Selective serotonin reuptake inhibitor

From Infogalactic: the planetary knowledge core
Jump to: navigation, search
Selective serotonin reuptake inhibitor
Drug class
Serotonin-2D-skeletal.svg
Class identifiers
Use major depressive disorder, anxiety disorders
ATC code N06AB
Biological target Serotonin transporter
Clinical data
AHFS/Drugs.com Drug Classes
Consumer Reports Best Buy Drugs
External links
MeSH D017367

Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitors[1] (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder and anxiety disorders.

The exact mechanism of SSRIs is unknown.[2] SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption 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 norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries.[3] The efficacy of SSRIs in mild or moderate cases of depression has been disputed.[4][5][6]

Medical uses

The main indication for SSRIs is major depressive disorder (also called "major depression", "clinical depression" and often simply "depression"). SSRIs are frequently prescribed for anxiety disorders, such as social anxiety disorder, 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.[7]

Depression

Antidepressants are recommended by the National Institute for Clinical Excellence (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy.[8] They recommend against their routine use in those who have chronic health problems and mild depression.[8]

There has been controversy regarding the efficacy of antidepressants in treating depression depending on its severity and duration.

  • Two meta-analyses published in 2008 (Kirsch) and 2010 (Fournier) found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between "relatively small" and "substantial".[4][9] The 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 serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine. The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication.[9] Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.[10][11]
  • A 2010 comprehensive review conducted by NICE concluded that antidepressants have no advantage over placebo in the treatment of short-term mild depression, but that the available evidence supported the use of antidepressants in the treatment of dysthymia and other forms of chronic mild depression.[12]
  • A 2012 meta-analysis of fluoxetine and venlafaxine concluded that statistically and clinically significant treatment effects were observed for each drug relative to placebo irrespective of baseline depression severity.[13]
  • In 2014 the U.S. FDA published a systematic review of all antidepressant maintenance trials submitted to the agency between 1985 and 2012. The authors concluded that maintenance treatment reduced the risk of relapse by 52% compared to placebo, and that this effect was primarily due to recurrent depression in the placebo group rather than a drug withdrawal effect.[14]

There does not appear to be a big difference in the effectiveness among the second generation antidepressants (SSRIs and SNRIs).[15]

In children there are concerns around the quality of the evidence on the meaningfulness of benefits seen.[16] If a medication is used, fluoxetine appears to be first line.[16]

Generalized anxiety disorder

SSRIs are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD,[17] and are superior to placebo in treating GAD.[18] The efficacy of different antidepressants is similar.[17][18]

Obsessive compulsive disorder

SSRIs are a second line treatment of adult obsessive compulsive disorder (OCD) with mild functional impairment and as first line treatment for those with moderate or severe impairment. In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.[19] SSRIs are efficacious in the treatment of OCD; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo.[20][21] Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration.[22][23][24]

Eating disorders

Anti-depressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.[17] SSRIs (fluoxetine in particular) are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized.

Similar recommendations apply to binge eating disorder.[17] SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.[25]

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.[26] Treatment guidelines from the National Institute of Health and Clinical Excellence[17] recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or obsessive-compulsive disorders.[25]

Stroke recovery

SSRIs have been used in the treatment of stroke patients, including those with and without symptoms of depression. A recent meta analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety. There was no statistically significant effect on death, motor deficits, or cognition.[27]

Premature ejaculation

SSRIs are effective for the treatment of premature ejaculation. Chronic administration is more efficacious than on demand use.[28]

Adverse effects

Side effects vary among the individual drugs of this class. However, certain types of adverse effects are found broadly among most if not all members of this class:

Sexual dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm).[35] Sexual problems are common with SSRIs.[36] Poor sexual function is also one of the most common reasons people stop the medication.[37]

Rarely symptoms of sexual dysfunction may persist after discontinuation of SSRI's.[35][38][39]

The mechanism by which SSRIs cause sexual side effects is not well understood as of 2015. A number of (non-SSRI) drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine and moclobemide.[40][41])

There is no FDA-approved treatment for SSRI-induced sexual dysfunction and there has been a lack of randomized, placebo-controlled, double-blind studies of potential treatments.[why?] There is evidence for the following management strategies: for erectile dysfunction, the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to bupropion; and for overall sexual dysfunction, switching to nefazodone.[42]

