Selective serotonin reuptake inhibitor
|Selective serotonin reuptake inhibitor|
|Use||Depression anxiety disorders, and some personality disorders.|
|Biological target||Serotonin transporter|
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor (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.
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. They are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed.
- 1 Medical uses
- 2 Adverse effects
- 2.1 Sexual dysfunction
- 2.2 Cardiovascular
- 2.3 Discontinuation syndrome
- 2.4 Suicide risk
- 2.5 Pregnancy and breastfeeding
- 2.6 Bleeding tendencies
- 2.7 Overdose
- 3 Contraindications and drug interactions
- 4 List of agents
- 5 Mechanism of action
- 6 Society and culture
- 7 See also
- 8 References
- 9 External links
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.
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. They recommend against their routine use in those who have chronic health problems and mild depression. There has been controversy regarding the efficacy of antidepressants in treating depression depending on its severity and duration. A 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. Two meta-analyses published in 2008 and 2011 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". Unlike the NICE study, these studies did not discriminate between the acutely and chronically depressed. 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 SNRI (serotonin and norepinephrine reuptake inhibitor) 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. Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants. 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. However, this analysis included only 6 studies out of the over 2,000 that have been done, involved just 2 medications, and did not involve studies with placebo washout periods typically used as controls.
SSRIs are recommended by NICE over tricyclics due to their superior tolerability. One study showed that SSRIs have greater adverse effects than TCAs in the elderly, though the authors caution that more research is needed. There does not appear to be a substantial difference in efficacy among the various second generation antidepressants (SSRIs and SNRIs).
Generalized anxiety disorder
SSRIs are recommended by the National Institute for Health and Clinical 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.
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 as a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. 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.
Anti-depressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. 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.
Clinical trials have generated mostly negative results for the use of SSRI's in the treatment of anorexia nervosa. Treatment guidelines from the National Institute of Health and Clinical Excellence 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.
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.
A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand" treatment, a few hours before coitus, clomipramine gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. 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, with on-demand sertraline, paroxetine or clomipramine, and with the pause–squeeze technique.
General side effects are mostly present during the first one to four 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 six to eight 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:
- drowsiness or somnolence
- headache (very common as a short-term side effect)
- extremely vivid or strange dreams
- mydriasis (pupil dilation)
- changes in appetite
- insomnia and/or changes in sleep
- excessive diarrhea
- weight loss/gain (measured by a change in bodyweight of 7 pounds)
- increased risk of bone fractures by 1.7 fold
- changes in sexual behaviour (see the next section)
- increased feelings of depression and anxiety (which may sometimes provoke panic attacks)
- autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
- suicidal ideation (thoughts of suicide)
- cognitive disorders
- Syndrome of inappropriate antidiuretic hormone hypersecretion
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.
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.
SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm). Initial studies found the indicence of sexual side effects from SSRIs not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in most patients.
Symptoms of sexual dysfunction occasionally persist after discontinuing SSRIs. The incidence of this adverse effect is unknown. A limited series of published case reports describe a loss of genital sensation and other side effects continuing years after cessation of therapy.
The mechanism by which SSRIs cause sexual side effects is not well understood. In part, it is thought that stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine and norepinephrine release from the substantia nigra. A number of (non-SSRI) drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine and moclobemide,.
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. 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.
Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0.0003 percent. SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals. A number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use. More recently, however, concerns about cardiac problems have led to a reduction in the recommended maximum dose of two types of SSRI's. The recommended maximum daily dose of citalopram was reduced to 40 mg for most people and 20 mg for those older than age 60 and some others. The recommended maximum daily dose of escitalopram was reduced to 10 mg for those older than age 65; the maximum daily dose for most other people remained unchanged at 20 mg. 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.
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. 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.
Children and adolescents
Several studies have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents. 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%; More infrequently, studies have been inconclusive. However, 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. 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.
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. 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.
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. Also among high-risk adult patients, antidepressant drug treatment does not seem related to suicide attempts and death.
- 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.
