Selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitors (SSRIs) are a

SSRIs are the most widely prescribed antidepressants in many countries.[3] The efficacy of SSRIs in mild or moderate cases of depression has been disputed^[4] and may or may not be outweighed by side effects, especially in adolescent populations.^[5][6][7][8]

Medical uses

The main indication for SSRIs is

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.^[10] They recommend against their routine use by those who have chronic health problems and mild depression.^[10]

There has been controversy regarding the efficacy of SSRIs 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".^[6][11] 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.^[11] Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.^[12][13]
• 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; some of the authors however disclosed substantial relationships with pharmaceutical industries.^[14]
• 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".^[8] Fredrik Hieronymus et al. criticized the review as inaccurate and misleading, but they also disclosed multiple ties to pharmaceutical industries and receipt of speaker's fees.^[15]
• In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective. They showed that "In terms of efficacy, all antidepressants were more effective than placebo, with odds ratios (ORs) ranging between 2.13 (95% credible interval [CrI] 1.89–2.41) for amitriptyline and 1.37 (1.16–1.63) for reboxetine."^[16]

The use of SSRIs in children with depression remains controversial. A 2021 Cochrane review concluded that, for children and adolescents, SSRIs "may reduce depression symptoms in a small and unimportant way compared with placebo."^[17] However, it also noted significant methodological limitations that make drawing definitive conclusions about efficacy difficult. Fluoxetine is the only SSRI authorized for use in children and adolescents with moderate to severe depression in the United Kingdom.^[18]

Social anxiety disorder

Some SSRIs are effective for

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,^[22] and are superior to placebo in treating GAD. The efficacy of different antidepressants is similar.^[22]

Obsessive–compulsive disorder

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.^[23] In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects.^[24] 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.^[25][26] 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.^[27][28][29]

Panic disorder

Paroxetine CR was superior to placebo on the primary outcome measure. In a 10-week randomized controlled, double-blind trial escitalopram was more effective than placebo.^[30] Fluvoxamine, another SSRI, has shown positive results.^[31] However, evidence for their effectiveness and acceptability is unclear.^[32]

Eating disorders

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.^[33] 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.^[33] SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.^[34]

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa.^[35] Treatment guidelines from the National Institute of Health and Clinical Excellence^[33] 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 depression, anxiety, or OCD.^[34]

Stroke recovery

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2021 meta-analysis of randomized controlled clinical trials found no evidence pointing to their routine use to promote recovery following stroke.^[36]

Premature ejaculation

SSRIs are effective for the treatment of premature ejaculation. Taking SSRIs on a chronic, daily basis is more effective than taking them prior to sexual activity.^[37] The increased efficacy of treatment when taking SSRIs on a daily basis is consistent with clinical observations that the therapeutic effects of SSRIs generally take several weeks to emerge.^[38] Sexual dysfunction ranging from decreased libido to anorgasmia is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs.^[39] However, for those with premature ejaculation, this very same side effect becomes the desired effect.

Other uses

SSRIs such as sertraline have been found to be effective in decreasing anger.^[40]

Side effects

Side effects vary among the individual drugs of this class. They may include akathisia.^{[41][42][43][44]}

Sexual dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm).^[45] Sexual problems are common with SSRIs.^[46] Poor sexual function is one of the most common reasons people stop the medication.^[47]

The mechanism by which SSRIs may cause sexual side effects is not well understood as of 2021^[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.^[48] 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.^[49]

A number of non-SSRI drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine, tranylcypromine and moclobemide^[50][51][52]).

Several studies have suggested that SSRIs may adversely affect semen quality.^[53]

While

Post-SSRI sexual dysfunction (PSSD)[55]^[56] refers to a set of symptoms reported by some people who have taken SSRIs or other serotonin reuptake-inhibiting (SRI) drugs, in which sexual dysfunction symptoms persist for at least three months^[57][58][59] after ceasing to take the drug. The status of PSSD as a legitimate and distinct pathology is contentious; several researchers have proposed that it should be recognized as a separate phenomenon from more common SSRI side effects.^[60]

The reported symptoms of PSSD include reduced

Diagnostic criteria for PSSD were proposed in 2022,[57] but as of 2023, there is no agreement on standards for diagnosis.^[56] It is considered a distinct phenomenon from antidepressant discontinuation syndrome, post-acute withdrawal syndrome, and major depressive disorder,^[61][60] and should be distinguished from sexual dysfunction associated with depression^[61] and persistent genital arousal disorder.^[56] There are limited treatment options for PSSD as of 2023 and no evidence that any individual approach is effective.^[56] The mechanism by which SRIs may induce PSSD is unclear;^[61] neurobiological and cognitive factors may act in combination to cause the problem.^[56] As of 2023, prevalence is unknown.^[56] A 2020 review stated that PSSD is rare, underreported, and "increasingly identified in online communities".^[63]

Reports of PSSD have occurred with almost every SSRI (

Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed.^[71][72]

Cardiac

SSRIs do not appear to affect the risk of

SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven hemostasis.[83] SSRIs interact with

