How should I manage a patient with major depressive disorder who is taking sertraline 50 mg daily and low‑dose doxepin 5 mg nightly but remains depressed with suicidal ideation?

Management of Treatment-Resistant Major Depressive Disorder with Active Suicidal Ideation

This patient requires immediate escalation of both pharmacologic and psychotherapeutic interventions, with sertraline dose optimization to 200 mg daily, addition of cognitive-behavioral therapy, and urgent safety planning—all while maintaining close monitoring for worsening suicidality during the critical first 1–2 weeks of any medication change.

Immediate Safety Assessment and Monitoring

• Conduct an urgent suicide risk assessment documenting specific plan, intent, access to lethal means, recent attempts, psychotic features, and family history of suicide or bipolar disorder. 1
• Implement a written safety plan that (1) restricts access to lethal means, (2) identifies a responsible third party for daily monitoring, and (3) establishes emergency contact protocols. 1
• All patients on antidepressants must be evaluated within 1–2 weeks of any dose change for emergent suicidal thoughts, agitation, irritability, or unusual behavioral changes, because suicide risk peaks during the initial 1–2 months of treatment. 2
• SSRIs increase suicide-attempt risk in adults, with the highest risk during early treatment phases; daily observation by family or caregivers is mandatory. 2

Pharmacologic Optimization

Sertraline Dose Escalation

• Increase sertraline from 50 mg to 200 mg daily (the maximum FDA-approved dose), advancing in 50 mg increments at weekly intervals, because 50 mg is often subtherapeutic and patients not responding to initial dosing may benefit from titration to the full dose range. 2
• The FDA label explicitly states that while 50 mg once daily is the recommended initial therapeutic dose, patients not responding may benefit from dose increases up to 200 mg/day, with dose changes occurring at intervals of no less than 1 week given sertraline's 24-hour elimination half-life. 2
• Sertraline 50 mg daily represents the starting dose but is not necessarily the optimal therapeutic dose for all patients; controlled trials demonstrating efficacy used a dose range of 50–200 mg/day. 2, 3

Addressing the Doxepin 5 mg

• Doxepin 5 mg nightly is a subtherapeutic dose for depression (antidepressant doses typically start at 25–75 mg) and is likely being used only for sleep or anxiety. 1
• This low dose contributes minimal antidepressant effect and should not be counted as an adequate antidepressant trial. 1
• Continue doxepin 5 mg for now if it provides symptomatic relief for insomnia, but recognize it does not constitute meaningful antidepressant therapy. 1

Mandatory Addition of Psychotherapy

• Add cognitive-behavioral therapy (CBT) immediately and concurrently with medication optimization—not sequentially—because combination therapy in patients with active suicidal ideation produces statistically superior outcomes compared to antidepressant monotherapy, with remission rates nearly doubling (57.5% vs 31.0%, P < 0.001). 1
• CBT specifically reduces suicidal ideation and behavior by more than 50% in patients with recent self-directed violence, with most patients attending fewer than 12 sessions. 1
• Dialectical behavior therapy (DBT) is an alternative evidence-based psychotherapy that reduces suicidal self-directed violence and should be considered if CBT is unavailable or if borderline personality features are present. 1

Treatment Response Timeline and Next Steps

Week 1–2 Assessment

• Reassess within 1–2 weeks for therapeutic effects, adverse effects (nausea, insomnia, agitation), and most critically, worsening suicidality or emergence of akathisia (which has been linked to treatment-emergent suicidal ideation with SSRIs). 1, 2
• Monitor for serotonin syndrome symptoms (agitation, confusion, tremor, tachycardia, hyperthermia) as dose increases. 2

Week 6–8 Assessment

• If symptom reduction is <50% on validated scales (PHQ-9, HAM-D, MADRS) by 6–8 weeks at the maximum sertraline dose of 200 mg, the patient meets criteria for treatment-resistant depression and requires further intervention. 1

If Inadequate Response After Sertraline Optimization

Augmentation Strategies (Preferred Over Switching)

• Add bupropion SR (starting 150 mg daily, target 300 mg daily) to the optimized sertraline dose, because augmentation with bupropion achieves remission rates comparable to switching antidepressants while producing significantly lower discontinuation rates due to adverse events (12.5% vs 20.6% with buspirone). 1
• Bupropion augmentation avoids metabolic and extrapyramidal side effects but is contraindicated if seizure disorder or eating disorder is present. 1

Alternative: Switch to SNRI

• If augmentation is not tolerated or preferred, switch to venlafaxine (starting 37.5–75 mg daily, target 150–225 mg daily) or duloxetine (starting 30 mg daily, target 60 mg daily), because SNRIs demonstrate modest superiority over switching to another SSRI in patients who failed initial therapy. 1

Consideration of Ketamine/Esketamine for Persistent Suicidal Ideation

• If suicidal ideation persists despite optimized sertraline (200 mg) plus CBT, consider referral for ketamine infusion (0.5 mg/kg IV) or intranasal esketamine, which produce rapid improvement in suicidal ideation within 24 hours, with benefits lasting at least 1 week and up to 6 weeks in some cases. 1
• In meta-analysis, 55% of patients receiving ketamine reported no suicidal ideation after 24 hours and 60% at 7 days. 1

Treatment Duration After Response

• Continue antidepressant therapy for at least 4–9 months after achieving satisfactory response for a first depressive episode. 2
• For recurrent depression (≥2 prior episodes), maintain treatment for ≥1 year or longer to prevent relapse. 1

Critical Pitfalls to Avoid

• Do not continue sertraline 50 mg indefinitely without dose optimization—this represents inadequate dosing and delays effective treatment. 2, 3
• Do not rely on doxepin 5 mg as meaningful antidepressant therapy—it is a subtherapeutic dose. 1
• Do not delay adding CBT—psychotherapy must be initiated concurrently with medication changes in patients with suicidal ideation, not after medication "fails." 1
• Do not prescribe benzodiazepines or phenobarbital—these may reduce self-control and disinhibit suicidal behavior. 1
• Prescribe the smallest quantity of tablets consistent with good management to reduce overdose risk, given that sertraline overdose can cause tachycardia, hypertension, tremors, agitation, confusion, and hyperthermia. 2, 4
• Screen for bipolar disorder before escalating antidepressant therapy, as treating unrecognized bipolar depression with an antidepressant alone may precipitate a manic episode. 2