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Selective Serotonin Reuptake Inhibitors

Selective Serotonin Reuptake Inhibitors

Article Author:
Andrew Chu
Article Editor:
Roopma Wadhwa
11/7/2020 7:51:08 PM
For CME on this topic:
Selective Serotonin Reuptake Inhibitors CME
PubMed Link:
Selective Serotonin Reuptake Inhibitors


Selective serotonin reuptake inhibitors (SSRIs) are a class of medications that are most commonly prescribed for the treatment of depression. They are often used as first-line pharmacotherapy for depression and numerous other psychiatric disorders due to their safety, efficacy, and tolerability. They are approved for use in both adult and pediatric patients.[1]

The current SSRIs in use in the United States are:

  • Fluoxetine
  • Sertraline
  • Paroxetine
  • Fluvoxamine
  • Citalopram
  • Escitalopram
  • Vilazodone

SSRIs currently have FDA labeled indications to treat the following conditions:

  • Major depressive disorder
  • Generalized anxiety disorder
  • Bulimia nervosa
  • Bipolar depression[2]
  • Obsessive-compulsive disorder
  • Panic disorder
  • Premenstrual dysphoric disorder
  • Treatment-resistant depression
  • Post-traumatic stress disorder
  • Social anxiety disorder

Other off-label uses include but are not limited to: Binge eating disorder, Body dysmorphic disorder, fibromyalgia, premature ejaculation, paraphilias, autism, Raynaud phenomenon, and vasomotor symptoms associated with menopause.[3]

Mechanism of Action

The therapeutic actions of SSRIs have their basis on increasing deficient serotonin that researchers postulate as the cause of depression in the monoamine hypothesis. As the name suggests, SSRIs exert action by inhibiting the reuptake of serotonin, thereby increasing serotonin activity. Unlike other classes of antidepressants, SSRIs have little effect on other neurotransmitters, such as dopamine or norepinephrine. SSRIs also have relatively fewer side effects compared to TCAs and MAOIs due to having fewer effects on adrenergic, cholinergic, and histaminergic receptors.

SSRIs inhibit the serotonin transporter (SERT) at the presynaptic axon terminal. By inhibiting SERT, an increased amount of serotonin (5-hydroxytryptamine or 5HT) remains in the synaptic cleft and can stimulate postsynaptic receptors for a more extended period.[4][5][6]


SSRIs are only available orally and come in multiple forms, including tablets, capsules, or liquid suspension/solution. There are currently no parenteral (IV, IM, SubQ), rectal, or other forms of SSRIs. SSRI administration is typically once-daily medication in the morning or nighttime. Except for vilazodone, SSRIs may be taken with or without food. Vilazodone should be administered with food.[6]

Adverse Effects

The popularity and widespread use of SSRIs is due in part to their relatively fewer side effects compared to previous commonly used antidepressants such as TCAs and MAOIs. SSRIs have little or no effect on dopamine, norepinephrine, histamine, or acetylcholine (except for paroxetine). This characteristic leads to fewer complaints of side effects such as xerostomia, sedation, constipation, urinary retention, and cognitive impairments.[7][8]

Increased tolerability compared to other classes of medications make SSRIs first-line options for their indicated uses. Although relatively safer due to their selectively for serotonin, SSRIs are not without risks. 

In 2004, the FDA issued a black box warning for SSRIs and other antidepressant medications due to a possible increased risk of suicidality among pediatric and young adult (up to age 25) populations. The risk and benefits of initiating SSRI therapy on acutely suicidal patients must be weighed, keeping in mind that depression itself is a large risk factor for suicidality and requires treatment. Common side effects from SSRIs include sexual dysfunction, sleep disturbances, weight changes, anxiety, dizziness, xerostomia, headache, and gastrointestinal distress.[9][10]

SSRIs also have the potential to prolong the QT interval, which can lead to fatal arrhythmia, torsade de pointes. Citalopram has correlations with a longer QT duration than the other medications in this class.[11][12] Coagulopathy also correlates with SSRI use.[13] Although infrequent, as with all medications that increase serotonin activity, it is important to be aware of the risk of serotonin syndrome, particularly when prescribing multiple medications that may have serotonergic effects.

