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Apr.22.2020

Selective Serotonin Reuptake Inhibitors (SSRIs)

Summary

  • Selective serotonin reuptake inhibitors (SSRIs), as the class name indicates, act primarily by inhibiting the reuptake of serotonin by the serotonin transporter, thereby increasing the synaptic concentration of serotonin that remains available to bind to postsynaptic receptors.
  • SSRIs are comparable to other antidepressants in efficacy, but are markedly safer and better tolerated than first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors); consequently, they are preferred for the treatment of numerous psychiatric disorders, including major depression and anxiety disorders.[49961][58403][58404][50542][50550][49959][62891]
  • SSRIs differ from each other with respect to their degree of selectivity for the serotonin transporter; however, this has not translated into clinical superiority of any SSRI.
  • The choice of agent is dependent upon factors such as drug interactions, previous patient response, drug-specific precautions, and efficacy for the specific condition being treated.[50534]
  • SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The maximum recommended dose of citalopram was reduced to reflect the dose-related risk of QT prolongation and torsade de pointes associated with the drug. The product labels have various recommendations regarding use of SSRIs in patients with long QT syndrome, risk factors for QT prolongation, or coadministration with other drugs that cause QT prolongation.[28269][59321]
  • Escitalopram is the least likely of the SSRIs to be subject to clinically significant metabolic (CYP450 system) drug-drug interactions.
  • Paroxetine is the only SSRI with strong warnings regarding pregnancy risks; epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations.[28260][46229][62732]
  • Based on available data, paroxetine and sertraline may be the preferred SSRIs to use in females who are breast-feeding.[45642][46229][61269][62732]

Pharmacology/Mechanism of Action

SSRIs inhibit the reuptake of serotonin by serotonin transporters located on presynaptic neurons, resulting in increased synaptic availability of serotonin at postsynaptic receptors. Therefore, the therapeutic action is presumed to result from presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition, and it evolves over several weeks to months of treatment. The desensitization of 5-HT1A autoreceptors in the dorsal raphe nucleus is one potentially important mechanism. The drug agents in the SSRI class do differ in their degree of selectivity for binding to the serotonin transporter (escitalopram > citalopram > sertraline > fluvoxamine > paroxetine > fluoxetine) and their potency of serotonin reuptake inhibition (paroxetine > sertraline > escitalopram > fluoxetine > citalopram > fluvoxamine), but these factors have not been proven to lead to clinically relevant differences in efficacy.[50533][50589][50591][50542]

SSRIs do not have a significant affinity for histaminergic, alpha-1 adrenergic, postsynaptic dopamine, GABA, or glutamate receptors nor do they inhibit monoamine oxidase (MAO). The receptor binding activity of SSRIs results in a more favorable safety and adverse event profile compared with first-generation antidepressants such as tricyclics and monoamine oxidase inhibitors. Paroxetine is the only SSRI with clinically relevant anticholinergic effects. These effects may be additive with other anticholinergic medications in any patient, but geriatric adults may be more susceptible to the anticholinergic effects of the drug than younger adults.[64280][63923]

Therapeutic Use

Major depressive disorder

  • Given the absence of consistent or compelling drug class-based differences in efficacy or tolerability in the treatment of depression, the SSRIs are not preferentially recommended over SNRIs.[49959][50533][50534]
  • The choice of an SSRI for each patient is based on several factors including tolerability, drug interactions, prior history of response, and efficacy for the selected indication.[49959][50534][50533][50542][58403][58404][62891]
  • Although no SSRI has an FDA-approved indication for the treatment of persistent depressive disorder (dysthymia), a meta-analysis of 9 randomized placebo-controlled trials (n = 1,454) of an antidepressant in the treatment of dysthymia showed that antidepressants, including SSRIs, are highly effective for this condition.[50594]
  • Some SSRIs have been approved for major depression in pediatric patients; guidelines from the American Academy of Child and Adolescent Psychiatry recommend their use when nonpharmacologic treatment is insufficient or illness severity is high. Fluoxetine is approved for the treatment of depression in children and adolescents. Escitalopram is approved for the treatment of depression in adolescents.[49959][57775][62891][28270][32127]
  • Paroxetine is not FDA-approved for the treatment of major depression in children and adolescents. Three well-controlled trials have shown that paroxetine is no more effective than placebo for the treatment of depression in pediatric patients.[62891]