Several small studies have suggested that SSRIs may adversely affect semen quality.[43]

Cardiac

SSRIs do not appear to affect the risk of coronary heart disease (CHD) in those without a previous diagnosis of CHD.[44] A large cohort study suggested no substantial increase in the risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy.[45] A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use.[46] The recommended maximum daily dose of citalopram and escitalopram was reduced due to concerns with QT interval prolongation.[47][48][49] 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 SSRIs.[50]

Bleeding

SSRIs interact with anticoagulants, like warfarin and aspirin.[51][52][53][54] This includes an increased risk of GI bleeding, and post operative bleeding.[51] The relative risk of intracranial bleeding is increased, but the absolute risk is very low.[55] SSRIs are known to cause platelet dysfunction.[56][57] This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure.[58][59]

Discontinuation syndrome

Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, paresthesias, insomnia, and electric shock-like sensations. Paroxetine may produce discontinuation-related symptoms at a greater rate than other SSRIs, though qualitatively similar effects have been reported for all SSRIs.[60][61] Discontinuation effects appear to be less for fluoxetine, perhaps owing to its long half-life and the natural tapering effect associated with its slow clearance from the body. One strategy for minimizing SSRI discontinuation symptoms is to switch the patient to fluoxetine and then taper and discontinue the fluoxetine.[60]

Suicide risk

Children and adolescents

Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.[62][63][64] 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%;[65] According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment.[66][67][68] The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment".[69] The European Psychiatric Association places the excess risk in the first two weeks of treatment and, based on a combination of epidemiological, prospective cohort, medical claims, and randomized clinical trial data, concludes that a protective effect dominates after this early period. A 2012 Cochrane review found that at six to nine months, suicidal ideation remained higher in children treated with antidepressants compared to those treated with psychological therapy.[70]

A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between the fluoxetine group and a placebo group.[71] 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.[72]

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.[73] 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 is not licensed for this use.[74]

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.[75]
  • 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.[76]
  • 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.[77]
  • 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.[78]
  • 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.[62]

Pregnancy and breastfeeding

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases.[79] In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold.[80][81]

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies.[82] A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that just missed statistical significance.[83] Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants.[84] Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.[81]

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.[85][86][87]

Maternal SSRI use may be associated with autism,[88] however, a large cohort study published in 2013 found no significant association between SSRI use and autism in offspring.[89]

Neonatal abstinence syndrome

Several studies have documented neonatal abstinence syndrome, a syndrome of neurological, gastrointestinal, autonomic, endocrine and/or respiratory symptoms among a large minority of infants with intrauterine exposure. These syndromes are short-lived, but insufficient long-term data is available to determine whether there are long-term effects.[90][91]

Persistent pulmonary hypertension

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but very 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. It is associated with about a 25% risk of significant long-term neurological deficits.[92] A 2014 meta analysis found no increased risk of persistent pulmonary hypertension associated with exposure to SSRI's in early pregnancy and a slight increase in risk associates with exposure late in pregnancy; "an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn.".[93] A review published in 2012 reached conclusions very similar to those of the 2014 study.[94]

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.[95] However, case reports of SSRI poisoning have indicated that severe toxicity can occur[96] and deaths have been reported following massive single ingestions,[97] although this is exceedingly uncommon when compared to the tricyclic antidepressants.[95]

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.[98] Other reported significant effects include coma, seizures, and cardiac toxicity.[95]

The SSRIs, in decreasing toxicity in overdose, can be listed as follows:[99]

Contraindications and drug interactions

The following drugs may precipitate serotonin syndrome in people on SSRIs:[100][101]

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use.[52][54][102] NSAIDs include:

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochromes.[103][104]

Drug Name CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 CYP2B6
Citalopram + 0 0 + 0 0
Escitalopram 0 0 0 + 0 0
Fluoxetine + ++ +/++ +++ + +
Fluvoxamine +++ ++ +++ + + +
Paroxetine + + + +++ + +++
Sertraline + + +/++ + + +

Legend:
0 — no inhibition.
+ — mild inhibition.
++ — moderate inhibition.
+++ — strong inhibition.

