What is the recommended medication algorithm for treating Major Depressive Disorder (MDD)?

Major Depressive Disorder Medication Algorithm

First-Line Treatment: Choose Either Medication or Psychotherapy

For initial treatment of MDD, clinicians should offer either a second-generation antidepressant (SGA) OR cognitive behavioral therapy (CBT), as both demonstrate equivalent efficacy for response and remission. 1

Medication Selection (SGAs)

• Start with an SSRI as the preferred SGA class, including:

  • Fluoxetine 20 mg daily 2, 3
  • Sertraline 50 mg daily 4
  • Escitalopram 10 mg daily 1
  • Paroxetine 20 mg daily 1
  • Citalopram 20 mg daily 1

• Alternative SGAs include:

  • Bupropion XL 150 mg daily, increase to 300 mg after 4 days 2
  • SNRIs (venlafaxine) 1

• Dosing considerations: Higher starting doses of SSRIs (above typical starting doses) are associated with 4% higher response rates (54.8% vs 50.8%) but also higher discontinuation rates due to adverse events (16.5% vs 9.8%) 5. Balance efficacy against tolerability based on patient presentation.

Psychotherapy as Monotherapy

• CBT monotherapy shows no difference in response or remission compared to SGAs after 8-52 weeks 1
• Interpersonal therapy shows equivalent outcomes to SGAs 1

Combination Therapy (SGA + CBT)

• Adding CBT to SGAs does not significantly improve response or remission rates compared to SGA monotherapy in most trials 1
• One trial showed improvement in 3 of 5 work-functioning measures with combination therapy, though clinical significance is uncertain 1

Second-Line Treatment: After Initial Treatment Failure

Switching Strategies

When patients fail to respond to an initial SGA, switch to a different SGA (e.g., from sertraline to bupropion or venlafaxine) 1

• Moderate-quality evidence shows no difference in response between different SGAs when switching 1
• Allow adequate trial duration (typically 4-8 weeks at therapeutic dose) before declaring treatment failure 1

Augmentation Strategies

• Consider augmentation with atypical antipsychotics (aripiprazole, quetiapine) for treatment-resistant MDD 6
• These agents are FDA-approved only as adjunctive treatment, not monotherapy 7

Alternative: Switch to Cognitive Therapy

• Switching from an SGA to cognitive therapy is an option for non-responders 1

Special Populations and Presentations

MDD with Psychotic Features

Combine an SSRI with a second-generation antipsychotic as first-line treatment, as this combination is significantly more effective than either medication alone 8

• Preferred SSRIs: sertraline, escitalopram, or fluoxetine 8
• Continue full-dose combination therapy for at least 6 months after significant improvement 8
• ECT is equally effective and should be considered for rapid improvement needs, medication failures, or high suicide risk 8

Adolescents with MDD

• Fluoxetine combined with CBT is the most studied and effective combination in adolescents 9
• Continue treatment for 6-12 months after symptom remission before slow taper 9

Treatment Monitoring

Assessment Tools

• Use standardized measures at each visit: PHQ-9 or Hamilton Depression Rating Scale (HAM-D) 1, 8
• Response defined as: ≥50% reduction in measured severity 1, 8
• Remission defined as: HAM-D score ≤7 1

Treatment Duration

• Acute phase: Continue treatment for several months beyond initial response 2
• Maintenance: For first or second episodes, continue for at least 6 months after significant improvement 8
• Discontinuation: Taper dose when stopping (e.g., reduce from 300 mg to 150 mg before discontinuation) 2

Critical Safety Considerations

Suicidality Monitoring

• Antidepressants increase risk of suicidal thoughts and behaviors in children, adolescents, and young adults 2
• Monitor closely for worsening depression and emergence of suicidal ideation, especially during treatment initiation 2
• No increased risk in patients ≥65 years 2

Drug Interactions

• Allow 14 days washout when switching between MAOIs and SGAs 2
• Serotonin syndrome risk with concomitant serotonergic drugs (triptans, other antidepressants) 4
• Bleeding risk increases when combining SSRIs with NSAIDs, aspirin, or warfarin 4

Hepatic/Renal Impairment

• Moderate-severe hepatic impairment: Maximum bupropion dose 150 mg every other day 2
• Renal impairment (GFR <90 mL/min): Consider dose reduction and/or frequency adjustment 2

Pitfalls to Avoid

• Do not combine SGAs with interpersonal therapy as augmentation—one trial showed SGA monotherapy had better remission than the combination 1
• Avoid alcohol with all antidepressants despite lack of potentiation in studies 4
• Do not use atypical antipsychotics as monotherapy for uncomplicated MDD—they are only approved as adjunctive treatment 7
• Ensure adequate dose and duration before declaring treatment failure (minimum 4-8 weeks at therapeutic dose) 1