 

Dose Comparisons of SSRIs in the Treatment of Depression

 

Daily dose

Citalopram

20-40 mg/day

Escitalopramc

10-20 mg/day

Fluoxetinea

20-80 mg/day

Fluvoxamineb

50-300 mg/day

Paroxetine

20-60 mg/day

Sertraline

50-200 mg/day

a Longest elimination half-life of all SSRIs; active metabolite with the longest elimination half-life of any SSRI; b Immediate-release form requires twice-daily dosing with daily doses greater than 100 mg/day in adults and 50 mg/day in children; c S-enantiomer of citalopram

Anxiety

  • Some SSRIs are approved for treating anxiety disorders, such as generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and social anxiety disorder; none have been shown to be superior to another, regardless of formal indication. SSRIs are considered first-line treatment options for these conditions in adults.[50542][50550][59024]
  • SSRIs are considered first-line therapy for childhood anxiety disorders requiring pharmacologic treatment, although few indications are FDA approved, and long-term safety and efficacy data are limited.[50832]
  • The choice of an SSRI for each patient is based on several factors including tolerability, drug interactions, prior history of response, and efficacy for the selected indication.

Other uses

  • SSRIs have been used in the treatment of premenstrual dysphoric disorder (PMDD); the SSRIs may be used continuously or just during the luteal phase for PMDD symptoms.[44059][43999][28343]
  • Other clinical uses for SSRIs include treatment of premature ejaculation and the treatment of hot flashes associated with menopause. Paroxetine (Brisdelle) is approved by the FDA for the treatment of moderate to severe vasomotor symptoms associated with menopause.[55186]

Comparative Efficacy

  • A meta-analysis of all head-to-head clinical trials of SSRIs showed very few significant differences between agents in treatment response (50% or greater reduction in symptoms as measured by a change from baseline in score on a validated instrument); however, greater efficacy was demonstrated by escitalopram and sertraline compared with fluoxetine or paroxetine.[50533]
  • In this same meta-analysis, escitalopram and sertraline also had the best overall acceptability profile (measured by all-cause discontinuation rates).[50533]

Adverse Reactions/Toxicities

Gastrointestinal adverse reactions

Gastrointestinal effects are the most common adverse events in patients receiving SSRI treatment. Nausea is the most common ADR with any SSRI during the first 2 weeks of therapy. It is most often transient and of mild to moderate intensity. Diarrhea, dry mouth, constipation, and vomiting are other common gastrointestinal ADRs. Pooled data from 15 studies comparing the risk of gastrointestinal effects of SSRIs indicated that sertraline had a higher incidence of diarrhea than citalopram, fluoxetine, fluvoxamine, or paroxetine. Administration with food may offset some adverse GI effects, such as nausea.[50534][28260][28269][28270][28343][32127][44058][43998][43999][50507]

Sexual dysfunction

Sexual dysfunction is commonly reported with the use of serotonergic agents such as SSRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.[50534][28260][28269][28270][28343][32127][44058][43998][43999][50507]

Bleeding

Impaired platelet aggregation may occur during treatment with SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Mild (e.g., epistaxis) to severe (e.g., gastrointestinal bleeding) adverse effects have been documented during the use of SSRIs, especially in combination with other drugs that have antiplatelet (e.g., aspirin) or anticoagulant effects.[28260][28269][28270][28343][32127][44058][43998][43999][50507]

Dermatologic and hypersensitivity reactions

Severe dermatologic and hypersensitivity reactions, including anaphylactoid reactions, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported rarely. Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash.[28270][32127][62974]

Hyponatremia

SSRIs may cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to becoming dehydrated, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome is reversible upon discontinuation of the causative SSRI.[28260][28269][28270][28343][32127][44058][43998][43999][50507]

Bone fractures

SSRIs appear to interfere with bone formation and have been associated with an increased incidence of osteoporotic fractures, although a causal relationship has not been proven.[42688]