List of agents

Drugs in this class include:

Most common:

Other:

Selective serotonin reuptake inhibitors (SSRIs)
Citalopram structure.svg

Citalopram

Dapoxetine Structural Formulae V.1.svg

Dapoxetine

Escitalopram.svg

Escitalopram

Fluoxetine-2D-skeletal.svg

Fluoxetine

Fluvoxamine2DACS.svg

Fluvoxamine

Indalpine.png

Indalpine

Paroxetine-2D-skeletal.svg

Paroxetine

Sertraline Structural Formulae.png

Sertraline

Zimelidine Structural Formulae V.1.svg

Zimelidine

Related agents

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

Mechanism of action

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).

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. In the short run this leads to an increase in signalling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of pre-synaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to down-regulation of post-synaptic serotonin receptors.[105] Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB.[106] Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of SSRIs.

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.[107] 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.[108]

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 to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.[109] 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 antidepressants also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

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.[106]

Society and culture

Controversy

  • A study examining publication of results from FDA-evaluated antidepressants concluded that those with favorable results were much more likely to be published than those with negative results.[110]

David Healy has argued that warning signs were available for many years prior to regulatory authorities moving to put warnings on antidepressant labels that they might cause suicidal thoughts.[111] At the time these warnings were added, others argued that the evidence for harm remained unpersuasive[112][113] and others continued to do so after the warnings were added.[114][115]

