SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed and may be outweighed by side effects.
Antidepressants are recommended by the UK National Institute for Health and Care 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.
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". The 2008 meta-analysis combined 35 clinical trials submitted to the 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. Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.
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 persistent depressive disorder and other forms of chronic mild depression.
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.
In 2014, the US 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.
A 2017 systematic review stated that "SSRIs versus placebo seem to have statistically significant effects on depressive symptoms, but the clinical significance of these effects seems questionable and all trials were at high risk of bias. Furthermore, SSRIs versus placebo significantly increase the risk of both serious and non-serious adverse events. Our results show that the harmful effects of SSRIs versus placebo for major depressive disorder seem to outweigh any potentially small beneficial effects". Fredrik Hieronymus et al. criticized the review as inaccurate and misleading.
In 2018, a review of 21 different antidepressants found that all analysed antidepressants were more efficacious than placebo in adults with major depressive disorder. Effect sizes measured at 8-weeks after treatment onset however were modest.
There does not appear to be a difference in effectiveness between medications in the second generation antidepressants (SSRIs and SNRIs).
In children, there are concerns around the quality of the evidence on the meaningfulness of benefits seen. If a medication is used, fluoxetine appears to be first line.
Social anxiety disorder
Some SSRIs are effective for social anxiety disorder, although their effects on symptoms is not always robust and their use is sometimes rejected in favor of psychological therapies. Paroxetine was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder, sertraline and fluvoxamine were later approved for it too, escitalopram and citalopram are used off label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder.
Post traumatic stress disorder
PTSD is relatively hard to treat and generally treatment is not highly effective, SSRIs are no exception. They are not very effective for this disorder and only two SSRI are FDA approved for this condition, paroxetine and sertraline. Paroxetine has slightly higher response and remission rates for PTSD than sertraline but both are not fully effective for many patients. Fluoxetine is used off label but with mixed results, venlafaxine, an SNRI, is considered somewhat effective, although used off label too. Fluvoxamine, escitalopram and citalopram are not well tested in this disorder. Paroxetine remains the most suitable drug for PTSD as of now, but with limited benefits.
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, and are superior to placebo in treating GAD. The efficacy of different antidepressants is similar.
In Canada, SSRIs are a first line treatment of adult obsessive–compulsive disorder (OCD). In the UK they are first line treatment only with moderate to severe functional impairment and as second line treatment for those with mild impairment, though, as of early 2019, this recommendation is being reviewed . In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. SSRIs, especially fluvoxamine, which is the first one to be FDA approved for OCD, are efficacious in its treatment; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo. 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.
Antidepressants 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.
Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.
Clinical trials have generated mostly negative results for the use of SSRIs 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 OCD.
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.
SSRIs are effective for the treatment of premature ejaculation. Chronic administration is more efficacious than on demand use.
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:
The mechanism by which SSRIs may cause sexual side effects is not well understood as of 2015[update]. The range of possible mechanisms includes (1) nonspecific neurological effects (e.g., sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function. Management strategies include: 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.
Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and a decrease in bone mineral density, as well as increased fracture risk, a relationship that appears to persist even with adjuvant bisphosphonate therapy. However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal. There also appears to be an increase in fracture-inducing falls with SSRI use, suggesting the need for increased attention to fall risk in elderly patients using the medication. The loss of bone density does not appear to occur in younger patients taking SSRIs.
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.
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. 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%. According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment. The National Institute for Health and Care Excellence (NICE) places the excess risk in the "early stages of treatment". 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 2014 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.
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.
It is unclear whether SSRIs affect the risk of suicidal behavior in 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.
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" appears to have led to a 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 suggest 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.
In 2016 a study criticized the effects of the FDA Black Box suicide warning inclusion in the prescription. The authors discussed the suicide rates might increase also as a consequence of the warning.
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. 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. Use is also associated preterm birth.
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. A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that just missed statistical significance. 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. Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.
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
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.
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. 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.". A review published in 2012 reached conclusions very similar to those of the 2014 study.
Neuropsychiatric effects in offspring
According to a 2015 review available data found that "some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs (autism spectrum disorders)" even though a large cohort study published in 2013 and a cohort study using data from Finland's national register between the years 1996 and 2010 and published in 2016 found no significant association between SSRI use and autism in offspring. The 2016 Finland study also found no association with ADHD, but did find an association with increased rates of depression diagnoses in early adolescence.
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.
