not seem related to suicide attempts and death.[38]
• A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.[45]
• On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new “SSRI-era” appear to have led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide.[46]
• A 2006 meta analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggests that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.[47]
• An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI's. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behavior. For adults between 25 and 64, the effect appears neutral on suicidal behavior but possibly protective for suicidal behavior for adults between the ages of 25 and 64. For adults older than 64, SSRI's seem to reduce the risk of both suicidal behavior.[36]

[edit] Suicide warnings

The FDA findings resulted in a black box warning on SSRI and other antidepressant medications regarding the increased risk of suicidal behavior in patients younger than 24.[48] Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.[49] In 2004 the Medicines and Healthcare products Regulatory Agency in the United Kingdom issued a warning about increases in 'insomnia, agitation, weight loss, headache, tremor, loss of appetite, self harm and suicidal thoughts' when the medications are used with children and adolescents.[50]

The introduction of a warning regarding the association between SSRIs and suicide by the FDA in 2004 led to a dramatic decrease in prescriptions of these medications to young people. Originally, there were concerns that the decrease in prescriptions caused by the warnings could increase the number of teenage suicides in the US.[51] However, the most recent data from the US National Center for Health Statistics put these concerns to rest. The suicide rates for persons younger than 25 has actually decreased between 2004 and 2007.[52][53]

[edit] Reduction in aggression

A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that non-significantly less aggression and hostility occurred in the fluoxetine group than in the placebo group.[54]

[edit] Pregnancy and breastfeeding

SSRIs are not considered major teratogens. They do, however, cross the placenta and may thus affect the newborn. In some studies sertraline and paroxetine or SSRIs as a group have been associated with congenital malformations, in particular, septal defects. Some evidence suggests that SSRIs are associated with other neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPHN). However, a meta-analysis published in 2006 found no statistically significant evidence that SSRI use during pregnancy increased risk to the fetus of cardiovascular malformations, major malformations, or minor malformations. [55] This same study did conclude that SSRI use during pregnancy caused a statistically significant increase in the risk of spontaneous abortion (odds ratio 1.7, 95% confidence interval 1.28-2.24).

The FDA issued a statement on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding.[56][57][58]

Maternal SSRI use may be associated with autism.[59]

[edit] Neonatal abstinence syndrome

Neonatal abstinence syndrome is a withdrawal syndrome in newborn babies. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.[60]

[edit] Permanent neuropsychological changes

Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant clomipramine when 8–21 days old, they develop behavioural changes in adulthood that resemble depression in humans.[61][62] In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine.[63] Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,[64][65] which are reversed by treatment with antidepressants.[66] By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.[67][68]

But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline have different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRIs behave normally. However, the young mice and rats also seem normal until they reach puberty and develop behavioural disturbances.[69][70]

The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor that regulates serotonin production results in low serotonin production after puberty.[71]

[edit] Persistent pulmonary hypertension

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the U.S. develop PPHN shortly after birth, and often they need intensive medical care. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.[72]

A population-based cohort study, which included 1.6 million live births in five Nordic countries, of women with filled SSRI prescriptions later than the 20th week gestation by last menstrual period demonstrated an increased risk of persistent pulmonary hypertension (PPHN) compared to control infants (adjusted RR 2.1, 95% CI 1.5-3). The increased risk of PPHN was of similar magnitude for the SSRI class of drugs (Fluoxetine, Citalopram, Paroxetine, Sertraline, Escitalopram). This study showed that the absolute risk of PPHN would only increase the incidence from 0.1 to 0.3 percent of live-births with late prenatal SSRI exposure.[73]

[edit] Bleeding tendencies

Many reports have been published incriminating SSRIs with increased bleeding tendencies. SSRIs are known to cause platelet dysfunction.[74][75] SSRIs, fluoxetine and sertraline have also been found to increase gastric acid secretion in rats and so can be ulcerogenic particularly when combined with NSAIDs.[76][77] Though the overall risk may be very small, case reports of life threatening bleeding have been reported.

[edit] Overdose

SSRIs appear safer in overdose when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions.[78] However, case reports of SSRI poisoning have indicated that severe toxicity can occur[79] and deaths have been reported following massive single ingestions,[80] although this is exceedingly uncommon when compared to the tricyclic antidepressants.[78]

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion.[81] Other reported significant effects include coma, seizures, and cardiac toxicity.[78]

Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.

[edit] Contraindications and drug interaction

One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). This is likely to cause severe serotonin syndrome/toxidrome.

People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). Tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant. Liver impairment is another contraindication for medications of this type.

SSRIs may increase blood levels and risk of toxicities of certain medications:

1. highly protein-bound medications like warfarin (coumadin) and digoxin
2. antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
3. beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
4. Tricyclic antidepressants like amitriptyline (Elavil, Endep) etc.
5. triptans like sumatriptan (Imitrex, Imigran) etc.
6. benzodiazepines like alprazolam (Xanax) or diazepam (Valium)[citation needed]
7. carbamazepine (Tegretol)
8. cisapride (Propulsid)
9. clozapine (Clozaril)
10. ciclosporin (Neoral)
11. haloperidol (Haldol)
12. phenytoin (Dilantin)
13. pimozide (Orap)
14. theophylline (Theo-dur)

Certain drugs may increase toxicities of SSRIs:

1. alcohol and other CNS depressants
2. methylene blue dye
3. diuretics (water pills)
4. MAOIs – possibly fatal serotonin syndrome/toxidrome
5. sympathomimetic drugs like pseudoephedrine (Sudafed)
6. lithium
7. sibutramine (Meridia)
8. MDMA (ecstasy)
9. zolpidem (ambien)[82]
10. dextromethorphan (cough suppressant) – increased risk of serotonin syndrome/toxidrome
11. tramadol (synergistic serotoninergic effect said to increase risk of seizure or serotonin syndrome/toxidrome)
12. pethidine/meperidine – increased risk of serotonin syndrome/toxidrome
13. herbal Saint John's wort or yohimbe – increased risk of serotonin syndrome/toxidrome

