What are the indications, contraindications (CI), mechanism of action (MOA), adverse reactions, drug interactions, and monitoring requirements for Sertraline (Selective Serotonin Reuptake Inhibitor - SSRI)?

Sertraline: Clinical Overview

Mechanism of Action

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that blocks presynaptic serotonin reuptake in the brain, increasing serotonin availability at the synaptic cleft. 1 This blockade leads to downregulation of inhibitory serotonin autoreceptors over time, which heightens serotonergic neuronal firing rate and increases serotonin release—explaining the delayed onset of therapeutic effect typically seen with SSRIs. 1

• Sertraline is a naphthalenamine derivative with predominant pharmacological action of inhibiting presynaptic serotonin reuptake. 2
• Unlike other SSRIs, sertraline is not a potent inhibitor of any cytochrome P450 isoenzyme systems, resulting in minimal drug-drug interactions. 3

FDA-Approved Indications

Sertraline is FDA-approved for major depressive disorder, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social anxiety disorder, and premenstrual dysphoric disorder (PMDD). 4, 2

• For pediatric patients (ages 6-18), sertraline should be considered for social anxiety, generalized anxiety, separation anxiety, and panic disorders. 1
• Sertraline is effective for acute treatment and long-term management across these anxiety and mood disorders. 5
• The drug is also effective for prevention of recurrence of depression with maintenance treatment of 12-24 months minimum after achieving remission. 1

Contraindications

Sertraline is absolutely contraindicated with MAOIs (including linezolid and IV methylene blue), pimozide, disulfiram (due to alcohol content in oral concentrate), and in patients with hypersensitivity to sertraline. 4

• Do not use sertraline within 14 days of stopping an MAOI or starting an MAOI within 14 days of stopping sertraline due to risk of serotonin syndrome. 4
• Concomitant use with pimozide is contraindicated due to QT prolongation risk. 4
• The oral concentrate formulation contains alcohol and must not be used with disulfiram (Antabuse). 4

Dosing and Pharmacokinetics

Sertraline requires once-daily dosing with typical antidepressant doses of 50-200 mg/day, though some patients may require twice-daily dosing at low doses. 1, 4

• Sertraline is slowly absorbed with extensive first-pass metabolism to N-desmethyl-sertraline, a weakly active metabolite. 2
• Elimination half-life ranges from 22-36 hours, supporting once-daily administration. 2
• At low doses of sertraline, pediatric patients may require twice-daily dosing due to pharmacokinetic considerations. 1
• Steady-state plasma concentrations vary widely (up to 15-fold) between patients on the same dose. 2
• No dosage adjustments are warranted for elderly patients based solely on age. 6

Adverse Reactions

Common Adverse Effects (>5% and twice placebo rate)

The most common adverse effects are gastrointestinal symptoms (nausea 25%, diarrhea 20%), sexual dysfunction (ejaculatory failure 17% in males), insomnia (21%), dry mouth (14%), and sweating (7%). 4

• Nausea is the most frequently reported adverse effect and a leading cause of discontinuation. 7, 4
• Sertraline shows higher rates of diarrhea compared to other SSRIs. 7
• Sexual dysfunction occurs commonly but is underreported in clinical trials; paroxetine has significantly higher rates than sertraline. 1, 7
• Bupropion has significantly lower rates of sexual adverse events than sertraline or fluoxetine. 1
• Other common effects include headache (25%), somnolence (13%), dizziness (12%), fatigue (12%), tremor (8%), and decreased libido (6%). 4

Serious Adverse Effects

Potentially serious adverse effects include suicidal thinking/behavior, behavioral activation/agitation, hypomania/mania, serotonin syndrome, seizures, abnormal bleeding, and bruxism. 1, 4

• Behavioral activation manifests as motor/mental restlessness, insomnia, impulsiveness, talkativeness, and feeling "keyed up"—this is dose-related and requires dose reduction, not increase. 8
• Bruxism (jaw clenching/teeth grinding) typically begins within 3-4 weeks of initiation or dose increase. 8
• Most adverse effects emerge within the first few weeks of treatment. 1
• Approximately 63% of patients receiving SSRIs experience at least one adverse effect during treatment. 7

Serotonin Syndrome

Serotonin syndrome is a potentially life-threatening condition characterized by mental status changes, autonomic instability, neuromuscular symptoms, and gastrointestinal symptoms. 4