In adults and children suffering from bipolar disorder, SSRIs may cause a bipolar switch from depression into hypomania/mania. When taken with mood stabilizers, the risk of switching is not increased, however when taking SSRI's as a monotherapy, the risk of switching may be twice or three times that of the average . The changes are not often easy to detect and require monitoring by family and mental health professionals. This switch might happen even with no prior (hypo)manic episodes and might therefore not be foreseen by the psychiatrist.
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.
Another important interaction of certain SSRIs involves paroxetine, a potent inhibitor of CYP2D6, and tamoxifen, an agent used commonly in the treatment and prevention of breast cancer. Tamoxifen is a prodrug that is metabolised by the hepatic cytochrome P450 enzyme system, especially CYP2D6, to its active metabolites. Concomitant use of paroxetine and tamoxifen in women with breast cancer is associated with a higher risk of death, as much as a 91 percent in women who used it the longest.
Although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) are in fact relatively selective as serotonin reuptake inhibitors (SRIs). They are about at least 10-fold selective for inhibition of serotonin reuptake over norepinephrine reuptake. The selectivity ratios are approximately 1:30 for venlafaxine, 1:9 for duloxetine, and 1:14 for desvenlafaxine. At low doses, these SNRIs act mostly as SSRIs; only at higher doses do they also prominently inhibit norepinephrine reuptake.Milnacipran (Ixel, Savella) and its stereoisomerlevomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1.
In the brain, messages are passed from a nerve cell to another 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 signaling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-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 downregulation 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.
Sigma receptor ligands
SSRIs at the human SERT and rat sigma receptors
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors.Fluvoxamine is an agonist of the σ1 receptor, while sertraline is an antagonist of the σ1 receptor, and paroxetine does not significantly interact with the σ1 receptor. None of the SSRIs have significant affinity for the σ2 receptor, and the SNRIs, unlike the SSRIs, do not interact with either of the sigma receptors. Fluvoxamine has by far the strongest activity of the SSRIs at the σ1 receptor. High occupancy of the σ1 receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. It is thought that agonism of the σ1 receptor by fluvoxamine may have beneficial effects on cognition. In contrast to fluvoxamine, the relevance of the σ1 receptor in the actions of the other SSRIs is uncertain and questionable due to their very low affinity for the receptor relative to the SERT.
The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients. This link has led scientists to investigate the effects of antidepressants on the immune system.
SSRIs were originally invented with the goal of increasing levels of available serotonin in the extracellular spaces. However, the delayed response between when patients first begin SSRI treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs. To investigate the apparent anti-inflammatory effects of SSRIs, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased. A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking SSRIs compared to non-medicated patients.
Treatment with SSRIs has shown reduced production of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response. These inflammatory cytokines have been shown to activate microglia which are specialized macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defense in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation. SSRIs inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages. SSRIs not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response.
In addition to affecting cytokine production, there is evidence that treatment with SSRIs has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that SSRIs can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation. SSRIs can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of SSRIs is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK and Notch signaling pathway.
The anti-inflammatory effects of SSRIs have prompted studies of the efficacy of SSRIs in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an SSRI, has also shown efficacy in animal models of graft vs. host disease. SSRIs have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory 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.
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. 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.
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. Furthermore, an investigation of 185 meta-analyses on antidepressants found that 79% of them had authors affiliated in some way to pharmaceutical companies and that they were also reluctant to reporting caveats for antidepressants.
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. At the time these warnings were added, others argued that the evidence for harm remained unpersuasive and others continued to do so after the warnings were added.
^Medford N, Sierra M, Baker D, David AS (2005). "Understanding and treating depersonalisation disorder". Advances in Psychiatric Treatment. 11 (2): 92–100. doi:10.1192/apt.11.2.92.
^ abNational Collaborating Centre for Mental Health (October 2009). "Depression Quick Reference Guide"(PDF). NICE clinical guidelines 90 and 91. The National Institute for Health and Care Excellence (NICE). Archived from the original(PDF) on September 28, 2013.
^Fountoulakis KN, Möller HJ (August 2010). "Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data". The International Journal of Neuropsychopharmacology. 14 (3): 405–412. doi:10.1017/S1461145710000957. PMID20800012.
^Hieronymus F, Lisinski A, Näslund J, Eriksson E (July 2017). "Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective". Acta Neuropsychiatrica. 30 (5): 244–250. doi:10.1017/neu.2017.23. PMID28718394.
^Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, Mager U, Thieda P, Gaynes BN, Wilkins T, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN (December 2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis". Annals of Internal Medicine. 155 (11): 772–85. doi:10.7326/0003-4819-155-11-201112060-00009. PMID22147715.