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs [83][84]:

1. Aspirin
2. Ibuprofen (Advil,Nurofen)
3. Naproxen (Aleve)

SSRIs also directly interfere with ligands of 5-HT receptors, like the psychedelics and entactogens. SSRIs strongly attenuate the effects of tryptamines (eg psilocybin and LSD), and phenethylamines (eg the 2C family), and almost completely eliminate the serotonergic effects of MDxx (eg MDMA). The exact mechanism that causes this interaction is still unclear.[citation needed] However, salvinorin A (found in Salvia divinorum) has no actions at the 5-HT2A serotonin receptor, nor is it known to have affinity for any other sites to date.

[edit] Mechanism of action

SSRIs are believed to act by inhibiting the reuptake of serotonin after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressants (TCA)s and 5-HT-prodrugs. However, the latter might be required in addition to SSRIs in certain situations.

[edit] Basic understanding

In the brain, messages are passed between two nerve cells via a chemical synapse, a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitters (including serotonin) into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient (postsynaptic) cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending (presynaptic) cell (a process called reuptake).

To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. The current model of SSRIs (the Monoamine Hypothesis) assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain.

Some current research points to more than just a single type of chemical signaling - the classic synapse model - involving serotonin. Astrocytes are "helper cells" in the brain that do not participate directly in chemical signaling, but play a part in homeostasis for many chemical levels in the brain. Recent research[85] suggests that serotonin is one of the hormones regulated by astrocytes, and that astrocytes actually uptake, package, and resend serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals, therefore appearing to function only to control the local levels of serotonin in the cerebrospinal fluid.

Still more research illustrates that the current model for the antidepressant activity of SSRIs may be misdirected, as a drug that works entirely opposite to SSRIs - Tianeptine, a selective serotonin reuptake enhancer - also exhibits antidepressant activity, especially in patients resistant to SSRI therapy. The effect of an SSRE in comparison to an SSRI requires that the nature of serotonin signaling in the areas of the brain related to mood and cognition needs further elucidation. If serotonin firing is regularly phasic (related to brain waves), or rapid and discrete, then SSRIs simply compress the signal potential at affected receptors (bringing down the maximum potential and bring up the minimum) by causing a constant leftover signal (serotonin left in the synaptic gap) coupled with weaker subsequent signals (due to the decrease in presynaptic serotonin available to send new signals). By this hypothetical model, SSREs increase the signal potential separation (min to max) at affected 5-HT sites by reducing the level of free cerebrospinal serotonin and increasing the amount uptaken into axons to send new signals.

[edit] Pharmacodynamics

SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.

However, there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptors, which serve as a feedback sensor for the cell. Activation of the autoreceptors (by agonists like serotonin) triggers a throttling back of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (downregulating) the sensitivity of the autoreceptors.[86]

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression.[87]

Most of the serotonin receptors on the surface of the cell are coupled to a G-protein inside it. These proteins activate or inhibit second messengers, which in turn affect transcription factors. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it.

These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested,[87] and why increased anxiety is a common side effect in the first few days or weeks of use.

[edit] Role in BDNF release

SSRIs act on signal pathways such as cAMP (Cyclic AMP) on the postsynaptic neuronal cell, which leads to the release of Brain Derived Neurotrophic Factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.[88]

[edit] Pharmacogenetics

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use.[89]Single-nucleotide polymorphisms of the 5-HT(2A) gene correlated with paroxetine discontinuation due to side effects in a group of elderly patients with major depression, but not mirtazapine (a non-SSRI antidepressant) discontinuation.[90]

[edit] Neuroprotection

Studies have suggested that SSRIs may promote the growth of new neural pathways or neurogenesis in rats.[91] Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance fenfluramine) as well as from depression itself. SSRIs have been found to induce programmed cell death in Burkitt lymphoma and the brain tumors neuroblastoma and glioma with minimal effect on normal tissue.[92][93]

[edit] Anti-inflammatory and immunomodulation

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disorder, in addition to somatic disease (such as autoimmune hypersensitivity) and it is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.[94][95][96][97][98]

SSRIs have demonstrated immunomodulatory and anti-inflammatory effects against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.[99][100][101][102]

Future serotonergic antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.[103]

[edit] SSRIs versus TCAs

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects.

There appears no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.[104] However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

[edit] SSRIs versus 5-HT-Prodrugs

Serotonin cannot be administered directly because when ingested orally, it will not cross the blood–brain barrier, and therefore would have no effect on brain functions. Also, serotonin would activate every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through. The selectivity of the membrane can be reduced for a drug by injecting it in a concentrated sugar solution. The high osmotic pressure of the sugar solution causes the endothelial cells of the capillaries to shrink, which opens gaps between their tight junctions and makes the barrier more permeable. As a result the drug can enter the brain tissue.

[edit] SSRIs together with 5-HT-Prodrugs

Biosynthetic serotonin is made from tryptophan, an amino acid. In 1989, the Food and Drug Administration made tryptophan available by prescription only, in response to an outbreak of eosinophilia-myalgia syndrome caused by impure L-tryptophan supplements sold over-the-counter. With current standards, L-tryptophan is again available over the counter in the US as well as supplement 5-HTP, which is a direct precursor to serotonin.