- 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.
- 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.
- 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.
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. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health. 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.
Pregnancy and breastfeeding
Administration during pregnancy of SSRI is associated with an increased rate of miscarriages, birth defects, persistent pulmonary hypertension of the newborn, newborn behavioral syndrome, and possibly long term behavioral problems. The risk of spontaneous abortion is increased about 1.7 fold.
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.
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.
Neuropsychological changes due to SSRI use in infancy
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. 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. Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. 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.
But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and norepinephrine 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.
The mechanism is currently unknown, but it seems that early life overstimulation of the 5-HT1 receptor that regulates serotonin production results in low serotonin production after puberty.
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.
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.
SSRIs appear to increase the risk of bleeding. This includes an increased risk of GI bleeding, post operative bleeding, and intracranial bleeding. SSRIs are known to cause platelet dysfunction.
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. However, case reports of SSRI poisoning have indicated that severe toxicity can occur and deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.
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. Other reported significant effects include coma, seizures, and cardiac toxicity.
The SSRIs, in decreasing toxicity in overdose, can be listed as follows:
- Citalopram (due to the potential for QT interval prolongation)
Contraindications and drug interactions
- methylene blue dye
- Monoamine oxidase inhibitors (MAOIs) including moclobemide, phenelzine, tranylcypromine, selegiline and methylene blue
- MDMA (ecstasy)
- St. John's wort
- Tricyclic antidepressants (TCAs)
- Serotonin-norepinephrine reuptake inhibitors (SNRIs)
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.
0 — no inhibition.
+ — mild inhibition.
++ — moderate inhibition.
+++ — strong inhibition.
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, Floxyfral)
- indalpine (Upstene) (discontinued)
- paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)
- sertraline (Zoloft, Lustral, Serlain, Asentra, Tresleen)
- zimelidine (Zelmid, Normud) (discontinued)
|Selective serotonin reuptake inhibitors (SSRIs)|
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.
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. Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB. 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.
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. 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.
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. 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.
Society and culture
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. 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.
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. Specifically, critics allege that manufacturers inaccurately portray antidepressants as 'correcting' chemical imbalances. They contend that 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.
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. 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.
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%.
Other critics have argued that 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.
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.. In Canada, the drug approval process is carried out by Health Canada.
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. Lawsuits alleging that SSRIs caused birth defects have been particularly popular.
One lawsuit of particular note accuses Pfizer, the maker of Zoloft, of "deceptively marketing Zoloft as a 'highly effective treatment for depression', while knowing that the medication was virtually indistinguishable from a sugar pill at best." This lawsuit was filed in 2013 as a consumer class action suit in the US District Court of Northern California.
- Dopamine reuptake inhibitor (DRI)
- Norepinephrine reuptake inhibitor (NRI)
- Norepinephrine-dopamine reuptake inhibitor (NDRI)
- Reuptake inhibitor
- Serotonin reuptake inhibitor (SRI)
- Serotonin-norepinephrine reuptake inhibitor (SNRI)
- Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)
- Noradrenergic and specific serotonergic antidepressant (NaSSA)
- Selective serotonin reuptake enhancer (SSRE)
- Selective serotonin releasing agent (SSRA)
- Barlow, David H. Durand, V. Mark (2009). "Chapter 7: Mood Disorders and Suicide". Abnormal Psychology: An Integrative Approach (Fifth ed.). Belmont, CA: Wadsworth Cengage Learning. p. 239. ISBN 0-495-09556-7. OCLC 192055408.
- 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.
- Jay C. Fournier, MA; Robert J. DeRubeis, PhD; Steven D. Hollon, PhD; Sona Dimidjian, PhD; Jay D. Amsterdam, MD; Richard C. Shelton, MD; Jan Fawcett, MD (January 2010). "Antidepressant Drug Effects and Depression Severity". The Journal of the American Medical Association 303 (1): 47–53. doi:10.1001/jama.2009.1943. PMC 3712503. PMID 20051569.