QT interval prolongation

SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of SSRIs have varying recommendations regarding use in patients with long QT syndrome, risk factors for QT prolongation, and coadministration with other drugs that cause QT prolongation. The product label for citalopram contains the strongest warnings due to cases of torsade de pointes (TdP), ventricular tachycardia, and sudden death occurring with the drug. In addition, the initially approved maximum recommended dose of citalopram was reduced to address the dose-related risk of QT prolongation and TdP. In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. The manufacturer of fluoxetine recommends caution in patients with risk factors for QT interval prolongation due to postmarketing reports of QT interval prolongation and ventricular arrhythmia including TdP. The majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, the use of fluvoxamine is not a significant risk factor for the development of QT prolongation; however, there have been postmarketing reports of QT prolongation and TdP and the manufacturer recommends avoiding fluvoxamine in patients with long QT syndrome. Because cases of QT prolongation and TdP have been reported with escitalopram and sertraline, the manufacturers recommend avoiding use with other medications known to prolong the QTc interval. Sertraline is often an SSRI of choice given a fairly large amount of data involving use in depressed patients with comorbid cardiac risk factors (e.g., recent myocardial infarction, unstable angina, chronic heart failure).[28343][28260][28269][28270][32127][47184][50507][59321][64391][64392][64396]

Neonatal abstinence syndrome

After birth, symptoms consistent with a discontinuation syndrome (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) have been reported in infants exposed to SSRIs in utero, particularly during the third trimester. When treating a pregnant woman with an SSRI during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, tapering of the serotonergic agent prior to delivery may be considered as an alternative.[46229] [62732][50547][28260][28269][28270][28343][32127][44058][43998][43999][50507]

Drug Interactions

MAO inhibitors

SSRIs are contraindicated in patients receiving MAO inhibitors or within 2 weeks of their discontinuation. Medications with MAOI activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SSRIs because of an increased risk of serotonin syndrome.[28260][28269][28270][28343][32127][44058][43998][43999][50507]

SSRIs, SNRIs, and other serotonergic drugs

Any use of an SSRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John's wort, tramadol, lithium, buspirone, and others.[28260][28269][28270][28343][32127][44058][43998][43999][50507]

Antithrombotic drugs

Anticoagulants, antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin should be administered with caution to any patient taking an SSRI, especially in the elderly. Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.[28260][28269][28270][28343][32127][44058][43998][43999][50507]

Drugs that prolong the QT interval

SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of these SSRIs have varying recommendations regarding coadministration with other drugs that cause QT prolongation. Because citalopram has been associated with QT interval prolongation, torsade de pointes (TdP), and sudden death, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Additionally, if patients are also receiving a CYP2C19 inhibitor, the maximum recommended daily dose of citalopram is 20 mg due to the risk of QT interval prolongation. The manufacturers of sertraline and escitalopram recommend avoiding coadministration with other drugs that prolong the QT interval. Practitioners should review the potential for drug interactions prior to prescribing concurrent therapies, taking into account risk versus benefit for the individual patient. Pimozide and thioridazine, two antipsychotics with a well-established risk of QT prolongation and TdP, are contraindicated for use with SSRIs due to an increased risk of QT prolongation and TdP, which may be precipitated by SSRI-induced CYP inhibition and/or additive QT-prolonging effects.[28260][28269][28270][28343][32127][44058][43998][43999][50507][59321]

Drugs that are metabolized by CYP450 isozymes

All SSRIs are metabolized by CYP450 enzymes to some extent. Although SSRIs do not have a narrow therapeutic index (NTI), dosage adjustments are recommended during concurrent use of citalopram, a CYP2C19 substrate, and inhibitors of CYP2C19 due to dose-dependent QT prolongation which can occur with citalopram. Other important interactions occur with SSRIs that are potent inhibitors of CYP isoenzymes, including fluoxetine, paroxetine, and fluvoxamine. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, which can cause elevations in plasma concentrations of CYP2D6 substrates. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19; clinically significant interactions may occur with drugs such as warfarin. Although sertraline is a less potent inhibitor of CYP2D6 than fluoxetine or paroxetine, it may be necessary to reduce the dosage of concomitantly administered drugs metabolized by CYP2D6. Because escitalopram has less inhibitory effects on CYP2D6 than paroxetine or fluoxetine, clinically significant drug interactions with CYP2D6 substrates are not as likely to occur. Because escitalopram is metabolized by multiple isoenzymes, inhibition of a single enzyme may not significantly elevate escitalopram concentrations.[28260][28269][28270][28343][32127][44058][43998][43999][50507][50595]

