Selective Serotonin Reuptake Inhibitor
   HOME

TheInfoList



OR:

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
s in the treatment of
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
,
anxiety disorder Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, and other psychological conditions. SSRIs increase the
extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
level of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
serotonin by limiting its
reabsorption In renal physiology, reabsorption or tubular reabsorption is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption'' (and not ''absorp ...
(reuptake) into the presynaptic cell. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having strong affinity for the
serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein th ...
and only weak affinity for the
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
and dopamine transporters. 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 or may not be outweighed by side effects, especially in adolescent populations.


Medical uses

The main indication for SSRIs is
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
; however, they are frequently prescribed for
anxiety disorder Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, such as
social anxiety disorder Social anxiety disorder (SAD), also known as social phobia, is an anxiety disorder characterized by sentiments of fear and anxiety in social situations, causing considerable distress and impaired ability to function in at least some aspects ...
,
generalized anxiety disorder Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functio ...
,
panic disorder Panic disorder is a mental and behavioral disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, ...
,
obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental and behavioral disorder in which an individual has intrusive thoughts and/or feels the need to perform certain routines repeatedly to the extent where it induces distress or impairs general ...
(OCD),
eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's physical or mental health. Only one eating disorder can be diagnosed at a given time. Types of eating disorders include binge eating ...
s,
chronic pain Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between acute and chronic pain is sometimes determined by the amount of time since onset. Two commonly used markers are pain that continues ...
, and, in some cases, for
posttraumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on ...
(PTSD). They are also frequently used to treat
depersonalization disorder Depersonalization-derealization disorder (DPDR, DPD) is a mental disorder in which the person has persistent or recurrent feelings of depersonalization or derealization. Depersonalization is described as feeling disconnected or detached from on ...
, although with varying results.


Depression

Antidepressants are recommended by the UK
National Institute for Health and Care Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas: * the use of health technologies withi ...
(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 Cognitive therapy (CT) is a type of psychotherapy developed by American psychiatrist Aaron T. Beck. CT is one therapeutic approach within the larger group of cognitive behavioral therapies (CBT) and was first expounded by Beck in the 1960s. Co ...
. They recommend against their routine use by those who have chronic health problems and mild depression. 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". The 2008 meta-analysis combined 35 clinical trials submitted to the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) before licensing of four newer antidepressants (including the SSRIs
paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
and
fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
, the non-SSRI antidepressant
nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it fro ...
, and the serotonin and norepinephrine reuptake inhibitor (SNRI)
venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
). 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 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. * 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, but they also disclosed multiple ties to pharmaceutical industries and receipt of speaker's fees. 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. In children, there are concerns around the quality of the evidence on the meaningfulness of benefits seen. If a medication is used,
fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
appears to be first line.


Social anxiety disorder

Some SSRIs are effective for
social anxiety Social anxiety is the anxiety and fear specifically linked to being in social settings (i.e., interacting with others). Some categories of disorders associated with social anxiety include anxiety disorders, mood disorders, autism spectrum diso ...
disorder, although their effects on symptoms is not always robust and their use is sometimes rejected in favor of psychological therapies.
Paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder,
sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
and fluvoxamine were later approved for it, too,
escitalopram Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...
and
citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soc ...
are used off label with acceptable efficacy, while
fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
is not considered to be effective for this disorder.


Post-traumatic stress disorder

PTSD Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a ...
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 Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functio ...
(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.


Obsessive–compulsive disorder

In Canada, SSRIs are a first-line treatment of adult
obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental and behavioral disorder in which an individual has intrusive thoughts and/or feels the need to perform certain routines repeatedly to the extent where it induces distress or impairs general ...
(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.


Panic disorder

Paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
CR was superior to placebo on the primary outcome measure. In a 10-wk randomized controlled, double-blind trial
escitalopram Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...
was more effective than placebo. Fluvoxamine, another SSRI, has shown positive results. However, evidence for their effectiveness and acceptability is unclear.


Eating disorders

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of
bulimia nervosa Bulimia nervosa, also known as simply bulimia, is an eating disorder characterized by binge eating followed by purging or fasting, and excessive concern with body shape and weight. The aim of this activity is to expel the body of calories eaten ...
. 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 Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFED, ...
. 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 Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by underweight, low weight, Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thi ...
. 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.


Stroke recovery

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2019 meta-analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety but the studies had a high risk of bias. No reliable evidence points to their routine use to promote recovery following stroke. Thrombosis risk is reduced because SSRIs limit serotonin availability to platelets, so benefits, such as stroke recovery, of reduced clotting go up, with SSRIs.