SSRIs are metabolized by and have effects on the cytochrome P450 system. Fluoxetine, paroxetine, sertraline, citalopram, and escitalopram are inhibitors of CYP2D6. Fluoxetine and fluvoxamine are inhibitors of CYP2C19. Fluvoxamine is an inhibitor of CYP1A2.[6]


SSRIs are contraindicated with the concurrent use of MAOIs, linezolid, and other medications that increase serotonin levels and could put patients at risk for life-threatening serotonin syndrome.

Paroxetine is contraindicated in pregnancy and is classified as category D/X due to its teratogenic effects in causing cardiovascular defects, specifically cardiac malformations, if prescribed in the first trimester.[14]


The effect of SSRIs may take up to 6 weeks before the patients feel the effects of treatment.[15] If patients are tolerating the current dose, the clinician can consider an increase in dosage after several weeks.

All patients under the age of 25 should be continually assessed for suicidal ideation and other unusual behaviors, as highlighted in the FDA black box warning for all SSRI medications.

For patients with cardiac risk factors, an EKG may be an option to monitor for QT prolongation and arrhythmias.

Weight should be regularly measured and tracked to determine if there are any adverse metabolic changes.

Vital signs should also be regularly measured to monitor for adverse changes.

Anxiety, insomnia, and sexual dysfunction (delayed ejaculation, decreased sexual desire, and anorgasmia) require regular assessment.


SSRI overdose is relatively infrequent due to their increased safety profile and tolerability compared to other classes of antidepressants. SSRI overdoses are rarely fatal and usually do not have serious consequences. Out of all the SSRIs, citalopram and escitalopram are more likely to cause overdose due to differences in their structures. Citalopram and escitalopram have an increased risk of cardiotoxicity due to QT prolongation, which can progress to serious arrhythmias such as Torsades.

Serotonin syndrome is a life-threatening consequence of increased serotonergic activity. It can result from overdosing on SSRIs or from combining multiple medications that increase serotonin levels. Serotonin syndrome is characterized by mental status changes, autonomic dysfunction, and dystonias. Findings may include agitation, tachycardia, hypertension, hyperthermia, hyperreflexia, tremor, nausea, vomiting, and clonus.[16] Serotonin syndrome may present similarly to neuroleptic malignant syndrome and malignant hyperthermia. This fact is especially important to keep in mind since commonly prescribed psychiatric medications can cause both serotonin syndrome and neuroleptic malignant syndrome. In general, serotonin syndrome is distinguishable by taking a thorough history. Serotonin syndrome also has a rapid onset and resolution. There is no definitive treatment for serotonin syndrome aside from discontinuing the offending agent, supportive measures and benzodiazepines for agitation. Cyproheptadine has shown some success in several small studies and case reports for patients who do not respond to initial treatment.

Enhancing Healthcare Team Outcomes

SSRIs are currently some of the most commonly prescribed medications. They are used to treat numerous conditions and may be used in many settings, not just in primary care or psychiatry. Patients may be on these medications for the long-term. Therefore, it is essential to have accurate medication reconciliation by physicians, pharmacists, nursing staff, and other health professionals.

Serotonin syndrome is important to keep in mind due to the widespread use of SSRIs. If suspected by a triage nurse in an emergency setting, it is important that the emergency medicine physician immediately begin supportive treatment. Coordinating with the intensivist and ICU nursing staff may also be required as treatment may require immediate sedation and intubation. A neurologist may also be important for ongoing care. Although there is no definitive treatment for serotonin syndrome, researchers have trialed cyproheptadine with some success in small studies and case reports.[17][18][19][20] [Level 4]


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