Selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors 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 primarily work by blocking serotonin reabsorption via the serotonin transporter, leading to gradual changes in brain signaling and receptor regulation, with some also interacting with sigma-1 receptors, particularly fluvoxamine, which may contribute to cognitive effects. Marketed SSRIs include six main antidepressants—citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline—and dapoxetine, which is indicated for premature ejaculation. Fluoxetine has been approved for veterinary use in the treatment of canine separation anxiety.
SSRIs are the most widely prescribed antidepressants in many countries. In adults, they are recommended as a first-line treatment for moderate to severe depression, while for mild depression non-drug treatments are preferred unless the patient chooses medication. SSRIs have modest benefits over placebo, with uncertain clinical significance, and may produce a substantial drug-specific response in only a minority of patients. There is no consistent evidence linking depression to low serotonin levels, and long-term use may reduce serotonin concentrations. Fifty years after their introduction, SSRIs remain widely used for depression, though their effectiveness, mechanisms, and role in medicalizing normal life remain debated.
Their effectiveness, especially for mild to moderate depression, remains debated due to mixed research findings and concerns about bias, placebo effects, and adverse outcomes. SSRIs can cause a range of side effects, including movement disorders like akathisia and various forms of sexual dysfunction—such as anorgasmia, erectile dysfunction, and reduced libido—with some effects potentially persisting long after discontinuation. SSRIs pose drug interaction risks by potentially causing serotonin syndrome, reducing efficacy with NSAIDs, and altering drug metabolism through CYP450 enzyme inhibition. SSRIs are safer in overdose than tricyclics but can still cause severe toxicity in large or combined doses. Stopping SSRIs abruptly can cause withdrawal symptoms, so tapering, especially from paroxetine, is recommended, with fluoxetine causing fewer issues.
Medical uses
The main indication for SSRIs is major depressive disorder; however, they are frequently prescribed for anxiety disorders, such as social anxiety disorder, generalized anxiety disorder, panic disorder, obsessive–compulsive disorder, eating disorders, chronic pain, and, in some cases, for post-traumatic stress disorder. They are also frequently used to treat depersonalization disorder, although with varying results.Depression
In adults
In 2022, the UK National Institute for Health and Care Excellence recommended that antidepressants be offered as a first-line treatment for moderate to severe depression, but for mild depression, non-drug interventions are preferred unless the patient chooses medication. They recommended that antidepressants should not be routinely offered for mild depression and should generally be used only if non-drug treatments fail or the patient prefers medication.In a 2018 review, all 21 studied antidepressants were more effective than placebo for major depressive disorder. SSRIs remain the most widely prescribed antidepressants, emerging options like anti-inflammatory drugs and ketamine may have higher efficacy and remission rates in treating depression.
The commonly used definition of antidepressant "response" as a 50% symptom reduction dichotomizes continuous data, which methodologists note can inflate effect sizes, exaggerate drug–placebo differences, and may not reliably indicate clinical significance. A large FDA trial analysis found that SSRIs and other antidepressants produced only modest average benefits over placebo, with about 15% of patients experiencing a substantial drug-specific response. SSRIs and other antidepressants may have average treatment effects that fall below the minimal important difference on common depression outcome measures, leaving their clinical significance in acute moderate-to-severe depression uncertain.
There is no consistent evidence that depression is caused by lowered serotonin activity or concentrations, with some data suggesting that long-term antidepressant use may reduce serotonin levels.
In children
The NICE Guideline recommends that SSRIs should not be used to treat depression in children and young people, except for fluoxetine, which may be considered for moderate to severe depression when psychological therapies alone are insufficient. In the United States, they are approved for use in pediatric patients; however, individuals under 25 years of age should be closely monitored for an increased risk of suicidality, as indicated by the FDA black box warning.SSRIs have the best outcomes when combined with cognitive-behavioral therapy. Their benefits are modest and tolerability varies. The benefits may be clinically unimportant and there are uncertain effects on suicide risk.
Social anxiety disorder
SSRIs show some evidence of effectiveness for social anxiety disorder, including reducing relapse and disability, but the overall quality of evidence is low to moderate and tolerability is slightly lower than placebo.Post-traumatic stress disorder
Two SSRIs are FDA-approved for PTSD: paroxetine and sertraline. The 2023 VA/DoD guideline for PTSD recommends the SSRIs sertraline and paroxetine as first-line pharmacological treatments when trauma-focused therapy is unavailable or not preferred; evidence for other SSRIs is insufficient, and medications are recommended to be tailored to each patient's individual needs. A 2022 Cochrane review found that SSRIs improve PTSD symptoms in 58% of patients compared with 35% on placebo and are considered first-line treatment.Generalized anxiety disorder
SSRIs are recommended by the National Institute for Health and Care Excellence for the treatment of generalized anxiety disorder in adults who have not responded to initial interventions such as education, self-help strategies, or psychological therapies.SSRIs are more effective than placebo for treating GAD with similar overall acceptability, though they increase dropout due to adverse effects.
Obsessive–compulsive disorder
In Canada, SSRIs are a first-line treatment of adult obsessive–compulsive disorder. 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.SSRIs are more effective than placebo for reducing OCD symptoms and global severity in children and adolescents, and combining them with exposure therapy is probably more effective than using an SSRI alone.
Panic disorder
SSRIs are approved to treat panic disorder. SSRIs may be more effective than placebo in reducing panic disorder symptoms, but they are associated with a higher risk of adverse effects and may be less well tolerated.Eating disorders
Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. SSRIs are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized.Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss.
Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa. Treatment guidelines from the National Institute of Health and Clinical Excellence recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depression, 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 2021 meta-analysis of randomized controlled clinical trials found no evidence pointing to their routine use to promote recovery following stroke. A 2022 meta-analysis of randomized controlled trials suggested that citalopram could improve dependence, motor ability, and cognitive function in stroke patients, without similar findings for fluoxetine.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 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. However, for those with premature ejaculation, this very same side effect becomes the desired effect.Other uses
SSRIs such as sertraline are effective in decreasing anger, and fluoxetine has been proven effective in reduction of attack frequency and intensity for Raynaud syndrome.Side effects
s vary among the individual drugs of this class. They may include akathisia.Sexual dysfunction
SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia. Sexual problems are common with SSRIs. Poor sexual function is one of the most common reasons people stop the medication.The mechanism by which SSRIs may cause sexual side effects is not well understood. The range of possible mechanisms includes nonspecific neurological effects that globally impair behavior including sexual function; specific effects on brain systems mediating sexual function; specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and direct or indirect effects on hormones mediating sexual function. Management strategies include: for erectile dysfunction the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to bupropion; and for overall sexual dysfunction, switching to nefazodone. Buspirone is sometimes used off-label to reduce sexual dysfunction associated with the use of SSRIs.
A number of non-SSRI drugs are not associated with sexual side effects.
Several studies have suggested that SSRIs may adversely affect semen quality.
While trazodone is a notorious cause of priapism, cases of priapism have also been reported with certain SSRIs.