See also

References

  1. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  2. http://pi.lilly.com/us/prozac.pdf page 20
  3. Preskorn SH, Ross R, Stanga CY (2004). "Selective Serotonin Reuptake Inhibitors". In Sheldon H. Preskorn, Hohn P. Feighner, Christina Y. Stanga and Ruth Ross. Antidepressants: Past, Present and Future. Berlin: Springer. pp. 241–62. ISBN 978-3-540-43054-4. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. 4.0 4.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  5. Kramer, Peter (7 Sep 2011). "In Defense of Antidepressants". The New York Times. Retrieved 13 July 2011.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  7. Medford, Nick. "Understanding and treating depersonalization disorder". Advances in Psychiatric Treatment (2005). Retrieved 2011-11-11.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. 8.0 8.1 "www.nice.org.uk" (PDF).<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 9.0 9.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  10. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  11. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  12. Depression: The NICE Guideline on the Treatment and Management of Depression in Adults (Updated Edition) (PDF). RCPsych Publications. 2010. ISBN 1-904671-85-3.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  14. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  15. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  16. 16.0 16.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  17. 17.0 17.1 17.2 17.3 17.4 "www.nice.org.uk" (PDF). Retrieved 2013-02-20.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> Cite error: Invalid <ref> tag; name "urlwww.nice.org.uk" defined multiple times with different content
  18. 18.0 18.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  19. "Obsessive-compulsive disorder: Core interventions in the treatment of obsessive-compulsive disorder and body dysmorphic disorder" (PDF).<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles> November 2005
  20. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  21. "Medscape Log In".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>[dead link]
  22. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  23. "Sertraline prescribing information" (PDF). Retrieved 2015-01-30.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  24. "Paroxetine prescribing information" (PDF). Retrieved 2015-01-30.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  25. 25.0 25.1 "National Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  26. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  27. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  28. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  29. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  30. Stahl SM, Lonnen AJ (2011). "The Mechanism of Drug-induced Akathsia". CNS Spectrums. PMID 21406165.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  31. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  32. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  33. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  34. September 23, 2012. "SSRIs and Depression". Emedicinehealth.com. Retrieved 2012-09-23.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  35. 35.0 35.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  36. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  37. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  38. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  39. http://pi.lilly.com/us/prozac.pdf Page 14.
  40. Clayton, Anita H. (2003). "Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge". Primary Psychiatry. 10 (1): 55–61.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  41. Kanaly KA, Berman JR (December 2002). "Sexual side effects of SSRI medications: potential treatment strategies for SSRI-induced female sexual dysfunction". Current Women's Health Reports. 2 (6): 409–16. PMID 12429073.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  42. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  43. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  44. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  45. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  46. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  47. FDA. "FDA Drug Safety".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  48. Citalopram and escitalopram: QT interval prolongation—new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings. From Medicines and Healthcare Products Regulatory Agency. Article date: December 2011
  49. "ref2" (PDF). Retrieved 2012-09-23.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  50. Pacher P, Ungvari Z, Nanasi PP, Furst S, Kecskemeti V (Jun 1999). "Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any?". Current medicinal chemistry. 6 (6): 469–80. PMID 10213794. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  51. 51.0 51.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  52. 52.0 52.1 Taylor, D; Carol, P; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 9780470979693.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  53. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  54. 54.0 54.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  55. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  56. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  57. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  58. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  59. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  60. 60.0 60.1 "PsychiatryOnline | APA Practice Guidelines | Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  61. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  62. 62.0 62.1 Stone MB, Jones ML (2006-11-17). "Clinical review: relationship between antidepressant drugs and suicidal behavior in adults" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  63. Levenson M, Holland C (2006-11-17). "Statistical Evaluation of Suicidality in Adults Treated with Antidepressants" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  64. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  65. Hammad TA (2004-08-16). "Review and evaluation of clinical data. Relationship between psychiatric drugs and pediatric suicidal behavior" (PDF). FDA. pp. 42, 115. Retrieved 2008-05-29.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  66. "Antidepressant Use in Children, Adolescents, and Adults".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  67. "FDA Medication Guide for Antidepressants". Retrieved 2014-06-05.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  68. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  69. "www.nice.org.uk" (PDF).<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  70. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  71. Meta-Analysis of Aggression and/or Hostility-Related Events in Children and Adolescents Treated with Fluoxetine Compared with Placebo Journal of Child and Adolescent Psychopharmacology. October 2007; 17(5) 713–718. doi:10.1089/cap.2006.0138.
  72. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  73. "Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants" (PDF). MHRA. 2004-12-01. Retrieved 2007-09-25.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  74. "Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data". MHRA. 2005-09-29. Retrieved 2008-05-29.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  75. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  76. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  77. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  78. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  79. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  80. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  81. 81.0 81.1 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  82. Einarson TR, Kennedy D, Einarson A (2012). "Do findings differ across research design? The case of antidepressant use in pregnancy and malformations". Journal of Population Therapeutics and Clinical Pharmacology = Journal De La Thérapeutique Des Populations Et De La Pharamcologie Clinique. 19 (2): e334–48. PMID 22946124. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  83. Riggin L, Frankel Z, Moretti M, Pupco A, Koren G (April 2013). "The fetal safety of fluoxetine: a systematic review and meta-analysis". Journal of Obstetrics and Gynaecology Canada : JOGC = Journal D'obstétrique Et Gynécologie Du Canada : JOGC. 35 (4): 362–9. PMID 23660045. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  84. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  85. "Breastfeeding Update: SDCBC's quarterly newsletter". Breastfeeding.org. Retrieved 2010-07-10.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>[dead link]
  86. "Using Antidepressants in Breastfeeding Mothers". kellymom.com. Retrieved 2010-07-10.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  87. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  88. "Antidepressant use during pregnancy and ... [Arch Gen Psychiatry. 2011] – PubMed – NCBI". Ncbi.nlm.nih.gov. 2012-05-24. Retrieved 2012-09-23.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  89. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  90. Fenger-Grøn J, Thomsen M, Andersen KS, Nielsen RG (September 2011). "Paediatric outcomes following intrauterine exposure to serotonin reuptake inhibitors: a systematic review". Danish Medical Bulletin. 58 (9): A4303. PMID 21893008. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  91. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  92. "Persistent Newborn Pulmonary Hypertension".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  93. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  94. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  95. 95.0 95.1 95.2 Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  96. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  97. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  98. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  99. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  100. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  101. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  102. Solomon H. Snyder. "J.L. Warner-Schmidt et.al "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans" PNAS 2011". Pnas.org. Retrieved 2012-09-23.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  103. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill Professional. ISBN 978-0071624428.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  104. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  105. Goodman, Louis S. (Louis Sanford); Brunton, Laurence L.; Chabner, Bruce.; Knollmann, Björn C. (2001). Goodman and Gilman's pharmacological basis of therapeutics. New York: McGraw-Hill. pp. 459–461. ISBN 0-07-162442-2.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  106. 106.0 106.1 Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print.
  107. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  108. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  109. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  110. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  111. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  112. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  113. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  114. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).
  115. Lua error in Module:Citation/CS1/Identifiers at line 47: attempt to index field 'wikibase' (a nil value).

External links