First-Line Treatment for Major Depressive Disorder and Generalized Anxiety Disorder
Either cognitive-behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI) should be initiated as first-line treatment for adults with major depressive disorder or generalized anxiety disorder, as both approaches demonstrate equivalent efficacy with moderate-quality evidence. 1, 2, 3
Treatment Selection Framework
Equal First-Line Options
The American College of Physicians strongly recommends that clinicians choose between CBT and second-generation antidepressants based on adverse-effect profile, cost, accessibility, and patient preference rather than presumed efficacy differences, because response rates (42–49%) and remission rates (46–54%) are statistically equivalent. 1, 2, 3
Moderate-quality evidence from 5 trials showed no difference in response when comparing SSRIs (fluoxetine, fluvoxamine, paroxetine, or sertraline) with CBT after 8 to 52 weeks of treatment. 1
Remission rates and functional capacity improvements are similar between both modalities. 1, 3
When to Choose CBT
CBT has fewer adverse effects than medications, lower relapse rates upon treatment discontinuation, and no risk of medication-related side effects. 3
CBT requires a trained therapist and is typically delivered over 8–16 weeks, focusing on identifying and challenging dysfunctional thought patterns, behavioral activation, and problem-solving strategies. 3
When to Choose Pharmacotherapy
Second-generation antidepressants are easier to implement in settings without trained CBT therapists and may provide more rapid symptom relief when started at therapeutic doses. 3
For generalized anxiety disorder specifically, first-line SSRIs include sertraline, paroxetine, or escitalopram; SNRIs include venlafaxine or duloxetine. 4
SSRIs have a number needed to treat of 7–8 for achieving remission. 2
Specific SSRI/SNRI Selection
General Adult Population
When choosing among SSRIs, prioritize adverse-effect profile, cost, and dosing convenience rather than presumed efficacy differences, because all SSRIs have comparable remission rates. 2
Escitalopram demonstrates superior tolerability and withdrawal rates compared with other SSRIs in umbrella reviews of systematic reviews. 5
The FDA-approved starting dose of escitalopram is 10 mg once daily, with potential increase to 20 mg after a minimum of one week for major depressive disorder or generalized anxiety disorder. 6
Older Adults (≥65 years)
Citalopram, sertraline, venlafaxine, and bupropion are preferred agents for older patients. 2
10 mg/day is the recommended dose for most elderly patients. 6
Paroxetine and fluoxetine should be avoided in older adults due to higher anticholinergic effects and less favorable profiles. 2
Specific Clinical Scenarios
Bupropion is the most effective first-choice antidepressant for cognitive symptoms (difficulty concentrating, indecisiveness, mental fog) and has the lowest rate of sexual adverse effects among antidepressants. 2
SNRIs (venlafaxine or duloxetine) are second-choice for cognitive symptoms and achieve higher remission rates (≈49% vs 42%) when chronic pain co-exists with depression. 2
Combination Therapy
Low-quality evidence from 2 trials showed no difference in response or remission when comparing SSRI monotherapy with SSRI plus CBT in initial treatment, indicating combination therapy offers no advantage over monotherapy for first-line treatment. 1, 3
However, for severe depression with work-functioning impairment, combination therapy may produce superior functional outcomes. 2
Treatment Duration
Acute Phase (6–12 weeks)
Focus on achieving initial response (≥50% reduction in symptom severity) using standardized tools like PHQ-9 or Hamilton Depression Rating Scale. 3
Assess response within 1–2 weeks of initiation, monitoring for therapeutic effects, adverse effects, and suicidality. 2
Continuation Phase (4–9 months)
- After achieving remission of a first depressive episode, continue treatment for at least 4–9 months to prevent relapse. 1, 2, 3, 6
Maintenance Phase (≥1 year)
- For patients with recurrent depression (≥2 prior episodes), maintain treatment for at least 12 months or longer. 2, 3
Safety Monitoring
All patients should be evaluated within the first 1–2 weeks for emergent suicidal thoughts, agitation, irritability, or atypical behavior, because suicide risk peaks during the initial 1–2 months of SSRI treatment. 2
Adults aged 18–24 years have modestly increased risk of suicidal ideation or behavior when treated with SSRIs (OR = 2.30; 95% CI 1.04–5.09). 2
Adults aged 25–64 years show neutral effect on suicide risk, while adults ≥65 years demonstrate protective effect (OR = 0.06; 95% CI 0.01–0.58). 2
Approximately 63% of patients on second-generation antidepressants experience at least one adverse effect, most commonly nausea, vomiting, diarrhea, dizziness, dry mouth, fatigue, headache, and sexual dysfunction. 2
Treatment Modification at 6–8 Weeks
If symptom reduction is <50% on validated scales by weeks 6–8, modify treatment by dose escalation, switching antidepressant class, augmentation with bupropion or buspirone, or adding CBT. 2, 3
Switching from one SSRI to another produces no significant difference in response rates; therefore, switch to a different pharmacologic class (SNRI, bupropion, or mirtazapine) if needed. 2
Common Pitfalls to Avoid
Tricyclic antidepressants should not be used as first-line agents due to higher adverse-effect burden, increased overdose risk, and lack of superiority over second-generation antidepressants. 1, 2
Do not prescribe antidepressants for mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 2
Do not discontinue treatment prematurely—continue for a minimum of 4–9 months after response. 3
Do not assume all SSRIs have identical profiles; paroxetine has notably higher anticholinergic effects and sexual dysfunction rates. 2