Treatment of Major Depressive Disorder
Initial Pharmacotherapy Selection
For adults with major depressive disorder, initiate treatment with a second-generation antidepressant (SSRI, SNRI, or other newer agent) selected based on adverse effect profile, cost, and patient preference, as all agents demonstrate equivalent efficacy. 1
Specific Agent Selection
Start with escitalopram 20 mg/day, sertraline 50 mg/day, or fluoxetine 20 mg/day as first-line options, recognizing that no single second-generation antidepressant has demonstrated superior effectiveness over others 1, 2, 3, 4
For elderly patients (≥60 years), prefer escitalopram, mirtazapine (15-45 mg/day), or sertraline due to favorable adverse effect profiles and lower anticholinergic burden 2, 5, 6
Avoid paroxetine and fluoxetine in older adults due to higher adverse effect rates 2
Consider duloxetine (40-120 mg/day) for severe depression, noting it shows slightly greater symptom improvement than SSRIs but carries 67% increased risk of nausea, vomiting, and treatment discontinuation 2
Mirtazapine is preferred for older patients and those requiring appetite/sleep improvement 2
Critical Monitoring Protocol
Begin monitoring within 1-2 weeks of treatment initiation, as suicide risk is highest during the first 1-2 months of antidepressant therapy. 1, 7, 2
Week 1-2 Assessment
- Assess for suicidal ideation, agitation, irritability, and unusual behavioral changes at every visit 1, 7, 2
- Monitor for early adverse effects (nausea, headache, insomnia) 3, 5, 6
Weeks 2-8 Assessment
- Measure depression severity using standardized scales (PHQ-9 or Hamilton Depression Rating Scale) 1, 2
- Response is defined as ≥50% reduction in measured severity 1, 7
- Monitor for sexual dysfunction, weight changes, and gastrointestinal symptoms 7, 2
Treatment Modification Algorithm
If inadequate response occurs by 6-8 weeks, modify treatment immediately—do not continue ineffective therapy. 1, 7, 2
Modification Options
- Switch to a different second-generation antidepressant class (e.g., from SSRI to SNRI or mirtazapine) 2, 8
- Patients who fail sertraline may respond to fluoxetine, and vice versa, as these agents are not interchangeable despite both being SSRIs 8
- Consider duloxetine or mirtazapine as second-line agents after SSRI failure 2
Treatment Duration
Continue treatment for 4-9 months after achieving satisfactory response in first-episode depression. 1, 7, 3
- For patients with two or more prior episodes, extend maintenance treatment to at least 1 year or longer to prevent recurrence 1, 7
- For chronic depression, maintenance treatment should extend beyond 9 months 7
- Relapse (symptom return during acute/continuation phases) differs from recurrence (symptom return during maintenance phase, representing a new episode) 1, 7
Combination with Psychotherapy
Combine pharmacotherapy with cognitive behavioral therapy, interpersonal therapy, or other evidence-based psychotherapy for optimal outcomes, particularly in chronic depression. 1, 7
- Psychotherapy options include cognitive behavioral therapy, interpersonal therapy, acceptance and commitment therapy, and psychodynamic therapies 1
- The combination approach is most effective for chronic or recurrent depression 7
Important Clinical Caveats
- Antidepressants demonstrate greatest benefit over placebo specifically in severe depression; the difference from placebo is minimal in mild-to-moderate cases 2
- Approximately 63% of patients experience at least one adverse effect during treatment with second-generation antidepressants 2
- SSRIs are associated with increased risk for suicide attempts compared to placebo, necessitating vigilant monitoring especially in the first 1-2 months 7, 2
- Sexual dysfunction is common with SSRIs; consider switching agents if this becomes problematic 7
- Dose changes should not occur at intervals less than 1 week due to the 24-hour elimination half-life of most agents 3
- Sertraline requires no dosage adjustment based solely on age, and has low potential for drug interactions via cytochrome P450 enzymes—advantageous in elderly patients on multiple medications 5, 6