[edit] Society and culture

[edit] Criticism

In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicide. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning") that a pooled analysis of placebo controlled trials of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidal behavior that was twice that of placebo. At the same time, in adults SSRIs do not increase the risk of suicide.[105]

Critics of SSRIs claim that the widely disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.[106]

The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states, as evidenced by the fact that many report problems of sexual dysfunction, whose effects last long after the medication has been discontinued. Hence, it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug that causes the discontinuation syndrome.[107]

One possible mechanism is by inhibition of dopaminergic neurotransmission.[108]

Biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Psychiatrists[who?] claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit.[citation needed] On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.[109]

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy.

A widely reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, and two non-SSRI antidepressants nefazodone and venlafaxine). The authors found that although the antidepressants were statistically superior to placebo they did not exceed the NICE criteria for a 'clinically significant' effect. For more detail, see the section "Efficacy".

A study in The New England Journal of Medicine on a possible publication bias regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA, 37 with positive results were published in academic journals, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.[110]

Although controversial, the existence of an SSRI-related withdrawal syndrome mimicking depression may inflate the therapeutic effect size reported in long-term (more than 6 months) placebo controlled trials of SSRI’s, due to a reliance on randomized discontinuation designs. Discontinuation trials are a variant of the classic 2-arm placebo controlled randomized controlled trials used in shorter placebo controlled studies of SSRI’s.[111][112]

[edit] Regulation

All SSRIs are approved in the U.S. for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV).

Approved uses for SSRIs vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the Food and Drug Administration (FDA) approves drugs after trial results have been submitted by the pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency for human consumption throughout the European Union or by the regulatory agencies of individual countries for use within those countries.[citation needed]. In Canada, the drug approval process is carried out by Health Canada.

[edit] Lawsuits

Hundreds of lawsuits have been filed against drug manufacturers seeking compensation for harm attributed to the use of SSRIs. Suits based on product liability, for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. FDA asked manufacturers to include black box warnings on antidepressant drug packaging.[113] The inclusion of the black box warning may have led to a decrease in prescriptions of SSRIs and an increase in suicide.[114][115]

[edit] Gallery

[edit] See also

[edit] References

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105. ^ Gunnell D, Saperia J, Ashby D (2005). "Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review". BMJ 330 (7488): 385. DOI:10.1136/bmj.330.7488.385. PMC 549105. PMID 15718537. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=549105. 
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[edit] External links

Agonists: Azapirones: Alnespirone Binospirone Buspirone Enilospirone Eptapirone Gepirone Ipsapirone Perospirone Revospirone Tandospirone Tiospirone Umespirone Zalospirone; Antidepressants: Etoperidone Nefazodone Trazodone Vortioxetine; Antipsychotics: Aripiprazole Asenapine Clozapine Quetiapine Ziprasidone; Ergolines: Dihydroergotamine Ergotamine Lisuride Methysergide LSD; Tryptamines: 5-CT 5-MeO-DMT 5-MT Bufotenin DMT Indorenate Psilocin Psilocybin; Others: 8-OH-DPAT Adatanserin Bay R 1531 Befiradol BMY-14802 Cannabidiol Dimemebfe Ebalzotan Eltoprazine F-11,461 F-12,826 F-13,714 F-14,679 F-15,063 F-15,599 Flesinoxan Flibanserin Lesopitron LY-293,284 LY-301,317 MKC-242 Naluzotan NBUMP Osemozotan Oxaflozane Pardoprunox Piclozotan Rauwolscine Repinotan Roxindole RU-24,969 S 14,506 S-14,671 S-15,535 Sarizotan SSR-181,507 Sunepitron U-92,016-A Urapidil Vilazodone Xaliproden Yohimbine Antagonists: Antipsychotics: Iloperidone Risperidone Sertindole; Beta blockers: Alprenolol Cyanopindolol Iodocyanopindolol Oxprenolol Pindobind Pindolol Propranolol Tertatolol; Others: AV965 BMY-7,378 CSP-2503 Dotarizine Flopropione GR-46611 Isamoltane Lecozotan Mefway Metitepine/Methiothepin MPPF NAN-190 Robalzotan S-15535 SB-649,915 SDZ 216-525 Spiperone Spiramide Spiroxatrine UH-301 WAY-100,135 WAY-100,635 Xylamidine Agonists: Lysergamides: Dihydroergotamine Methysergide; Triptans: Almotriptan Avitriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-Ethyl-DMT 5-MT 5-(Nonyloxy)tryptamine; Others: CP-135,807 CP-286,601 GR-46611 L-694,247 L-772,405 PNU-109,291 PNU-142,633 Antagonists: Lysergamides: Metergoline; Others: Alniditan BRL-15,572 Elzasonan GR-127,935 Ketanserin LY-310,762 LY-367,642 LY-456,219 LY-456,220 Metitepine/Methiothepin Ritanserin Yohimbine Ziprasidone   Agonists: Phenethylamines: 2C-B 2C-E 2C-I 2C-T-2 2C-T-7 2C-T-21 DOB DOC DOI DOM MDA MDMA Mescaline; Piperazines: Aripiprazole mCPP TFMPP; Tryptamines: 5-CT 5-MeO-α-ET 5-MeO-α-MT 5-MeO-DET 5-MeO-DiPT 5-MeO-DMT 5-MeO-DPT 5-MT α-ET α-Methyl-5-HT α-MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: A-372,159 AL-38022A CP-809,101 Dimemebfe Lorcaserin Medifoxamine MK-212 Org 12,962 ORG-37,684 Oxaflozane PNU-22394 Ro60-0175 Ro60-0213 Vabicaserin WAY-629 WAY-161,503 YM-348 Antagonists: Atypical antipsychotics: Clorotepine Clozapine Iloperidone Melperone Olanzapine Paliperidone Pimozide Quetiapine Risperidone Sertindole Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine Pipamperone; Antidepressants: Agomelatine Amitriptyline Amoxapine Aptazapine Etoperidone Fluoxetine Mianserin Mirtazapine Nefazodone Nortriptyline Tedatioxetine Trazodone; Others: Adatanserin CEPC Cinanserin Cyproheptadine Deramciclane Dotarizine Eltoprazine Esmirtazapine FR-260,010 Ketanserin Ketotifen Latrepirdine Metitepine/Methiothepin Methysergide Pizotifen Ritanserin RS-102,221 S-14,671 SB-200,646 SB-206,553 SB-221,284 SB-228,357 SB-242,084 SB-243,213 SDZ SER-082 Xylamidine   Agonists: Lysergamides: Dihydroergotamine Ergotamine Lisuride LSD Mesulergine Metergoline Methysergide; Tryptamines: 2-Methyl-5-HT 5-BT 5-CT 5-MT Bufotenin E-6801 E-6837 EMD-386,088 EMDT LY-586,713 N-Methyl-5-HT Tryptamine; Others: WAY-181,187 WAY-208,466 Antagonists: Antidepressants: Amitriptyline Amoxapine Clomipramine Doxepin Mianserin Nortriptyline; Atypical antipsychotics: Aripiprazole Asenapine Clorotepine Clozapine Fluperlapine Iloperidone Olanzapine Tiospirone; Typical antipsychotics: Chlorpromazine Loxapine; Others: BGC20-760 BVT-5182 BVT-74316 Cerlapirdine EGIS-12,233 GW-742,457 Ketanserin Latrepirdine Lu AE58054 Metitepine/Methiothepin MS-245 PRX-07034 Ritanserin Ro04-6790 Ro 63-0563 SB-258,585 SB-271,046 SB-357,134 SB-399,885 SB-742,457 Agonists: Lysergamides: LSD; Tryptamines: 5-CT 5-MT Bufotenin; Others: 8-OH-DPAT AS-19 Bifeprunox E-55888 LP-12 LP-44 RU-24,969 Sarizotan Antagonists: Lysergamides: 2-Bromo-LSD Bromocriptine Dihydroergotamine Ergotamine Mesulergine Metergoline Methysergide; Antidepressants: Amitriptyline Amoxapine Clomipramine Imipramine Maprotiline Mianserin; Atypical antipsychotics: Amisulpride Aripiprazole Clorotepine Clozapine Olanzapine Risperidone Sertindole Tiospirone Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine; Others: Butaclamol EGIS-12,233 Ketanserin LY-215,840 Metitepine/Methiothepin Pimozide Ritanserin SB-258,719 SB-258,741 SB-269,970 SB-656,104 SB-656,104-A SB-691,673 SLV-313 SLV-314 Spiperone SSR-181,507 Vortioxetine