- Kramer, Peter (7 Sep 2011). "In Defense of Antidepressants". The New York Times. Retrieved 13 July 2011.
- Ronald Pies, MD (April 2010). "Antidepressants Work, Sort of-Our System of Care Does Not". Journal of Clinical Psychopharmacology 30 (2): 101–104. doi:10.1097/JCP.0b013e3181d52dea. PMID 20520282.
- Medford, Nick. "Understanding and treating depersonalization disorder". Advances in Psychiatric Treatment (2005). Retrieved 2011-11-11.
- Depression: The NICE Guideline on the Treatment and Management of Depression in Adults (Updated Edition). RCPsych Publications. 2010. ISBN 1-904671-85-3.
- Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (February 2008). "Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration". PLoS Medicine 5 (2): e45. doi:10.1371/journal.pmed.0050045. PMC 2253608. PMID 18303940.
- Horder J, Matthews P, Waldmann R (June 2010). "Placebo, Prozac and PLoS: significant lessons for psychopharmacology". Journal of Psychopharmacology 25 (10): 1277–88. doi:10.1177/0269881110372544. PMID 20571143.
- Fountoulakis KN, Moller H-J (August 2010). "Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data". International Journal of Neuropsychopharmacology 14 (3): 1–8. doi:10.1017/S1461145710000957. PMID 20800012.
- John Kelley (March 2, 2010). "Antidepressants: Do They "Work" or Don't They?". Scientific American.
- Coupland CA, Dhiman P, Barton G, et al. (August 2011). "A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database". Health Technol Assess 15 (28): 1–202, iii–iv. doi:10.3310/hta15280. PMID 21810375.
- Gartlehner G, Hansen RA, Morgan LC, et al. (December 2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis". Ann. Intern. Med. 155 (11): 772–85. doi:10.7326/0003-4819-155-11-201112060-00009. PMID 22147715.
- "www.nice.org.uk". Retrieved 2013-02-20.
- Kapczinski F, Lima MS, Souza JS, Schmitt R (2003). "Antidepressants for generalized anxiety disorder". In Kapczinski, Flavio FK. Cochrane Database Syst Rev (2): CD003592. doi:10.1002/14651858.CD003592. PMID 12804478.
- Arroll B, Elley CR, Fishman T, et al. (2009). "Antidepressants versus placebo for depression in primary care". In Arroll, Bruce. Cochrane Database Syst Rev (3): CD007954. doi:10.1002/14651858.CD007954. PMID 19588448.
- "Medscape Log In".
- "National Guideline Clearinghouse | Practice guideline for the treatment of patients with eating disorders".
- Flament MF, Bissada H, Spettigue W (March 2012). "Evidence-based pharmacotherapy of eating disorders". Int. J. Neuropsychopharmacol. 15 (2): 189–207. doi:10.1017/S1461145711000381. PMID 21414249.
- Mead GE, Hsieh CF, Lee R, et al. (2012). "Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery". In Mead, Gillian E. Cochrane Database Syst Rev 11: CD009286. doi:10.1002/14651858.CD009286.pub2. PMID 23152272.
- Waldinger MD (November 2007). "Premature ejaculation: state of the art". The Urologic Clinics of North America 34 (4): 591–9, vii–viii. doi:10.1016/j.ucl.2007.08.011. PMID 17983899.
- Waldinger MD, Zwinderman AH, Olivier B (October 2004). "On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment". European Urology 46 (4): 510–5; discussion 516. doi:10.1016/j.eururo.2004.05.005. PMID 15363569.
- Abdel-Hamid IA, El Naggar EA, El Gilany AH (February 2001). "Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation". International Journal of Impotence Research 13 (1): 41–5. doi:10.1038/sj.ijir.3900630. PMID 11313839.
- Wang WF, Wang Y, Minhas S, Ralph DJ (April 2007). "Can sildenafil treat primary premature ejaculation? A prospective clinical study". International Journal of Urology 14 (4): 331–5. doi:10.1111/j.1442-2042.2007.01606.x. PMID 17470165.