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. 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.
Sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
ranging from decreased libido to
anorgasmia Anorgasmia is a type of sexual dysfunction in which a person cannot achieve orgasm despite adequate stimulation. Anorgasmia is far more common in females (4.6 percent) than in males and is especially rare in younger men. The problem is greater in ...
is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs. 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 Anger, also known as wrath or rage, is an intense emotional state involving a strong uncomfortable and non-cooperative response to a perceived provocation, hurt or threat. A person experiencing anger will often experience physical effects, suc ...
.


Side effects

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s vary among the individual drugs of this class and may include: * increased risk of
bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...
s *
akathisia Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...
*
suicidal ideation Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
(thoughts of
suicide Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
) and other risks (see below)


Sexual dysfunction

SSRIs can cause various types of
sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
such as
anorgasmia Anorgasmia is a type of sexual dysfunction in which a person cannot achieve orgasm despite adequate stimulation. Anorgasmia is far more common in females (4.6 percent) than in males and is especially rare in younger men. The problem is greater in ...
,
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of ma ...
, diminished
libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act ...
, genital numbness, and
sexual anhedonia Sexual anhedonia, also known as pleasure dissociative orgasmic disorder, is a condition in which an individual cannot feel pleasure (see anhedonia) from an orgasm. It is thought to be a variant of hypoactive sexual desire disorder. Overview No ...
(pleasureless orgasm). Sexual problems are common with SSRIs. While initial trials showed side effects in 5-15% of users (based on spontaneous reporting by users), later studies (based on asking patients directly) have shown side effect rates from 36% to 98%. Poor sexual function is also one of the most common reasons people stop the medication. In some cases, symptoms of sexual dysfunction may persist after discontinuation of SSRIs. This combination of symptoms is sometimes referred to as Post-SSRI Sexual Dysfunction (PSSD). On the 11th of June 2019 the
Pharmacovigilance Risk Assessment Committee The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
of the European Medicines Agency concluded that a possible relationship exists between SSRI use and persistent sexual dysfunction after cessation of use. The committee concluded that a warning should be added to the label of SSRIs and SNRIs regarding this possible risk. The mechanism by which SSRIs may cause sexual side effects is not well understood . 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 Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
; and for overall sexual dysfunction, switching to
nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it fro ...
. A number of non-SSRI drugs are not associated with sexual side effects (such as
bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
,
mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is ...
,
tianeptine Tianeptine, sold under the brand names Stablon and Coaxil among others, is an atypical antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel ...
,
agomelatine Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other ...
and moclobemide). Several studies have suggested that SSRIs may adversely affect semen quality. While trazodone (an antidepressant with
alpha adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
blockade) is a notorious cause of priapism, cases of priapism have also been reported with certain SSRIs (e.g. fluoxetine, citalopram).


Emotional blunting

Certain antidepressants may cause emotional blunting, characterized by reduced intensity of both positive and negative emotions as well as symptoms of
apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of inter ...
, indifference, and
amotivation Amotivational syndrome is a chronic psychiatric disorder characterized by signs that are linked to cognitive and emotional states such as detachment, blunted emotion and drives, executive functions like memory and attention, disinterest, passivi ...
. It may be experienced as either beneficial or detrimental depending on the situation. This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs, but may be less with atypical antidepressants like
bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
,
agomelatine Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other ...
, and
vortioxetine Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. It is taken by mouth. Common side e ...
. Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses. It can be decreased by reducing dosage, discontinuing the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.


Violence

Researcher David Healy and others have reviewed available data, concluding that SSRIs increase violent acts, in adults and children, both on therapy and during withdrawal. This view is also shared by some patient activist groups.


Vision

Acute narrow-angle
glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye re ...
is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed.


Cardiac

SSRIs do not appear to affect the risk of
coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves Ischemia, the reduction of blood flow to the myocardium, heart muscle due to build-up o ...
(CHD) in those without a previous diagnosis of CHD. A large cohort study suggested no substantial increase in the risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy. A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use. The recommended maximum daily dose of
citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soc ...
and
escitalopram Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...
was reduced due to concerns with QT prolongation. In overdose, fluoxetine has been reported to cause
sinus tachycardia Sinus tachycardia is an elevated sinus rhythm characterized by an increase in the rate of electrical impulses arising from the sinoatrial node. In adults, sinus tachycardia is defined as a heart rate greater than 100 beats per minute (bpm). Th ...
,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ...
, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRIs.


Bleeding

SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven hemostasis. SSRIs interact with
anticoagulants Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they ...
, like
warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent ...
, and antiplatelet drugs, like
aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...
. This includes an increased risk of GI bleeding, and post operative bleeding. The relative risk of intracranial bleeding is increased, but the absolute risk is very low. SSRIs are known to cause platelet dysfunction. This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure.


Fracture risk

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 Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
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.


Bruxism

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extrace ...
and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching.


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 brain zaps. 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.