"Lustral" redirects here. For the electronic music band, see Lustral (band).

Sertraline

Systematic (IUPAC) name
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine
Clinical data
Trade names	Zoloft
AHFS/Drugs.com	monograph
MedlinePlus	a697048
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	44%
Protein binding	98.5%
Metabolism	Hepatic (N-demethylation mainly by CYP2B6)[1]
Half-life	Approximately 26 hours
Excretion	Renal
Identifiers
CAS number	79617-96-2 Y
ATC code	N06AB06
PubChem	CID 68617
DrugBank	DB01104
ChemSpider	61881 Y
UNII	QUC7NX6WMB Y
KEGG	D02360 Y
ChEBI	CHEBI:9123 Y
ChEMBL	CHEMBL809 Y
Chemical data
Formula	C17H17Cl2N
Mol. mass	306.229 g/mol
SMILES	eMolecules & PubChem
Y (what is this?)  (verify)

Sertraline hydrochloride (trademark names Zoloft and Lustral) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in both adults and children. In 2007, it was the most prescribed antidepressant on the U.S. retail market, with 29,652,000 prescriptions.[2]

The efficacy of sertraline for depression is similar to that of older tricyclic antidepressants, but its side effects are much less pronounced. Differences with newer antidepressants are subtler and also mostly confined to side effects. Evidence suggests that sertraline may work better than fluoxetine (Prozac) for some subtypes of depression.[3] Sertraline is highly effective for the treatment of panic disorder, but cognitive behavioral therapy in combination with sertraline is a better treatment for obsessive-compulsive disorder than sertraline alone.[4] Although approved for social phobia and posttraumatic stress disorder, sertraline leads to only modest improvement in these conditions.[5][6] Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.

Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects; however, has relatively mild effects on both cognition and vigilance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these favorable effects on cognition and vigilance.[7][8] In pregnant women taking sertraline, the drug was present in significant concentrations in fetal blood, and was also associated with a higher rate of various birth defects. Similarly to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal behavior.

[edit] Medical uses

Sertraline is used for a number of conditions including: major depression, obsessive-compulsive disorder (OCD), Body dysmorphic disorder (BDD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder).[9] It has also been used for premature ejaculation and vascular headaches but evidence of the effectiveness in treating those conditions is less robust.[9]

[edit] Depression

The original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression.[10] Nevertheless, a considerable body of later research established it as one of the drugs of choice for the treatment of depression in outpatients. Despite the negative results of early trials, sertraline is often used to treat depressed inpatients as well.[11] Sertraline is effective for both severe depression[12] and dysthymia, a milder and more chronic variety of depression. In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia[13][14][15][16] and comparable to imipramine (Tofranil) in that respect.[14] Sertraline also improved the depression of dysthymic patients to a greater degree than group cognitive behavioral therapy or interpersonal psychotherapy, and adding psychotherapy to sertraline did not seem to enhance the outcome.[15][16] These results also held up in a two-year follow-up of sertraline-treated and interpersonal-therapy-treated groups.[17] In the treatment of depression accompanied by OCD, sertraline performed significantly better than desipramine (Norpramine) on the measures of both OCD and depression.[18] Sertraline was equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it was better tolerated.[19] Sertraline treatment of depressed patients with co-morbid personality disorders improved their personality traits, and this improvement was almost independent from the improvement of their depression.[20]

