What is the recommended treatment for an adult patient with major depression, possibly with a history of suicidal ideation or severe symptoms?

Treatment of Major Depressive Disorder

For adult patients with major depressive disorder, initiate either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI), with combination therapy strongly preferred for severe depression or history of suicidal ideation. 1, 2

First-Line Treatment Selection

The American College of Physicians provides a strong recommendation (moderate-quality evidence) that clinicians select between CBT or second-generation antidepressants as initial treatment, as both demonstrate equivalent effectiveness. 1 However, this equivalence applies primarily to moderate depression—severe presentations require a different approach.

For Moderate Depression (Choose One):

• Cognitive Behavioral Therapy alone has demonstrated medium to large effect sizes (SMD 0.50-0.73) compared to usual care in network meta-analyses. 3
• Second-generation antidepressants (SSRIs: sertraline, escitalopram, citalopram, or fluoxetine; SNRIs: venlafaxine) show small to medium effect sizes (SMD 0.23-0.48) over placebo. 3
• Selection between SSRIs should be based on adverse effect profiles: paroxetine carries higher sexual dysfunction rates and should be avoided as first-line. 4

For Severe Depression or Suicidal Ideation (Combination Required):

Combination therapy (antidepressant + psychotherapy) is mandatory for severe presentations, producing nearly double the remission rates compared to monotherapy (57.5% vs 31.0%, P < 0.001). 2 This represents the highest quality recent evidence and should not be considered optional. 2

• Initiate SSRI or SNRI concurrently with CBT—not sequentially. 2
• SNRIs (venlafaxine) demonstrate slightly superior efficacy over SSRIs for severe symptoms, though with higher nausea rates. 2, 5
• If psychotic features are present, add an atypical antipsychotic (quetiapine, aripiprazole, risperidone, or olanzapine) to the antidepressant. 6

Treatment Phases and Duration

Depression treatment follows three distinct phases that dictate continuation decisions: 1, 2

• Acute phase (6-12 weeks): Assess response within 1-2 weeks; modify treatment by 6-8 weeks if inadequate response (defined as <50% symptom reduction on PHQ-9 or HAM-D). 2, 4
• Continuation phase (4-9 months): Continue treatment for minimum 4-9 months after satisfactory response for first episodes. 1, 2
• Maintenance phase (≥1 year): Extend to ≥1 year for recurrent episodes or patients with two or more prior episodes. 2, 4

Critical Monitoring Parameters

Monitor for suicidality within 1-2 weeks of treatment initiation and throughout the acute phase, as SSRIs increase risk for nonfatal suicide attempts compared to placebo. 4, 6 This risk is particularly elevated in severe or psychotic depression. 6

Additional monitoring includes: 2, 4

• Therapeutic response using validated tools (PHQ-9, HAM-D, MADRS)
• Adverse effects requiring medication adjustment
• Treatment adherence (up to 50% of patients demonstrate non-adherence, which can masquerade as treatment resistance) 2

Treatment-Resistant Depression Algorithm

If inadequate response after 6-8 weeks at therapeutic doses: 2

1. Verify adequate trial: Minimum 4 weeks at maximum FDA-approved dose with documented adherence. 2
2. Add CBT if not already initiated: Produces statistically superior outcomes in treatment-resistant cases. 2
3. Medication adjustments: Switch to different antidepressant class, add second antidepressant, or augment with non-antidepressant (atypical antipsychotic). 2

Treatment-resistant depression is formally defined as failure to respond to two or more adequate antidepressant trials within the current episode. 2

Common Pitfalls to Avoid

• Premature discontinuation: Most antidepressants require 4-6 weeks for therapeutic effects; inadequate duration is a leading cause of apparent treatment failure. 2
• Underdosing: Ensure maximum FDA-approved doses are reached before declaring treatment failure (e.g., sertraline up to 200mg, venlafaxine up to 225-375mg). 7, 5
• Monotherapy for severe depression: Using antidepressant alone when combination therapy is indicated results in half the remission rate. 2
• Ignoring adherence issues: Check plasma levels if adherence is uncertain before escalating treatment. 2