Serotonin syndrome

Serotonin syndrome is typically caused by the use of two or more
serotonergic Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...
drugs, including SSRIs.
Serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
is a condition that can range from mild (most common) to deadly. Mild symptoms may consist of increased heart rate,
fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
, shivering,
sweating Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distri ...
,
dilated pupil Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, as ...
s,
myoclonus Myoclonus is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus (myo "muscle", clonic "jerk") describes a medical sign and, generally, i ...
(intermittent jerking or twitching), as well as
hyperreflexia Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate upper disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by highe ...
. Concomitant use of SSRIs or SNRIs for depression with a triptan for
migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few ho ...
does not appear to heighten the risk of the serotonin syndrome. Taking
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, esp ...
s (MAOIs) in combination with SSRIs can be fatal, since MAOIs disrupt
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fir ...
, an enzyme which is needed to break down serotonin and other neurotransmitters. Without monoamine oxidase, the body is unable to eliminate excess neurotransmitters, allowing them to build up to dangerous levels. The prognosis for recovery in a hospital setting is generally good if serotonin syndrome is correctly identified. Treatment consists of discontinuing any serotonergic drugs and providing supportive care to manage agitation and
hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
, usually with
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s.


Suicide risk


Children and adolescents

Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents. For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s on children with
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
found statistically significant increases of the risks of "possible
suicidal ideation Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
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
correlation In statistics, correlation or dependence is any statistical relationship, whether causal or not, between two random variables or bivariate data. Although in the broadest sense, "correlation" may indicate any type of association, in statisti ...
al, the true nature of the relationship is unclear. In 2004, the
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptabl ...
(MHRA) in the
United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...
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 Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
(Zoloft) and fluvoxamine (Luvox), and only for the treatment of
obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental and behavioral disorder in which an individual has intrusive thoughts and/or feels the need to perform certain routines repeatedly to the extent where it induces distress or impairs general ...
. Fluoxetine is not licensed for this use.


Adults

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 A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
and compared to therapeutic interventions other than
tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
. 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 ''Suicide Risk'' was an ongoing comic book series that ran for 25 issues from 2013 until 2015. It was written by Mike Carey and drawn by Elena Casagrande Elena may refer to: People * Elena (given name), including a list of people and charact ...
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.


Risk of death

A 2017
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
found that antidepressants including SSRIs were associated with significantly increased risk of death (+33%) and new
cardiovascular complication Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina pectoris, angina and myocardial infarction (commonly known as a heart attack). Other CVDs in ...
s (+14%) in the general population. Conversely, risks were not greater in people with existing
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
.


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 with
preterm birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...
. 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. 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 vessel Blood vessels are the structures of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from ...
s 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 Health care or healthcare is the improvement of health via the prevention, diagnosis, treatment, amelioration or cure of disease, illness, injury, and other physical and mental impairments in people. Health care is delivered by health pr ...
. 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 Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
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.


Overdose

SSRIs appear safer in
overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.
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 syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Other reported significant effects include
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
,
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
s, and cardiac toxicity. Poisoning is also known in animals, and some toxicity information is available for veterinary treatment.


Bipolar switch

In adults and children with
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, SSRIs may cause a bipolar switch from depression into
hypomania Hypomania (literally "under mania" or "less than mania") is a mental and behavioural disorder, characterised essentially by an apparently non-contextual elevation of mood (euphoria) that contributes to persistently disinhibited behaviour. The in ...
/
mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...
. 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.


Interactions

The following drugs may precipitate
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
in people on SSRIs: *
Linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vanco ...
*
Monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...
(MAOIs) including moclobemide,
phenelzine Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is primarily used as an antidepressant and anxiolytic. Along with tranylcypromine and ...
,
tranylcypromine Tranylcypromine, sold under the brand name Parnate among others,Drugs.co Page accessed April 17, 2016 is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme mono ...
,
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
and
methylene blue Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. Methylene blue is a thiazine dye. As a medication, it is mainly used to treat methemoglobinemia by converting the ferric iron in hemoglob ...
*
Lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...
* Sibutramine *
MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...
(ecstasy) *
Dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...
* Tramadol * 5-HTP * Pethidine/meperidine * St. John's wort *
Yohimbe ''Corynanthe johimbe'', synonym ''Pausinystalia johimbe'', common name yohimbe, is a plant species in the family Rubiaceae native to western and central Africa (Nigeria, Cabinda, Cameroon, Congo-Brazzaville, Gabon, Equatorial Guinea). Extract ...
*
Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
(TCAs) * Serotonin-norepinephrine reuptake inhibitors (SNRIs) * Buspirone * Triptan *
Mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is ...
*
Methylene blue Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. Methylene blue is a thiazine dye. As a medication, it is mainly used to treat methemoglobinemia by converting the ferric iron in hemoglob ...
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. NSAIDs include: *
Aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...
*
Ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus ...
(Advil, Nurofen) *
Naproxen Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formula ...
(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. Legend:
0no inhibition
+mild inhibition
++moderate inhibition
+++strong inhibition The CYP2D6 enzyme is entirely responsible for the metabolism of
hydrocodone Hydrocodone, also known as dihydrocodeinone, is an opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe en ...
,
codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...
and dihydrocodeine to their active metabolites (
hydromorphone Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by m ...
,
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Ther ...
, and
dihydromorphine Dihydromorphine (Paramorfan, Paramorphan) is a semi-synthetic opioid structurally related to and derived from morphine. The 7,8-double bond in morphine is reduced to a single bond to get dihydromorphine.Rama Rao Nadendla. Principles Of Organic ...
, respectively), which in turn undergo phase 2
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosi ...
. These opioids (and to a lesser extent
oxycodone Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...
, tramadol, and
methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to hero ...
) have interaction potential with selective serotonin reuptake inhibitors. The concomitant use of some SSRIs (
paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
and
fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
) with
codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...
may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy. 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.