[edit] Comparison with tricyclic antidepressants

The effect of sertraline on the core symptoms of depression is similar to that of tricyclic antidepressants (TCAs); however, it is better tolerated and results in a better quality of life. Similar improvement of depression scores was seen in studies comparing sertraline with clomipramine (Anafranil)[12] and amitriptyline (Elavil).[21][22] At the same time, sertraline resulted in a much lower rate of side effects than amitriptyline (49%, vs. 72% for amitriptyline and 32% for placebo), particularly dry mouth, somnolence, constipation and increased appetite.[22] However, there were more cases of nausea and sexual dysfunction in the sertraline group.[21][22] Participants taking sertraline showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function.[22]

A large and thorough double-blind study compared sertraline—prescribed for chronic (longer than two years) depression or depression with dysthymia—to the "gold standard" of depression treatment, the TCA imipramine (Tofranil). Sertraline was equivalent to imipramine for both of these indications during the first 12 weeks of the study[23][24][25] and the 16-week continuation phase.[26] Only 11% of patients on sertraline suffered from severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, micturition disorder and sweating were observed more often with imipramine, and diarrhea and insomnia with sertraline.[24] Patients on sertraline also reported significantly better social and physical functioning. The 30% of the patients treated with sertraline or imipramine who achieved a remission during the trial did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on social adjustment and other measures of interpersonal functioning.[25]

TCAs as a group are considered to work better than selective serotonin reuptake inhibitors for melancholic depression[27] and in inpatients,[28] but not necessarily for simply more severe depression.[29] In line with this generalization, sertraline was no better than placebo in inpatients (see History) and as effective as the TCA clomipramine for severe depression.[12] The comparative efficacy of sertraline and TCAs for melancholic depression has not been studied. A 1998 review suggested that, due to its pharmacology, sertraline may be more efficacious than other SSRIs and equal to TCAs for the treatment of melancholic depression.[30] A later open-label study of general practice patients, funded by Pfizer, found that sertraline had equal efficacy in melancholic vs. non-melancholic patients, as well as in previous TCA non-responders vs. all other patients.[31]

[edit] Comparison with other antidepressants

According to a meta-analysis of 12 new-generation antidepressants, sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with unipolar major depression. Reboxetine was significantly worse.[32]

Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of moclobemide (Aurorix),[33]nefazodone (Serzone),[34]escitalopram (Lexapro),[35]bupropion (Wellbutrin),[36]citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil) and mirtazapine (Remeron).[37] Compared to patients on bupropion, those taking sertraline had much higher rates of sexual dysfunction (61% vs. 10% for men and 41% vs. 7% for women), nausea, diarrhea, somnolence and sweating, as well as a higher rate of discontinuation due to side effects (13% vs. 3%).[36]Meta-analysis by the independent Cochrane Collaboration indicated that sertraline is more effective for the treatment of depression than fluoxetine (Prozac), with a 1.4 times higher probability of response, and is possibly better tolerated.[38] The greatest advantage of sertraline over fluoxetine was seen among severely depressed and melancholic patients with low anxiety.[3] Comparative studies of sertraline and venlafaxine (Effexor) found marginal differences in favor of venlafaxine[39][40][41] or no differences.[42]

[edit] Depression in the elderly

Sertraline used for the treatment of depression in elderly (older than 60) patients was superior to placebo and comparable to another SSRI fluoxetine, and TCAs amitriptyline, nortriptyline (Pamelor) and imipramine. Sertraline had much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurred more frequently with sertraline. In addition, sertraline appeared to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup.[43] A 2003 trial of sertraline vs. placebo in elderly patients showed a statistically significant (that is, unlikely to occur by chance), but clinically very modest improvement in depression and no improvement in quality of life.[44] The authors were sharply criticized by Bernard Carroll, a one-time chairman of the FDA Psychopharmacological Drugs Advisory Committee,[45] for presenting these results as positive: "The study has all the hallmarks of an 'experimercial,' a cost-is-no-object exercise driven by a corporate sponsor to create positive publicity for its product in a market niche. ... Thus does the corporate mandate to put lipstick on the pig prevail over the academic duty to communicate independent analyses of the data."[46]

[edit] Obsessive-compulsive disorder

Placebo-controlled studies have demonstrated sertraline to be effective for the treatment of OCD in adults and children.[47][48][49][50] It was better tolerated and, based on intention to treat analysis, performed better than the gold standard of OCD treatment clomipramine.[51] Sertraline was also marginally more efficacious than fluoxetine (Prozac).[52] It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression.[53] The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.[54] If the patient were completely non-responsive to the maximal recommended dose of sertraline (200 mg), further increasing the dose did not significantly improve the response rates. However, patients with a partial but incomplete response to sertraline at 200 mg did see a clinically significant reduction in symptoms, when the dose was titrated up to a maximum of 400 mg. Incidence of side effects at 400 mg was found to be comparable to 200 mg.[55]

The patients who responded to sertraline during a short-term trial sustained their improvement when the treatment continued for a year[56] and longer.[57] At the same time, the prolonged treatment may not be necessary for everyone. In a double-blind study, half of the subjects who had been successfully treated for a year were discontinued from sertraline. Only 48% of the patients in the discontinuation group were able to complete the study; however, these completers fared as well as the subjects who continued taking sertraline.[58]

Cognitive behavioral therapy alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.[59][60] A review mentions that sertraline can be used for the treatment of OCD co-morbid with Tourette syndrome;[61] however, sertraline may cause exacerbation of tics in Tourette syndrome.[62]

