Selective Serotonin Reuptake Inhibitors (SSRIs)
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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.
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.
Dose Comparisons of SSRIs in the Treatment of Depression
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
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.
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.
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.
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.
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.
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.
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).
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. 
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.
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.
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.
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.
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.
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.
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.
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.
Small concentrations of SSRIs have been measured in breast milk; there are no data on the effects of SSRIs on milk production. Benefits of breast-feeding need to be weighed against potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk; this agent has a longer half-life than the other SSRIs and a breastfed child should be monitored for these potential side effects. 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 during lactation.
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.
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