^Flament MF, Bissada H, Spettigue W (March 2012). "Evidence-based pharmacotherapy of eating disorders". The International Journal of Neuropsychopharmacology. 15 (2): 189–207. doi:10.1017/S1461145711000381. PMID21414249.
^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". Osteoporosis International. 23 (1): 365–75. doi:10.1007/s00198-011-1778-8. PMID21904950.
^Stahl SM, Lonnen AJ (2011). "The Mechanism of Drug-induced Akathsia". CNS Spectrums. PMID21406165.
^ abBahrick AS (2008). "Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence". The Open Psychology Journal. 1: 42–50. doi:10.2174/1874350100801010042.
^Gitlin MJ (September 1994). "Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches". The Journal of Clinical Psychiatry. 55 (9): 406–13. PMID7929021.
^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. PMID12429073.
^Koyuncu H, Serefoglu EC, Ozdemir AT, Hellstrom WJ (September 2012). "Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation". International Journal of Impotence Research. 24 (5): 171–3. doi:10.1038/ijir.2012.12. PMID22573230.
^Podolej GS, Babcock C (January 2017). "Emergency Department Management Of Priapism". Emergency Medicine Practice. 19 (1): 1–16. PMID28027457.
^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. PMID10213794.
^ abWeinrieb 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:10.1517/14740322.214.171.1247. PMID15794724.
^ abTaylor D, Carol P, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN9780470979693.
^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. PMID21190637.
^ abde 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.65.7.795. PMID18606952.
^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. PMID16443409.
^Andrade C, Sandarsh S, Chethan KB, Nagesh KS (2010). "Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms". The Journal of Clinical Psychiatry. 71 (12): 1565–75. doi:10.4088/JCP.09r05786blu. PMID21190637.
^de Abajo FJ (2011). "Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients". Drugs & Aging. 28 (5): 345–67. doi:10.2165/11589340-000000000-00000. PMID21542658.
^Eom CS, Lee HK, Ye S, Park SM, Cho KH (May 2012). "Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis". Journal of Bone and Mineral Research. 27 (5): 1186–95. doi:10.1002/jbmr.1554. PMID22258738.
^Fernandes BS, Hodge JM, Pasco JA, Berk M, Williams LJ (January 2016). "Effects of Depression and Serotonergic Antidepressants on Bone: Mechanisms and Implications for the Treatment of Depression". Drugs & Aging. 33 (1): 21–5. doi:10.1007/s40266-015-0323-4. PMID26547857.
^Nyandege AN, Slattum PW, Harpe SE (April 2015). "Risk of fracture and the concomitant use of bisphosphonates with osteoporosis-inducing medications". The Annals of Pharmacotherapy. 49 (4): 437–47. doi:10.1177/1060028015569594. PMID25667198.
^Winterhalder L, Eser P, Widmer J, Villiger PM, Aeberli D (December 2012). "Changes in volumetric BMD of radius and tibia upon antidepressant drug administration in young depressive patients". Journal of Musculoskeletal & Neuronal Interactions. 12 (4): 224–9. PMID23196265.
^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. PMID16894062.
^ abCox GR, Callahan P, Churchill R, Hunot V, Merry SN, Parker AG, Hetrick SE (November 2014). "Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents". The Cochrane Database of Systematic Reviews (11): CD008324. doi:10.1002/14651858.CD008324.pub3. PMID25433518.
^Tauscher-Wisniewski S, Nilsson M, Caldwell C, Plewes J, Allen AJ (October 2007). "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. 17 (5): 713–8. doi:10.1089/cap.2006.0138. PMID17979590.
^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. PMID17074941.
^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". Journal of Affective Disorders. 94 (1–3): 3–13. doi:10.1016/j.jad.2006.04.003. PMID16712945.
^Hall WD, Lucke J (2006). "How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?". The Australian and New Zealand Journal of Psychiatry. 40 (11–12): 941–50. doi:10.1111/j.1440-1614.2006.01917.x. PMID17054562.
^Martínez-Aguayo JC, Arancibia M, Concha S, Madrid E (2016). "Ten years after the FDA black box warning for antidepressant drugs: A critical narrative review". Archives of Clinical Psychiatry. 43 (3): 60–66. doi:10.1590/0101-60830000000086.
^Eke AC, Saccone G, Berghella V (November 2016). "Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis". BJOG. 123 (12): 1900–1907. doi:10.1111/1471-0528.14144. PMID27239775.
^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. 19 (2): e334–48. PMID22946124.
^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. 35 (4): 362–9. doi:10.1016/S1701-2163(15)30965-8. PMID23660045.