[edit] Panic disorder

In four large double-blind studies sertraline was shown to be superior to placebo for the treatment of panic disorder. The response rate was independent of the dose (50–200 mg). In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as "improved" on sertraline reported better quality of life than the ones who "improved" on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo.[63][64] Sertraline was equally effective for men and women[64] and for patients with or without agoraphobia.[65] Previous unsuccessful treatment with benzodiazepines did not diminish its efficacy.[66] However, the response rate was lower for the patients with more severe panic.[65] Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine (Paxil)[67] or the gold standard of panic disorder treatment alprazolam (Xanax).[68] While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine (Anafranil), imipramine (Tofranil), clonazepam (Klonopin), alprazolam, fluvoxamine (Luvox) and paroxetine) indicates approximate equivalence of these medications.[63] Although panic disorder is considered to be a chronic condition, continuous treatment may not be necessary for everyone. In a double-blind discontinuation trial, abruptly stopping sertraline after one year of successful treatment resulted in relapse of the disorder in 33% of the patients vs. 13% of those who continued taking sertraline over the following 28 weeks. The patients experienced distinct withdrawal syndrome, expressed primarily as insomnia and dizziness, and the authors noted that a significant part of the relapse rate among the discontinued patients could possibly be accounted for by the withdrawal syndrome.[69] Confirming these hypotheses, in another study, gradual discontinuation of sertraline after 12 weeks of treatment did not lead to the return of panic symptoms. In the same study, discontinuation of paroxetine caused exacerbation of panic in about a fifth of the previously responding patients. The authors attributed this difference to the more severe withdrawal syndrome with paroxetine, which even discontinuation over three weeks could not remedy.[67]

[edit] Social phobia

Sertraline has been successfully used for the treatment of social phobia (social anxiety disorder).[70] In a flexible dosing study, it appeared that a higher dose range was needed for adequate response. Furthermore, improvement was achieved slowly, separating from the placebo response only by week six, and continuing to increase until week 12.[71] The response was higher among the patients with later onset, especially adult onset, of the disorder.[5] Among the different rating scales, the clinician-rated global improvement demonstrated the highest difference vs. placebo, while the patient self-rated quality of life differed from placebo only modestly. The greatest improvement of quality of life was observed among the most impaired patients.[71] In addition to psychological components of social phobia, such as fear and avoidance, sertraline also ameliorated some physiological components, such as blushing and palpitations but not sweating and trembling.[72] In a four-way placebo-controlled comparison trial of sertraline and exposure therapy, sertraline performed significantly better than placebo, while the exposure therapy resulted in only marginal improvement. The combination of sertraline and exposure therapy was not significantly better than sertraline alone; however, it appeared that the response was achieved faster with the combined treatment.[73]

[edit] Premenstrual dysphoric disorder

According to several double-blind studies, sertraline is effective in alleviating the symptoms of PMDD, a severe form of premenstrual syndrome. Significant improvement was observed in 50–60% of cases treated with sertraline vs. 20–30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline.[74][75][76] Despite the well-known sexual side effects of sertraline, significantly higher improvement of sexual functioning was achieved by the sertraline group as compared to the placebo group.[77] A three-way comparison of sertraline, norepinephrine reuptake inhibitor tricyclic antidepressant desipramine, and placebo demonstrated the superiority of sertraline, while desipramine fared no better than placebo.[78] Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment.[77][79][80] Although the luteal-phase treatment may be more acceptable to patients, there have been indications that by the end of a three-month period it is less well-tolerated than the continuous treatment. The study authors suggested that the continuous treatment may allow the tolerance to side effects of sertraline to develop faster.[77] The most recent (2006) trial findings indicate that continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) may both afford the highest effectiveness and minimize the side effects.[81]

[edit] Posttraumatic stress disorder

Two double-blind placebo-controlled studies confirmed the efficacy of sertraline for severe chronic PTSD in civilians, with the mean duration of the illness more than ten years. Physical or sexual assault was the traumatic event for more than 60% of the subjects, and 75% of them were women. Over the 12-week period, 53–60% of the patients treated with sertraline were much or very much improved vs. 32–38% for placebo.[6][82] The treatment was continued for another year with some participants from both trials. The condition of the responders further improved; some of the patients who did not respond to the initial 12-week trial slowly improved as well, so that about half of them were classified as responders by the end of the following 24 weeks. The authors noted that the medication worked more slowly for those with more severe symptoms.[83][84] Discontinuation of the successful treatment after six months resulted in the return of the PTSD symptoms in 52% of the patients vs. 16% in those who continued taking sertraline.[85] Longer-term treatment has been advocated in such cases.[84]

Three-way (placebo–sertraline–third antidepressant) comparison trials of sertraline for PTSD found it to be better than placebo and equivalent to venlafaxine (Effexor)[86] or citalopram (Celexa),[87] and in a two-way comparison it had the same efficacy as nefazodone (Serzone).[88] Sertraline was not effective for veterans with combat-related PTSD.[89][90]

[edit] Other indications

Two large placebo-controlled clinical trials of sertraline for generalized anxiety disorder have been conducted. While one trial demonstrated highly significant improvements on all measures used, including anxiety, depression and quality of life,[91] the other showed more marginal improvement of anxiety and quality of life.[92] Small double-blind studies of sertraline for eating disorders, such as binge eating disorder,[93][94]night eating syndrome[95] and bulimia nervosa[96] indicated its effectiveness.

