What is the evidence-based treatment algorithm for depression?

Evidence-Based Algorithm for Depression Treatment

Initial Assessment and Severity Stratification

Screen all patients with depressive symptoms for bipolar disorder risk before initiating any antidepressant treatment, including detailed psychiatric history and family history of suicide, bipolar disorder, and depression. 1, 2, 3

• Use validated severity assessment tools (e.g., Hamilton Depression Rating Scale, Beck Depression Inventory) to categorize depression as mild, moderate, or severe 4, 5
• Assess for suicidal ideation, psychotic features, substance use, and co-occurring anxiety disorders 4, 5
• Evaluate for melancholic features and chronicity, which may influence treatment selection 6, 5

Treatment Algorithm by Severity

Mild Depression (First-Line)

Do not initiate antidepressants for mild depression; psychological interventions are the appropriate first-line treatment. 7

• Offer cognitive behavioral therapy (CBT), interpersonal therapy, problem-solving therapy, or behavioral activation as monotherapy 7, 5
• Consider structured physical activity (minimum 30 minutes of moderate-intensity exercise on most days) or relaxation training as adjunctive approaches 7, 8
• The drug-placebo difference for antidepressants is virtually nonexistent in mild depression, while adverse events (sexual dysfunction, gastrointestinal symptoms, sleep disturbances) occur in over 60% of patients 7

Moderate Depression (First-Line)

Initiate psychological therapy as first-line treatment; reserve pharmacotherapy for patients without access to therapy, those expressing medication preference, or those not improving with psychological interventions. 4

Psychological interventions (choose one):

• Cognitive behavioral therapy (CBT) - most robust evidence 4, 5
• Behavioral activation 4, 5
• Interpersonal therapy 4, 5
• Problem-solving therapy 4, 5
• Mindfulness-based stress reduction 4

Pharmacotherapy (if psychological therapy unavailable or ineffective):

• Initiate a second-generation antidepressant (SSRI or SNRI) at standard starting dose 4
• Fluoxetine, sertraline, paroxetine, escitalopram, or citalopram show equivalent efficacy (SMD 0.23-0.48 over placebo) 4, 5
• Critical monitoring requirement: Assess weekly during the first month for clinical worsening, suicidality, agitation, irritability, hostility, impulsivity, or akathisia 1, 2, 3
• Prescribe smallest quantity consistent with good management to reduce overdose risk 1, 2

Severe Depression (First-Line)

Initiate combination treatment with both antidepressant medication and psychotherapy, which provides superior outcomes compared to either modality alone (SMD 0.30-0.33 benefit over monotherapy). 5

• Start SSRI at standard dose with concurrent CBT or interpersonal therapy 4, 5
• For severe depression with psychotic features, consider antipsychotic augmentation from initiation 4
• For patients with history of medication response, severe vegetative symptoms, or inability to engage in psychotherapy, pharmacotherapy may be initiated first 4

Treatment Timeline and Response Assessment

Week 0-4:

• Assess response at week 2 and week 4 using validated instruments 8, 5
• Monitor closely for suicidality and behavioral activation syndrome (increased risk in patients <25 years) 1, 2, 3
• If no response by week 4 with SSRI 50mg equivalent, increase to 100mg equivalent 6

Week 4-8:

• Continue current strategy if partial response is occurring; substantial additional improvement occurs between weeks 6-8 even without dose changes 6
• Do not prematurely escalate dose or switch medications before week 8 unless clinical deterioration occurs 6
• Assess at week 8 for adequate response (≥50% symptom reduction) 8, 6

Second-Step Treatment for Inadequate Response (After 8 Weeks)

If inadequate response after 8 weeks of optimized first-line treatment, add evidence-based psychological intervention (problem-solving therapy or CBT) to ongoing antidepressant before considering medication changes. 8

If psychological augmentation unavailable or ineffective after additional 4 weeks, implement pharmacologic strategy:

Augmentation options (equivalent efficacy):

• Add bupropion SR 150-300mg daily (lower discontinuation rates due to adverse events) 4, 8, 3
• Add aripiprazole 2-15mg daily (FDA-approved for adjunctive treatment) 8

Switching options (equivalent efficacy to augmentation):

• Switch to different SSRI or SNRI 4
• Switch to bupropion monotherapy 4
• Do not increase SSRI dose above 100mg sertraline-equivalent in non-responders; dose escalation to 200mg shows lower response rates (56% vs 70%) 6

Complementary Approaches with Evidence

Consider as adjunctive treatments to standard therapy:

• Omega-3 fatty acids (EPA/DHA), particularly for patients with comorbid coronary heart disease 8
• S-adenosyl-L-methionine (SAMe) 8
• Acupuncture, meditation, or yoga 8
• Avoid St. John's wort due to significant drug-drug interactions despite efficacy evidence 8

Treatment Duration and Maintenance

Continue antidepressant treatment for minimum 9-12 months after achieving remission to prevent relapse. 7

• Maintenance treatment delays recurrence of depression in placebo-controlled trials 1, 2
• For recurrent depression (≥3 episodes) or chronic depression, consider indefinite maintenance 5
• When discontinuing, taper gradually rather than abrupt cessation to minimize discontinuation syndrome 1, 2

Collaborative Care Implementation

Implement systematic follow-up and outcome assessment using collaborative care models, which significantly improve treatment effectiveness (SMD 0.42 over usual care). 5

• Schedule regular follow-up visits with structured symptom assessment 5
• Provide culturally informed and linguistically appropriate patient education about depression commonality, symptom patterns, and when to contact the medical team 4
• Include patient-identified caregivers or family members in psychoeducation when appropriate 4

Critical Safety Considerations

Highest-risk period for suicidality is during initial treatment weeks and at dose changes (increases or decreases). 1, 2, 3

• Patients <25 years have 14 additional cases of suicidality per 1000 treated (age <18) and 5 additional cases per 1000 (age 18-24) compared to placebo 1, 2, 3
• Adults ≥65 years have 6 fewer cases of suicidality per 1000 treated compared to placebo 1, 2, 3
• Instruct families and caregivers to monitor daily for agitation, unusual behavior changes, and emerging suicidality, with immediate reporting to providers 1, 2, 3
• If depression persistently worsens or severe/abrupt suicidality emerges, consider changing therapeutic regimen including possible discontinuation 1, 2, 3

Common Pitfalls to Avoid

• Never initiate antidepressants as monotherapy in patients with suspected bipolar disorder risk 1, 2, 3
• Never prescribe antidepressants for mild depression as first-line treatment 7
• Never increase SSRI dose in non-responders before week 8 unless deterioration occurs 6
• Never escalate sertraline-equivalent doses above 100mg in partial responders; this reduces response rates 6
• Never discontinue treatment before 9-12 months after remission 7
• Never use benzodiazepines for co-occurring anxiety in depression due to dependence risk 9