Safety Issues

Increased risk of suicide

The approved labeling for all antidepressants carries a boxed warning of an increased risk of suicidal thoughts and behavior in children and young adults, particularly during the first few months of therapy. Experts state that the apparent increase in suicidality reflected by a greater number of spontaneously reported events is mitigated by the lack of any completed suicides, the decline in overall suicidality on rating scales, and the greater number of patients who benefit from antidepressants than who experience these serious adverse effects. Careful assessment and monitoring of suicidality are warranted in all patients initiating treatment with an SSRI.[49959][50534][50832][62891]

QT interval prolongation

SSRIs, with the exception of paroxetine, have been associated with a modest but statistically significant increase in the QTc interval. The product labels of these SSRIs have varying recommendations regarding use in patients with long QT syndrome, risk factors for QT prolongation, and coadministration with other drugs that cause QT prolongation. The product label for citalopram contains the strongest warnings due to cases of torsade de pointes (TdP), ventricular tachycardia, and sudden death occurring with the drug. However, if citalopram therapy is considered essential in patients with risk factors for QT prolongation, baseline and periodic ECG monitoring is recommended. The manufacturer of fluoxetine recommends caution in patients with risk factors for QT interval prolongation due to reports of QT interval prolongation and TdP. The majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, the use of fluvoxamine is not a significant risk factor for the development of QT prolongation; however, there have been postmarketing reports of QT prolongation and TdP and the manufacturer recommends avoiding fluvoxamine in patients with long QT syndrome. Because cases of QT prolongation and TdP have been reported with escitalopram and sertraline, the manufacturers recommend avoiding use with other medications known to prolong the QTc interval.[28343][28260][28269][28270][32127][47184][50507][59321][64391][64392][64396]

Bipolar disorder

The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.[28343][28260][28269][28270][32127][47184][50507]

Pregnancy

Treatment with all selective serotonin reuptake inhibitors (SSRIs) during pregnancy should be individualized. The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including SSRIs, during the third trimester has been associated with neonatal complications, including prolonged hospitalization, respiratory support, and tube feeding. Paroxetine has a probable association with congenital cardiac defects as noted in several large retrospective cohort studies. A population-based cohort study from Denmark showed an increased prevalence of septal heart defects among children whose mothers were prescribed sertraline or citalopram in early pregnancy. While epidemiologic reports suggest an association between maternal use of SSRIs after 20 weeks gestation and the development of persistent pulmonary hypertension (PPHN) of the newborn, more recent retrospective studies have not shown an increased risk of PPHN with SSRI exposure. There are insufficient data to determine if the risk of PPHN is comparable among SSRIs or is associated with all SSRIs. Increasing evidence suggests an association between SSRI use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring; however, maternal psychiatric conditions are a confounder to the data. Use of SSRIs during the third trimester has been associated with a neonatal abstinence syndrome after delivery.[28260][46229][32025][47179][47180][47181][49961][50598][56001][62732]

Breast-feeding

Small concentrations of SSRIs have been measured in breast milk, with uncertain consequences for the infant. Benefits of breast-feeding need to be weighed against potential risk of infant drug exposure. However, a pooled analysis found that maternal use of sertraline and paroxetine usually produced undetectable or low drug concentrations in infant serum and, therefore, may be preferred SSRIs in breast-feeding mothers.[45642][46229][61269][62732]

Abrupt discontinuation

A discontinuation syndrome is possible when any SSRI is abruptly discontinued. The most commonly reported discontinuation symptoms include fatigue, abdominal pain, nausea, dizziness/light-headedness, tremor, chill, diaphoresis, and incoordination. Other reported symptoms include impaired memory, insomnia, shock sensations, ringing in the ears, dysphoric mood, irritability, anxiety, confusion, lethargy, emotional lability, hypomania, headaches, and agitation or aggression. In general, these symptoms are more frequent with SSRIs having a shorter half-life (e.g., paroxetine) than a long half-life (e.g., fluoxetine). The discontinuation symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and subside within 1 to 2 weeks, although a delay in the onset of these symptoms may be observed with fluoxetine due to the long half-life of the drug and its active metabolite. A slow, individualized taper is advisable for any SSRI, particularly after chronic use, to minimize discontinuation symptoms.[42869][64743]

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