Although sertraline can be used for the treatment of premature ejaculation[97] a comparative study found it to be inferior to another SSRI, paroxetine.[98] A general disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly.[99] For the occasional "on-demand", a few hours before coitus, treatment, clomipramine gave better results than paroxetine in one study,[100] while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.[101] The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,[102] with on-demand sertraline, paroxetine or clomipramine,[101] and with the pause–squeeze technique.[101][102]

A small study suggested that sertraline may help some children and adolescents with refractory syncope.[103] Subsequent case reports indicated that sertraline may itself cause syncope in adolescents[104] and that sertraline treatment of syncope may make it more frequent.[105][106]

[edit] Adverse effects

According to Pfizer, sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide (Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with disulfiram (Antabuse). The prescribing information recommends that treatment of the elderly and patients with liver impairment "must be approached with caution". Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.[107]

Among the common adverse effects associated with sertraline and listed in the prescribing information, those with the greatest difference from placebo are nausea (25% vs. 11% for placebo), ejaculation failure (14% vs. 1% for placebo), insomnia (21% vs. 11% for placebo), diarrhea (20% vs. 10% for placebo), dry mouth (14% vs. 8% for placebo), somnolence (13% vs. 7% for placebo), dizziness (12% vs. 7% for placebo), tremor (8% vs. 2% for placebo) and decreased libido (6% vs. 1% for placebo).[107] Those that most often resulted in interruption of the treatment were drowsiness (7%), nausea (3%), diarrhea (2%) and insomnia (2%).[107] Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology.[108]

Akathisia—that is, "inner tension, restlessness, and the inability to stay still"—caused by sertraline was observed in 16% of patients in a case series.[109] This and other reports[110][111][112] note that akathisia begins soon after the initiation of treatment or a dose increase; often, several hours after taking the medication. Akathisia usually disappears within several days after sertraline is stopped or its dose is decreased. In some cases, clinicians confused akathisia with anxiety and increased the dose of sertraline, causing further worsening of the patients' symptoms.[112] Experts note that because of the possible link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition".[113][114]

Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%.[115] Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg).[116] Although the difference did not reach statistical significance, the weight gain was lower for fluoxetine (Prozac) (1%) but higher for citalopram (Celexa), fluvoxamine (Luvox) and paroxetine (Paxil) (2.5%). Only 4.5% of the sertraline group gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.[116]

Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination.[117][118] In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls.[119] In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance.[120]

[edit] Overdosage

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities.[121]

[edit] In pregnancy and lactation

The studies comparing the levels of sertraline and its principal metabolite, desmethylsertraline, in mother's blood to their concentration in umbilical cord blood at the time of delivery indicated that fetal exposure to sertraline and its metabolite is approximately a third of the maternal exposure.[122][123] The use of sertraline during the first trimester of pregnancy was associated with increased odds of the following birth defects: omphalocele (six-fold), anal atresia and limb reduction defects (four-fold), and septal defects (two-fold); however these specific defects themselves are rare and therefore the absolute risks are small.[124] Concentration of sertraline and desmethylsertraline in breast milk is highly variable and, on average, is of the same order of magnitude as their concentration in the blood plasma of the mother. As a result, more than half of breast-fed babies receive less than 2 mg/day of sertraline and desmethylsertraline combined, and in most cases these substances are undetectable in their blood.[125] No changes in serotonin uptake by the platelets of breast-fed infants were found, as measured by their blood serotonin levels before and after their mothers began sertraline treatment.[126]

[edit] Sexual side effects

Like other SSRIs, sertraline is associated with sexual side effects, including arousal disorder and difficulty achieving orgasm. The observed frequency of sexual side effects depends greatly on whether they are reported by patients spontaneously, as in the manufacturer's trials, or actively solicited by the physicians. There have been several double-blind studies of sexual side effects comparing sertraline with placebo or other antidepressants.[127] While nefazodone (Serzone) and bupropion (Wellbutrin) did not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties vs. 18% before the treatment[127] (or 61% vs. 0% according to another paper).[36] Similarly, in a group of women who initially did not have difficulties achieving orgasm, 41% acquired this problem during treatment with sertraline.[36] A 40% rate of orgasm dysfunction (vs. 9% for placebo) on sertraline was observed in a mixed group in another study.[128]Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of patients on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved.[128]

Genital anesthesia,[129] loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months or years after the drug has been completely withdrawn.[130] This is known as Post SSRI Sexual Dysfunction.

[edit] Suicide

The FDA requires all antidepressants, including sertraline, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 2-fold increase of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase of suicidal behavior in the 18–24 age group.[131][132][133]

Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behavior with a marginal statistical significance by 37%[133] or 50%[132] depending on the statistical technique used. The authors of the FDA analysis note that "given the large number of comparisons made in this review, chance is a very plausible explanation for this difference".[132] The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior.[134] Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.[135][136]

[edit] Discontinuation syndrome

Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. This syndrome occurred in 60% of the remitted depressed patients taking sertraline in a blind discontinuation study, as compared to 14% of patients on fluoxetine and 66% of patients on paroxetine.[137] During the 5–8-day period when sertraline was temporarily replaced by placebo, the most frequent symptoms (reported by more than a quarter of patients) were irritability, agitation, dizziness, headache, nervousness, crying, emotional lability, bad dreams and anger. Around a third experienced mood worsening to the level generally associated with a major depressive episode.[137] In a double-blind study of remitted panic disorder patients, abrupt discontinuation of sertraline treatment resulted in insomnia and dizziness (both 16–17% vs. 4% for continuing treatment), although headache, depression and malaise did not increase significantly.[69] In another double-blind study of recovered panic disorder patients, the withdrawal syndrome was completely avoided when sertraline was gradually discontinued over three weeks, while patients stopping paroxetine treatment still suffered from it.[67]. There is at least one report of orthostatic hypotension as a result of Sertraline withdrawal [138].

[edit] Interactions

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro.[139] Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol.[140][141][142] This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase.[143][144] In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.[145] Sertraline is often used in combination with stimulant medication for the treatment of co-morbid depression and/or anxiety in ADHD[146] Studies have shown there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Sertraline has been shown to augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.[147]

Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; this effect was not considered to be clinically relevant.[143] As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.

Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver.[107][139][143][148]Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy,[149][150] and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.[151]

Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.[143]

[edit] Mechanism of action

Sertraline is primarily a serotonin reuptake inhibitor (SRI), with a binding affinity (Ki) of 3.3 nM.[152] Therapeutic doses of sertraline (50–200 mg/day) taken by patients for four weeks resulted in 80–90% inhibition of serotonin transporter (SERT) in striatum as measured by positron emission tomography. A daily 9 mg dose was sufficient to inhibit 50% of SERT.[153]

Sertraline is also a dopamine reuptake inhibitor, with a Ki=315 nM,[154] a σ1 receptor agonist with 5% of its SRI potency,[155] and an α1-adrenoreceptor antagonist with 1–10% of its SRI potency.[152] However, though confirming sertraline's high affinity for σ1 receptors, different studies suggest that the drug actually behaves as an antagonist at those.[156]

Sertraline demonstrated anti-fungal activity against Candida species in vivo.[157] Sertraline also inhibits dynamin 1 dependent endocytosis.[158]

[edit] Pharmacokinetics

Sertraline is absorbed slowly when taken orally, achieving its maximal concentration in the plasma 4–6 hours after ingestion. In the blood, it is 98.5% bound to plasma proteins. Its half-life in the body is 13–45 hours and, on average, is about 1.5 times longer in women (32 hours) than in men (22 hours), leading to a 1.5-times-higher exposure in women.[143] According to in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms: CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4. It appeared unlikely that inhibition of any single isoform could cause clinically significant changes in sertraline pharmacokinetics.[1][159] No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6;[160] however, poor CYP2C19 metabolizers had a 1.5-times-higher level of sertraline than normal metabolizers.[161]In vitro data also indicate that the inhibition of CYP2B6 should have even greater effect than the inhibition of CYP2C19, while the contribution of CYP2C9 and CYP3A4 to the metabolism of sertraline would be minor. These conclusions have not been verified in human studies.[1] Sertraline can be deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.[1] The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.[152]

Non-amine metabolites may also contribute to the antidepressant effects of this medication. Sertraline deaminated is O-2098, a compound that has been found to inhibit the dopamine reuptake transporter proteins in spite of its lack of a nitrogen atom.[162]

[edit] History

The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structures of neuroleptics chlorprothixene and thiothixene.[163][164] Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.[163][165][166]

Sertraline was approved by the U.S. Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year.[167] The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, Director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on outpatients with depression had been "modest to minimal". Other experts emphasized that the drug's effect on inpatients had not differed from placebo and criticized poor design of the trials by Pfizer.[168] For example, 40% of participants dropped out of the trials, significantly decreasing their validity.[169]

Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data).[170] It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 2000–01, having cost $45 million and $87 million in subsidies respectively.[171][172] Sertraline is less popular in the UK (2003 data) and Canada (2006 data)—in both countries it was fifth (among drugs marketed for the treatment of MDD, or antidepressants), based on the number of prescriptions.[173][174]

Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe obsessive-compulsive disorder (OCD). In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18.[175][176] However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.[177] In 2005, the FDA added a black box warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.[178]

The U.S. patent for Zoloft expired in 2006,[179] and sertraline is now available in generic form.

Zoloft came under public scrutiny in 1999 after it was discovered that Eric Harris, one of the two shooters involved in the Columbine High School massacre, had been taking the drug before switching to Luvox. However, Harris had started to plan the shooting before he was prescribed the medication.[180]

[edit] Controversy

The brand-name form of sertraline, Zoloft, was advertised to consumers by Pfizer using the following wording: "While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn't have to feel this way anymore." An essay published in the journal PLoS Medicine noted that there is no scientific support for the "serotonin imbalance" theory of depression, and criticized Pfizer and manufacturers of other SSRIs for using it. When asked to comment on this apparent breach of federal regulations, the FDA answered that such "reductionist statements" are acceptable to explain the neurochemistry of depression "to the fraction of the public that functions at no higher than a 6th-grade reading level."[181] However, the FDA reacted promptly with a Warning Letter when a Zoloft advertisement omitted information about the risk of suicidal behavior.[182]

[edit] References

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2. ^ The sertraline prescriptions were calculated as a total of prescriptions for Zoloft and generic sertraline using data from the charts for generic and brand name drugs, see: Verispan (2008-02-18). "Top 200 Generic Drugs by Units in 2007" (PDF). Drug Topics. http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=491181. Retrieved 2008-03-30.  and Verispan (2008-02-18). "Top 200 Brand Drugs by Units in 2007" (PDF). Drug Topics. http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=491207. Retrieved 2008-03-30. 
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5. ^ a b The BSPS15 criterion identified 28 (21%) of sertraline-treated patients and 4 (6%) of placebo-treated patients as responders. The 50% reduction in BSPS criterion identified 47 (35%) of sertraline-treated patients and 9 (13%) of placebo-treated patients as responders. Finally, the 50% reduction in MFQ-SP criterion identified 53 (39%) of sertraline-treated patients and 9 (13%) of placebo-treated patients as responders. Van Ameringen M, Oakman J, Mancini C, Pipe B, Chung H (2004). "Predictors of response in generalized social phobia: effect of age of onset". J Clin Psychopharmacol 24 (1): 42–8. DOI:10.1097/01.jcp.0000104909.75206.6f. PMID 14709946. 
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157. ^ Interaction of sertraline with Candida species selectively attenuates fungal virulence in vitro. PMID 12589952. 
158. ^ Takahashi, K; Miyoshi, H; Otomo, M; Osada, K; Yamaguchi, N; Nakashima, H (2010). "Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis". Biochemical and Biophysical Research Communications 391 (1): 382–7. DOI:10.1016/j.bbrc.2009.11.067. PMID 19913505. 
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