- Wu Q, Bencaz AF, Hentz JG, Crowell MD (January 2012). "Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies". Osteoporos Int 23 (1): 365–75. doi:10.1007/s00198-011-1778-8. PMID 21904950.
- (English) Stahl SM, Lonnen AJ. « The Mechanism of Drug-induced Akathsia » CNS Spectr. 2011. pii: Stahl. PMID 21406165
- (English) Lane RM. « SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. » J Psychopharmacol. 1998;12(2):192-214 PMID 9694033
- (English) Koliscak LP, Makela EH. « Selective serotonin reuptake inhibitor-induced akathisia. » J Am Pharm Assoc. (2003). 2009 Mar-Apr;49(2):e28-36; quiz e37-8 PMID 19289334
- (English) Leo RJ. « Movement disorders associated with the serotonin selective reuptake inhibitors. » J Clin Psychiatry. 1996 Oct;57(10):449-54 PMID 8909330
- September 23, 2012. "SSRIs and Depression". Emedicinehealth.com. Retrieved 2012-09-23.
- A landmark study in the use of anti-depressants and their role in step-therapy can be found in the STAR*D trial.
- Bahrick, Audrey (2008). "Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence". The Open Psychology Journal 1: 42–50. Retrieved 30 January 2014.
- Montejo, AL; Llorca G, Izquierdo JA, Rico-Villademoros F (2001). "Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction.". The Journal of Clinical Psychiatry. 62 Suppl 3: 10–21. PMID 11229449.
- Hu, XH; Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE (2004). "Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate". The Journal of Clinical Psychiatry 65: 959–65. doi:10.4088/JCP.v65n0712. PMID 15291685.
- Csoka, AB; Bahrick A, Mehtonen OP (2008). "Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors". The Journal of Sexual Medicine 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768.
- Kauffman, Robert P; Amanda Murdock (2007). "Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone". The Open Women's Health Journal 1: 1–3. Retrieved 30 January 2014.
- Csoka, AB; Shipko S (2006). "Persistent sexual side effects after SSRI discontinuation". Psychotherapy and Psychosomatics 75 (3): 187–8. doi:10.1159/000091777. PMID 16636635. Retrieved 30 January 2014.
- Bolton, James M.; Sareen, Jitender; Reiss, Jeffrey P. (September 2006). "Genital Anaesthesia Persisting Six Years after Sertraline Discontinuation". Journal of Sex & Marital Therapy 32 (4): 327–330. doi:10.1080/00926230600666410. Retrieved 30 January 2014.
- Clayton, Anita H. (2003). "Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge". Primary Psychiatry 10 (1): 55–61.
- 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.
- Balon R (2006). "SSRI-Associated Sexual Dysfunction". The American Journal of Psychiatry 163 (9): 1504–9; quiz 1664. doi:10.1176/appi.ajp.163.9.1504. PMID 16946173.
- Huffman, Grace Brooke (August 1997). "Cardiac effects in patients using SSRI antidepressants - selective serotonin reuptake inhibitor - Tips from Other Journals". American Family Physician.
- Pacher P, Kecskemeti V (2004). "Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns?". Current Pharmaceutical Design 10 (20): 2463–75. doi:10.2174/1381612043383872. PMC 2493295. PMID 15320756.
- Goldberg RJ (1998). "Selective serotonin reuptake inhibitors: infrequent medical adverse effects". Archives of Family Medicine 7 (1): 78–84. doi:10.1001/archfami.7.1.78. PMID 9443704.
- FDA. "FDA Drug Safety".
- "ref2" (PDF). Retrieved 2012-09-23.
- Pacher P, Ungvari Z, Nanasi PP, Furst S, Kecskemeti V (June 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.
- "PsychiatryOnline | APA Practice Guidelines | Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition".
- Renoir T (2013). "Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved". Front Pharmacol 4: 45. doi:10.3389/fphar.2013.00045. PMC 3627130. PMID 23596418.
- 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.
- 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.