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,[92]^[93][94][95] a relationship that appears to persist even with adjuvant bisphosphonate therapy.^[96] However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal.^[97] 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.^[97] The loss of bone density does not appear to occur in younger patients taking SSRIs.^[98]

Bruxism

Serotonin syndrome is typically caused by the use of two or more

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.[114] 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.^[115]

In 2004, the

• 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.[118]
• A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to
  tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.^[119]
• 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.[120]
• A 2006 meta-analysis of randomized 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.^[121]
• 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.^[106]
• 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.^[122]

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.[124] 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.^[125][126] Use is also associated with preterm birth.^[127] According to some researches, decreased body weight of the child, intrauterine growth retardation, neonatal adaptive syndrome, and persistent pulmonary hypertension also was noted.^[128]

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.^{[129] [130]} 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.^[131] Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies.^[126]

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.^{[132][133][134]}

Neonatal abstinence syndrome

Several studies have documented

The following drugs may precipitate serotonin syndrome in people on SSRIs:^[146][147]

• Linezolid
• Monoamine oxidase inhibitors (MAOIs) including moclobemide, phenelzine, tranylcypromine, selegiline and methylene blue
• Lithium
• Sibutramine
• MDMA (ecstasy)
• Dextromethorphan
• Tramadol
• 5-HTP
• Pethidine/meperidine
• St. John's wort
• Yohimbe
• Tricyclic antidepressants
  (TCAs)
• Serotonin-norepinephrine reuptake inhibitors
  (SNRIs)
• Buspirone
• Triptan
• Mirtazapine
• Methylene blue

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use.^{[85][87][148]} NSAIDs include:

• Aspirin
• Ibuprofen (Advil, Nurofen)
• Naproxen (Aleve)

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.^{[149][150][151]}

Legend:
0 – no inhibition
+ – mild inhibition
++ – moderate inhibition
+++ – strong inhibition

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine^[152] and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors.^[153][154] The concomitant use of some SSRIs (paroxetine and fluoxetine) with codeine may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy.^[155][156]

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.^[157]

Overdose

SSRIs appear safer in

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.^[161] Other reported significant effects include coma, seizures, and cardiac toxicity.^[158]

Poisoning is also known in animals, and some toxicity information is available for veterinary treatment.^[162]

Discontinuation syndrome

Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, paresthesias, insomnia, and

Their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects.[167] SSRIs mediate their action largely with high occupancy in a total of all serotonin transporters within the brain and through this slow downstream changes of large brain regions at therapeutic concentrations, whereas MDMA leads to an excess serotonin release in a short run. This could explain the absence of a "high" by antidepressants and in addition the contrary ability of SSRIs in expressing neuroprotective actions to the neurotoxic abilities of MDMA.^[168]

Sigma receptor ligands

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors.^[169][170] 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.^[169][170] None of the SSRIs have significant affinity for the σ₂ receptor.^[169][170] Fluvoxamine has by far the strongest activity of the SSRIs at the σ₁ receptor.^[169][170] High occupancy of the σ₁ receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research.^[169][170] It is thought that agonism of the σ₁ receptor by fluvoxamine may have beneficial effects on cognition.^[169][170] 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.^[171]

Anti-inflammatory effects

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

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.[173] 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.^[174][175] 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.^[176]

Treatment with SSRIs has shown reduced production of inflammatory cytokines such as

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.^[181]

Versus TCAs

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

There appears to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.^[182] 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 cyclic adenosine monophosphate (cAMP) 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.^[166]

List of SSRIs

Marketed

Antidepressants

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)

Structures

Citalopram	Escitalopram	Fluoxetine	Fluvoxamine	Paroxetine	Sertraline

Others

• Dapoxetine (Priligy)

Structures

Dapoxetine

Discontinued

Antidepressants

• Indalpine (Upstène)
• Zimelidine (Zelmid)

Structures

Indalpine	Zimelidine

Never marketed

Antidepressants

• Alaproclate (GEA-654)
• Centpropazine
• Cericlamine (JO-1017)
• Femoxetine (Malexil; FG-4963)
• Ifoxetine (CGP-15210)
• Omiloxetine
• Panuramine (WY-26002)
• Pirandamine (AY-23713)
• Seproxetine ((S)-norfluoxetine)

Structures

Alaproclate	Cericlamine	Femoxetine	Ifoxetine	Omiloxetine	Panuramine	Pirandamine	Seproxetine

Related drugs

Although described as

Fluoxetine was introduced in 1987 and was the first major SSRI to be marketed.

Controversy

A study examining publication of results from FDA-evaluated antidepressants concluded that those with favorable results were much more likely to be published than those with negative results.^[193] 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 reluctant to report caveats for antidepressants.^[194]

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.^[195] At the time these warnings were added, others argued that the evidence for harm remained unpersuasive^[196][197] and others continued to do so after the warnings were added.^[198][199]

In other organisms

SSRIs are common

An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety.^[201]

See also

• List of antidepressants
• Serotonin releasing agent (SRA)
• Serotonin–norepinephrine reuptake inhibitor (SNRI)
• Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)
• Dapoxetine

References