^Koren G, Nordeng HM (February 2013). "Selective serotonin reuptake inhibitors and malformations: case closed?". Seminars in Fetal & Neonatal Medicine. 18 (1): 19–22. doi:10.1016/j.siny.2012.10.004. PMID23228547.
^'t Jong GW, Einarson T, Koren G, Einarson A (November 2012). "Antidepressant use in pregnancy and persistent pulmonary hypertension of the newborn (PPHN): a systematic review". Reproductive Toxicology. 34 (3): 293–7. doi:10.1016/j.reprotox.2012.04.015. PMID22564982.
^Gentile S (August 2015). "Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods?". Journal of Affective Disorders. 182: 132–7. doi:10.1016/j.jad.2015.04.048. PMID25985383.
^Hviid A, Melbye M, Pasternak B (December 2013). "Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism". The New England Journal of Medicine. 369 (25): 2406–15. doi:10.1056/NEJMoa1301449. PMID24350950.
^ abcIsbister GK, Bowe SJ, Dawson A, Whyte IM (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". Journal of Toxicology. Clinical Toxicology. 42 (3): 277–85. doi:10.1081/CLT-120037428. PMID15362595.
^Borys DJ, Setzer SC, Ling LJ, Reisdorf JJ, Day LC, Krenzelok EP (1992). "Acute fluoxetine overdose: a report of 234 cases". The American Journal of Emergency Medicine. 10 (2): 115–20. doi:10.1016/0735-6757(92)90041-U. PMID1586402.
^Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K (1996). "Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine". European Journal of Clinical Pharmacology. 51 (1): 73–8. doi:10.1007/s002280050163. PMID8880055.
^ abMandrioli R, Protti M, Mercolini L (2017). "New-Generation, non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs". Current Medicinal Chemistry. 24 (7): 772–792. doi:10.2174/0929867324666170712165042. PMID28707591.
^ abMoltzen EK, Bang-Andersen B (2006). "Serotonin reuptake inhibitors: the corner stone in treatment of depression for half a century—a medicinal chemistry survey". Current Topics in Medicinal Chemistry. 6 (17): 1801–23. doi:10.2174/156802606778249810. PMID17017959.
^Goodman LS, Brunton LL, Chabner B, Knollmann BC (2001). Goodman and Gilman's pharmacological basis of therapeutics. New York: McGraw-Hill. pp. 459–461. ISBN978-0-07-162442-8.
^ abKolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print.
^ abcdefgHindmarch I, Hashimoto K (April 2010). "Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered". Human Psychopharmacology. 25 (3): 193–200. doi:10.1002/hup.1106. PMID20373470.
^Köhler S, Cierpinsky K, Kronenberg G, Adli M (January 2016). "The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants". Journal of Psychopharmacology. 30 (1): 13–22. doi:10.1177/0269881115609072. PMID26464458.
^Więdłocha M, Marcinowicz P, Krupa R, Janoska-Jaździk M, Janus M, Dębowska W, Mosiołek A, Waszkiewicz N, Szulc A (January 2018). "Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 80 (Pt C): 217–226. doi:10.1016/j.pnpbp.2017.04.026. PMID28445690.
^ abNazimek K, Strobel S, Bryniarski P, Kozlowski M, Filipczak-Bryniarska I, Bryniarski K (June 2017). "The role of macrophages in anti-inflammatory activity of antidepressant drugs". Immunobiology. 222 (6): 823–830. doi:10.1016/j.imbio.2016.07.001. PMID27453459.
^ abGobin V, Van Steendam K, Denys D, Deforce D (May 2014). "Selective serotonin reuptake inhibitors as a novel class of immunosuppressants". International Immunopharmacology. 20 (1): 148–56. doi:10.1016/j.intimp.2014.02.030. PMID24613205.
^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. PMID17096399.
^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. PMID10760555.
^Ebrahim S, Bance S, Athale A, Malachowski C, Ioannidis JP (February 2016). "Meta-analyses with industry involvement are massively published and report no caveats for antidepressants". Journal of Clinical Epidemiology. 70: 155–63. doi:10.1016/j.jclinepi.2015.08.021. PMID26399904.
^Khan A, Khan S, Kolts R, Brown WA (April 2003). "Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports". The American Journal of Psychiatry. 160 (4): 790–2. doi:10.1176/appi.ajp.160.4.790. PMID12668373.
^Kaizar EE, Greenhouse JB, Seltman H, Kelleher K (2006). "Do antidepressants cause suicidality in children? A Bayesian meta-analysis". Clinical Trials. 3 (2): 73–90, discussion 91–8. doi:10.1191/1740774506cn139oa. PMID16773951.