- Olfson M, Marcus SC, Shaffer D (August 2006). "Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study". Archives of General Psychiatry 63 (8): 865–72. doi:10.1001/archpsyc.63.8.865. PMID 16894062.
- Hammad TA (2004-08-116). "Review and evaluation of clinical data. Relationship between psychiatric drugs and pediatric suicidal behavior" (PDF). FDA. pp. 42; 115. Retrieved 2008-05-29.
- Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M (2007). "Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents". In Hetrick, Sarah E. Cochrane Database Syst Rev (3): CD004851. doi:10.1002/14651858.CD004851.pub2. PMID 17636776.
- 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.
- Gibbons RD, Hur K, Bhaumik DK, Mann JJ (November 2006). "The relationship between antidepressant prescription rates and rate of early adolescent suicide". The American Journal of Psychiatry 163 (11): 1898–904. doi:10.1176/appi.ajp.163.11.1898. PMID 17074941.
- "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.
- "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.
- Gunnell D, Saperia J, Ashby D (February 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.
- Fergusson D, Doucette S, Glass KC, et al. (February 2005). "Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials". BMJ 330 (7488): 396. doi:10.1136/bmj.330.7488.396. PMC 549110. PMID 15718539.
- Rihmer Z, Akiskal H (August 2006). "Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries". J Affect Disord 94 (1–3): 3–13. doi:10.1016/j.jad.2006.04.003. PMID 16712945.
- Hall WD, Lucke J (2006). "How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?". Aust N Z J Psychiatry 40 (11–12): 941–50. doi:10.1111/j.1440-1614.2006.01917.x. PMID 17054562.
- "FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications". FDA. 2007-05-02. Retrieved 2008-05-29.
- "www1.mhlw.go.jp" (PDF). Japanese Ministry of Health (in Japanese).
- "Questions and answers: Advice on SSRIs in children from the Committee on Safety of Medicine" (PDF). Medicines and Healthcare products Regulatory Agency.
- Domar, A. D.; Moragianni, V. A.; Ryley, D. A.; Urato, A. C. (31 October 2012). "The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond". Human Reproduction 28 (1): 160–71. doi:10.1093/humrep/des383. PMID 23117129.
- Rahimi, Roja; Shekoufeh Nikfar, Mohammad Abdollahi (2006). "Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials". Reproductive Toxicology 22 (4): 571–575. doi:10.1016/j.reprotox.2006.03.019. PMID 16720091.
- "Breastfeeding Update: SDCBC's quarterly newsletter". Breastfeeding.org. Retrieved 2010-07-10.[dead link]
- "Using Antidepressants in Breastfeeding Mothers". kellymom.com. Retrieved 2010-07-10.
- Gentile S, Rossi A, Bellantuono C (2007). "SSRIs during breastfeeding: spotlight on milk-to-plasma ratio". Archives of Women's Mental Health 10 (2): 39–51. doi:10.1007/s00737-007-0173-0. PMID 17294355.
- USA (2012-05-24). "Antidepressant use during pregnancy and ... [Arch Gen Psychiatry. 2011] - PubMed - NCBI". Ncbi.nlm.nih.gov. Retrieved 2012-09-23.
- Hviid, Anders; Mads Melbye and Björn Pasternak (19 December 2013). "Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism". The New England Journal of Medicine 369: 2406–2415. doi:10.1056/NEJMoa1301449. Retrieved 18 December 2013.
- Medicalnewstoday.com Medical News Today - Lancet Press Release. Feb 05 2005
- Vogel G, Neill D, Hagler M, Kors D (1990). "A new animal model of endogenous depression: a summary of present findings". Neuroscience and Biobehavioral Reviews 14 (1): 85–91. doi:10.1016/S0149-7634(05)80164-2. PMID 2183099.
- Velazquez-Moctezuma J, Aguilar-Garcia A, Diaz-Ruiz O (September 1993). "Behavioral effects of neonatal treatment with clomipramine, scopolamine, and idazoxan in male rats". Pharmacology, Biochemistry, and Behavior 46 (1): 215–7. doi:10.1016/0091-3057(93)90343-R. PMID 7902983.