• Symptoms include agitation, hallucinations, delirium, coma, tachycardia, labile blood pressure, hyperthermia, tremor, rigidity, myoclonus, hyperreflexia, seizures, nausea, vomiting, and diarrhea. 4
• Risk is highest with concomitant use of other serotonergic drugs (triptans, tricyclics, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort) or drugs impairing serotonin metabolism. 4
• Discontinue sertraline and all serotonergic agents immediately if serotonin syndrome occurs and initiate supportive treatment. 4

Drug Interactions

Sertraline has minimal inhibitory effects on major cytochrome P450 enzymes, resulting in few clinically significant drug-drug interactions compared to other SSRIs. 2, 3

Contraindicated Combinations

• MAOIs (including linezolid and IV methylene blue): Risk of serotonin syndrome. 4
• Pimozide: Risk of QT prolongation. 4
• Disulfiram with oral concentrate: Alcohol content in concentrate. 4

High-Risk Combinations Requiring Monitoring

• Other serotonergic drugs (triptans, tricyclics, fentanyl, lithium, tramadol, buspirone, tryptophan, St. John's Wort): Increased risk of serotonin syndrome. 4
• Drugs affecting hemostasis (NSAIDs, aspirin, warfarin): Increased bleeding risk. 1

Advantages Over Other SSRIs

• Unlike fluoxetine, fluvoxamine, and paroxetine, sertraline is not a potent inhibitor of cytochrome P450 isoenzymes. 3
• This provides particular advantages in elderly patients who typically receive multiple medications. 6

Monitoring Requirements

Initial Monitoring (Weeks 1-2)

Begin monitoring within 1-2 weeks of initiation for suicidal thoughts/behaviors, behavioral activation, and common adverse effects. 1

• The FDA mandates close monitoring for increases in suicidal thoughts and behaviors, particularly in the first 1-2 months of treatment. 1
• Monitor for emergence of agitation, irritability, unusual changes in behavior, anxiety, panic attacks, insomnia, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. 4
• Risk for suicide attempts is greatest during the first 1-2 months of treatment. 1
• Families and caregivers should be instructed to monitor daily and report symptoms immediately. 4

Early Treatment Phase (Weeks 2-6)

Assess therapeutic response and adverse effects regularly, with clinically significant improvement expected by week 6. 1

• The best-fitting model for SSRI response shows statistically significant improvement within 2 weeks, clinically significant improvement by week 6, and maximal improvement by week 12 or later. 1
• Early reduction of symptoms by 4 weeks is the best predictor of treatment response at 12 weeks. 1
• This pharmacodynamic profile supports slow up-titration to avoid exceeding optimal dose. 1

Ongoing Monitoring

If no adequate response occurs within 6-8 weeks, modify treatment by adjusting dose, switching medications, or adding other therapeutic modalities. 1

• Continue monitoring for adverse effects throughout treatment, particularly sexual dysfunction, weight changes, and bleeding. 1, 4
• Monitor for symptoms of behavioral activation (jaw tension, feeling "keyed up") which warrant dose reduction. 8
• Rule out serotonin syndrome if activation symptoms occur, checking for drug interactions that inhibit SSRI metabolism. 8

Special Monitoring Considerations

Screen patients for bipolar disorder risk before initiating sertraline, as antidepressant monotherapy may precipitate manic episodes. 4

• Obtain detailed psychiatric history including family history of suicide, bipolar disorder, and depression. 4
• Previous episodes of antidepressant-induced mania are a risk factor for sertraline-induced mania. 9
• Behavioral activation typically improves quickly after dose decrease, whereas true mania persists despite discontinuation. 9

Angle-Closure Glaucoma Risk

Pupillary dilation from sertraline may trigger angle-closure attack in patients with anatomically narrow angles without patent iridectomy. 4

Clinical Pitfalls to Avoid

Never increase sertraline dose when patients report jaw tension or feeling "keyed up"—these are dose-related adverse effects requiring dose reduction, not anxiety worsening. 8

• Do not dismiss behavioral activation symptoms as worsening anxiety; they represent genuine adverse effects requiring intervention. 8
• Avoid abrupt discontinuation; taper medication as rapidly as feasible while recognizing that abrupt discontinuation causes withdrawal symptoms. 4
• Do not overlook the need to screen for bipolar disorder before initiating treatment. 4
• Prescribe the smallest quantity of tablets consistent with good management to reduce overdose risk. 4

Treatment Duration and Discontinuation

Maintain pharmacotherapy for a minimum of 12-24 months after achieving remission, though longer treatment may be necessary due to relapse risk. 1

• The optimal trial duration to determine efficacy is 8-12 weeks. 1
• When discontinuing, taper medication to minimize withdrawal symptoms rather than stopping abruptly. 4
• Consider changing the therapeutic regimen if depression persistently worsens or emergent suicidality occurs. 4