What are the adjunct treatment options for patients with depression?

Adjunctive Treatment Options for Major Depressive Disorder

For patients with depression who have inadequate response to initial antidepressant therapy, add evidence-based psychological intervention (problem-solving therapy or cognitive behavioral therapy) as the first-step adjunctive treatment, with pharmacologic augmentation (aripiprazole or bupropion SR) reserved for those with insufficient response after 8 weeks. 1

First-Step Adjunctive Therapy: Psychological Interventions

Add psychological intervention to ongoing antidepressant medication rather than switching or adding another medication initially. 1 The most strongly supported options include:

• Problem-solving therapy is prioritized by the World Health Organization as the primary adjunctive therapy for moderate to severe depression when added to ongoing pharmacotherapy 1
• Cognitive behavioral therapy (CBT) provides similar efficacy and should be offered as an alternative evidence-based option 1, 2
• Interpersonal therapy represents another validated psychological approach for adjunctive treatment 1
• Acceptance and commitment therapy has demonstrated effectiveness as an adjunctive intervention 1

Assess response at 4 and 8 weeks using validated instruments (such as PHQ-9 or MADRS) to determine whether escalation to pharmacologic augmentation is needed. 1

Second-Step Adjunctive Therapy: Pharmacologic Augmentation

If psychological intervention added to antidepressant produces insufficient response after 8 weeks, proceed to pharmacologic augmentation:

Preferred Pharmacologic Augmentation Agents

• Aripiprazole is FDA-approved specifically for adjunctive treatment in unipolar depression and demonstrates significant efficacy, with remission rates of 36.8% versus 18.9% for placebo (P<.001) 1, 3, 4
• Bupropion SR shows lower discontinuation rates due to adverse events compared to other augmentation options 1

Both agents provide similar symptomatic relief when used as augmentation strategies. 2

Alternative Pharmacologic Augmentation Options

• Lithium has established efficacy as an augmentation agent for treatment-resistant depression 5
• Thyroid hormone (T3) can be considered for augmentation in select cases 5
• Second-generation antidepressants (adding a different class) represent another pharmacologic option 1

Different switching and augmentation strategies provide similar symptom relief, so selection should be based on adverse event profiles and patient-specific factors. 2

Complementary Approaches with Evidence

The American College of Physicians recognizes several complementary approaches as adjunctive options: 1

• Omega-3 fatty acids (EPA and DHA) are particularly recommended for patients with comorbid coronary heart disease and depression 1
• S-adenosyl-L-methionine (SAMe) has demonstrated efficacy as an adjunctive treatment 1, 2
• Exercise (minimum 30 minutes of moderate-intensity physical activity on most days) provides meaningful benefit 1
• St. John's wort shows evidence for efficacy but requires caution regarding drug interactions 1, 2
• Acupuncture, meditation, and yoga represent additional evidence-based complementary options 1, 2

Critical Monitoring and Safety Considerations

Monitor closely for suicidality, especially during the initial months of treatment or at times of dose changes. 4 All patients receiving antidepressants for any indication require monitoring for:

• Clinical worsening and emergence of suicidal ideation 4
• Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, or mania 4
• These symptoms may represent precursors to emerging suicidality and warrant consideration of changing the therapeutic regimen 4

For aripiprazole specifically, monitor for:

• Neuroleptic malignant syndrome (hyperpyrexia, muscle rigidity, altered mental status, autonomic instability) 4
• Tardive dyskinesia risk, which increases with duration of treatment 4
• Metabolic side effects including weight gain, lipid abnormalities, and glucose dysregulation 4

Monitor treatment adherence throughout, as this significantly impacts outcomes. 1

Common Pitfalls to Avoid

• Do not immediately switch antidepressants or add another antidepressant before attempting psychological intervention augmentation, as this avoids loss of partial response and the complications of wash-out and cross-titration 5
• Do not use benzodiazepines for anxiety management in depression due to dependence risk and potential worsening of outcomes 1
• Avoid prescribing antidepressants as monotherapy for mild depression initially, as psychological interventions should be first-line 6
• Do not stop treatment prematurely—continue for at least 9-12 months after recovery to prevent relapse 6

Evidence Quality Considerations

The certainty of evidence for most treatment comparisons is low, with high dropout rates, dosing inequalities, and small sample sizes limiting confidence. 2 However, the consistency of findings across multiple trials supports the recommended approach of sequential augmentation starting with psychological interventions. 1, 7

Collaborative care programs with systematic follow-up significantly improve treatment effectiveness (SMD 0.42,95% CI 0.23-0.61), making structured monitoring essential regardless of which augmentation strategy is selected. 7