- Hansen HH, Sánchez C, Meier E (December 1997). "Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression?". The Journal of Pharmacology and Experimental Therapeutics 283 (3): 1333–41. PMID 9400008.
- Popa D, Léna C, Alexandre C, Adrien J (April 2008). "Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior". The Journal of Neuroscience 28 (14): 3546–54. doi:10.1523/JNEUROSCI.4006-07.2008. PMID 18385313.
- Maciag D, Simpson KL, Coppinger D, et al. (January 2006). "Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry". Neuropsychopharmacology 31 (1): 47–57. doi:10.1038/sj.npp.1300823. PMC 3118509. PMID 16012532.
- Maciag D, Williams L, Coppinger D, Paul IA (February 2006). "Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment". European Journal of Pharmacology 532 (3): 265–9. doi:10.1016/j.ejphar.2005.12.081. PMC 2921633. PMID 16483567.
- Holden C (October 2004). "Neuroscience. Prozac treatment of newborn mice raises anxiety". Science 306 (5697): 792. doi:10.1126/science.306.5697.792. PMID 15514122.
- Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (October 2004). "Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice". Science 306 (5697): 879–81. doi:10.1126/science.1101678. PMID 15514160.
- Ansorge MS, Morelli E, Gingrich JA (January 2008). "Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice". The Journal of Neuroscience 28 (1): 199–207. doi:10.1523/JNEUROSCI.3973-07.2008. PMID 18171937.
- Misri S, Reebye P, Kendrick K, et al. (June 2006). "Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications". The American Journal of Psychiatry 163 (6): 1026–32. doi:10.1176/appi.ajp.163.6.1026. PMID 16741203.
- Maciag D, Coppinger D, Paul IA (December 2006). "Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development". Brain Research 1125 (1): 171–5. doi:10.1016/j.brainres.2006.10.009. PMC 1762094. PMID 17101120.
- FDA.gov, FDA Public Health Advisory - Treatment Challenges of Depression in Pregnancy
- , Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Norgaard M, Stephansson O, Valdimarsdottir U, Zoega H, Haglund B." Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries" BMJ 2012;344:d8012
- Weinrieb, RM; Auriacombe, M; Lynch, KG; Lewis, JD (March 2005). "Selective serotonin re-uptake inhibitors and the risk of bleeding". Expert opinion on drug safety 4 (2): 337–44. doi:10.1517/147403126.96.36.1997. PMID 15794724.
- Taylor, D; Carol, P; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 9780470979693.
- Andrade, C; Sandarsh, S; Chethan, KB; Nagesh, KS (December 2010). "Serotonin Reuptake Inhibitor Antidepressants and Abnormal Bleeding: A Review for Clinicians and a Reconsideration of Mechanisms". The Journal of Clinical Psychiatry 71 (12): 1565–1575. doi:10.4088/JCP.09r05786blu. PMID 21190637.
- de Abajo, FJ; García-Rodríguez, LA (July 2008). "Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents". Archives of General Psychiatry 65 (7): 795–803. doi:10.1001/archpsyc.65.7.79. PMID 18606952.
- http://www.neurology.org/content/early/2012/10/17/WNL.0b013e318271f848.abstract Selective serotonin reuptake inhibitors and brain hemorrhage
- Serebruany VL (February 2006). "Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something?". The American Journal of Medicine 119 (2): 113–6. doi:10.1016/j.amjmed.2005.03.044. PMID 16443409.
- Halperin D, Reber G (2007). "Influence of antidepressants on hemostasis". Dialogues in Clinical Neuroscience 9 (1): 47–59. PMC 3181838. PMID 17506225.
- Isbister G, Bowe S, Dawson A, Whyte I (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J Toxicol Clin Toxicol 42 (3): 277–85. doi:10.1081/CLT-120037428. PMID 15362595.