List of SSRIs


Marketed


Antidepressants

*
Citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soc ...
(Celexa) *
Escitalopram Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...
(Lexapro) *
Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
(Prozac) * Fluvoxamine (Luvox) *
Paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
(Paxil) *
Sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
(Zoloft)


Others

* Dapoxetine (Priligy)


Discontinued


Antidepressants

*
Indalpine Indalpine ( INN, BAN; brand name Upstène; developmental code name LM-5008) is a selective serotonin reuptake inhibitor (SSRI) class drug that was briefly marketed. It was discovered in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a ...
(Upstène) * Zimelidine (Zelmid)


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)


Related drugs

Although described as SNRIs, duloxetine (Cymbalta),
venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic di ...
(Effexor), and
desvenlafaxine Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat depression. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and is taken by mouth. It is recommended that the ...
(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, 1:10 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
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
levomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1.
Vilazodone Vilazodone, sold under the brand name Viibryd among others, is a medication used to treat major depressive disorder. It is taken by mouth. Common side effects include nausea, diarrhea, and trouble sleeping. Serious side effects may include inc ...
(Viibryd) and
vortioxetine Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. It is taken by mouth. Common side e ...
(Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS). Vilazodone is a 5-HT1A receptor
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...
while vortioxetine is a 5-HT1A receptor agonist and 5-HT3 and 5-HT7 receptor antagonist. Litoxetine (SL 81–0385) and lubazodone (YM-992, YM-35995) are similar drugs that were never marketed. They are SRIs and litoxetine is also a 5-HT3 receptor antagonist while lubazodone is also a 5-HT2A receptor antagonist.


Mechanism of action


Serotonin reuptake inhibition

In the
brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...
, messages are passed from a nerve cell to another via a
chemical synapse Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
, 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 Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...
and CREB.Kolb, Bryan and Wishaw Ian. An Introduction to Brain and Behavior. New York: Worth Publishers 2006, Print. 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.. Their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects.


Sigma receptor ligands

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally,
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s of the
sigma receptor Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
s. Fluvoxamine is an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the σ1 receptor, while
sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
is an antagonist of the σ1 receptor, and
paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
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 Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, ...
(PET) research. It is thought that agonism of the σ1 receptor by fluvoxamine may have beneficial effects on
cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thoug ...
. 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.


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
type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...
(RA), or
hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
, 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 Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
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 Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...
which are specialized macrophages that reside in the brain.
Macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
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 Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) as a result of interference with activation of
protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...
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 Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Co ...
. These studies have been performed in animal models but have shown consistent immune regulatory effects.
Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
, 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.


Pharmacogenetics

Large bodies of research are devoted to using
genetic marker A genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify individuals or species. It can be described as a variation (which may arise due to mutation or alteration in the genomic loci) that can be ...
s 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.


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 antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
s, 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 Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and ...
. Further, they have fewer and milder
side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
. 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 Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) on the postsynaptic neuronal cell, which leads to the release of
brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...
(BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.


History

Fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
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. 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. 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.


In other organisms

SSRIs are common
environmental contaminant Pollution is the introduction of contaminants into the natural environment that cause adverse change. Pollution can take the form of any substance (solid, liquid, or gas) or energy (such as radioactivity, heat, sound, or light). Pollutants, the ...
findings near human settlement.


See also

* List of antidepressants * Serotonin releasing agent * Serotonin–norepinephrine reuptake inhibitor


References


External links


WebMD – Selective Serotonin Reuptake Inhibitors
{{DEFAULTSORT:Selective Serotonin Reuptake Inhibitor Sigma receptor ligands Treatment of obsessive–compulsive disorder Treatment of depression