Best Adjunctive Therapy for Worsening Depression with Well-Controlled Anxiety
For worsening depression in a patient with well-managed anxiety, problem-solving treatment or cognitive behavioral therapy (CBT) should be added as adjunctive therapy to the current antidepressant regimen. 1
Primary Recommendation: Psychological Adjunctive Treatment
In moderate and severe depression, problem-solving treatment should be considered as adjunct treatment to ongoing pharmacotherapy. 1 This recommendation comes directly from WHO guidelines and prioritizes non-pharmacologic augmentation when anxiety symptoms are already controlled.
Alternative Psychological Options
Cognitive behavioral therapy (CBT), including behavioral activation, represents an equally strong first-line adjunctive psychological intervention for moderate to severe depression in patients already on medication. 1
Interpersonal therapy may also be considered as adjunctive psychological treatment if resources and trained providers are available. 1
Pharmacologic Augmentation Strategies (If Psychological Treatment Insufficient)
If psychological adjunctive treatment fails after 8 weeks or is not accessible, pharmacologic augmentation becomes necessary:
First-Line Pharmacologic Augmentation
Bupropion SR augmentation demonstrated similar efficacy to other augmentation strategies in the STAR*D trial, with lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%). 1
Aripiprazole augmentation is FDA-approved for adjunctive treatment in unipolar, nonpsychotic depression and showed superior remission rates (55.4%) compared to bupropion (34.0%) in one trial, though this study had high risk of bias. 1, 2
Important Consideration About Anxiety Control
Since anxiety is already well-controlled, avoid benzodiazepines or anxiolytic-focused augmentation strategies that could introduce unnecessary sedation or dependence risk without addressing the primary problem of worsening depression. 1
Buspirone augmentation showed similar efficacy to bupropion in STAR*D but had higher discontinuation rates (20.6% vs 12.5%) due to adverse events. 1
Adjunctive Physical Activity and Relaxation
- Advice on physical activity and relaxation training may be considered as adjunct treatment in moderate and severe depression, though these should supplement rather than replace primary adjunctive interventions. 1
Treatment Monitoring Algorithm
Assess treatment response at 4 weeks and 8 weeks using standardized validated instruments to monitor both depressive symptoms and ensure anxiety remains controlled. 3
If little improvement occurs after 8 weeks despite good adherence, consider adding a pharmacologic intervention to the psychological adjunctive therapy or switching the augmentation strategy. 3
Monitor for symptom relief, side effects, adverse events, and patient satisfaction at each assessment point. 3
Common Pitfalls to Avoid
Do not add benzodiazepines or increase anxiolytic medications when the primary problem is worsening depression with controlled anxiety—this addresses the wrong target symptom. 1
Avoid waiting beyond 8 weeks to adjust ineffective adjunctive treatment, as prolonged inadequate response worsens outcomes and increases chronicity risk. 3
Do not use antidepressant monotherapy switching as first-line when augmentation is indicated—the evidence from STAR*D showed similar efficacy between switch and augmentation strategies, but augmentation preserves any partial response to the current regimen. 1
Failing to use standardized instruments for monitoring makes it impossible to objectively determine treatment response and leads to delayed intervention adjustments. 3
Nuanced Evidence Considerations
The 2023 American College of Physicians guideline 1 found that various augmentation strategies (bupropion, buspirone, cognitive therapy) showed similar efficacy in STAR*D, with moderate certainty evidence. However, bupropion had superior tolerability compared to buspirone, making it the preferred pharmacologic option if psychological augmentation is insufficient or unavailable.
The WHO guidelines 1 explicitly recommend problem-solving treatment as adjunct therapy in moderate and severe depression, providing the strongest guideline-level support for this approach. This is particularly appropriate when anxiety is already controlled, as it avoids introducing medications that might destabilize the current successful anxiety management.