- Borys D, Setzer S, Ling L, Reisdorf J, Day L, Krenzelok E (1992). "Acute fluoxetine overdose: a report of 234 cases". Am J Emerg Med 10 (2): 115–20. doi:10.1016/0735-6757(92)90041-U. PMID 1586402.
- Oström M, Eriksson A, Thorson J, Spigset O (1996). "Fatal overdose with citalopram". Lancet 348 (9023): 339–40. doi:10.1016/S0140-6736(05)64513-8. PMID 8709713.
- Sporer K (1995). "The serotonin syndrome. Implicated drugs, pathophysiology and management". Drug Saf 13 (2): 94–104. doi:10.2165/00002018-199513020-00004. PMID 7576268.
- White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.
- Ener, RA; Meglathery, SB; Decker, WAV; Gallagher, RM (March 2003). "Serotonin Syndrome and Other Serotonergic Disorders". Pain Medicine 4 (1): 63–74. doi:10.1046/j.1526-4637.2003.03005.x. PMID 12873279.
- Boyer, EW; Shannon, M (2005). "The serotonin syndrome". The New England Journal of Medicine 352 (11): 1112–1120. doi:10.1056/NEJMra041867. PMID 15784664.
- 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.
- Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill Professional. ISBN 978-0071624428.
- Ciraulo, DA; Shader, RI (2011). Pharmacotherapy of Depression (2nd ed.). Springer. p. 49. doi:10.1007/978-1-60327-435-7. ISBN 978-1-60327-435-7.
- Goodman, Louis S. (Louis Sanford); Brunton, Laurence L.; Chabner, Bruce.; Knollmann, Björn C. (2001). Goodman Gilman's pharmacological basis of therapeuti. New York: McGraw-Hill. pp. 459–461. ISBN 0-07-162442-2.
- Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print.
- Rasmussen-Torvik LJ, McAlpine DD (2007). "Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils". Depression and Anxiety 24 (5): 350–7. doi:10.1002/da.20251. PMID 17096399.
- Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF (October 2003). "Pharmacogenetics of antidepressant medication intolerance". The American Journal of Psychiatry 160 (10): 1830–5. doi:10.1176/appi.ajp.160.10.1830. PMID 14514498.
- Anderson IM (April 2000). "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability". Journal of Affective Disorders 58 (1): 19–36. doi:10.1016/S0165-0327(99)00092-0. PMID 10760555.
- Healy D, Aldred G (2005). Antidepressant drug use and the risk of suicide. International Review of Psychiatry 17, 163–172.
- 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.
- Lacasse JR, Leo J (December 2005). "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature". PLoS Medicine 2 (12): e392. doi:10.1371/journal.pmed.0020392. PMC 1277931. PMID 16268734.
- Moncrieff J, Cohen D (July 2006). "Do Antidepressants Cure or Create Abnormal Brain States?". PLoS Medicine 3 (7): e240. doi:10.1371/journal.pmed.0030240. PMC 1472553. PMID 16724872.
- Valenstein, Elliot S. (1998). Blaming the brain: the truth about drugs and mental health. New York: Free Press. ISBN 0-684-84964-X.[page needed]
- Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". The New England Journal of Medicine 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864.
- Deshauer D, Moher D, Fergusson D, Moher E, Sampson M, Grimshaw J (May 2008). "Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials". CMAJ 178 (10): 1293–301. doi:10.1503/cmaj.071068. PMC 2335186. PMID 18458261.
- Geddes JR, Carney SM, Davies C, et al. (February 2003). "Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review". Lancet 361 (9358): 653–61. doi:10.1016/S0140-6736(03)12599-8. PMID 12606176.
- Sadaka Associates. "SSRI Birth Defect Lawsuits On The Rise". Pharma Watchdog. Retrieved 19 February 2014.
- Nordqvist, Christian. "Zoloft No Better Than Dummy Pill, Says Lawsuit". Medical News Today. Retrieved 19 February 2014.
- PROZAC Product/Prescribing Information at Eli Lilly and Company
- Serotonin uptake inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)