What is the best augmenting agent for a patient with severe Major Depressive Disorder (MDD), Obsessive-Compulsive Disorder (OCD), and Generalized Anxiety Disorder (GAD) who has achieved a partial response to 200mg of sertraline (Zoloft)?

Aripiprazole Augmentation for Partial Response to Sertraline

For a patient with severe MDD, OCD, and GAD showing partial response to 200mg sertraline, aripiprazole augmentation is the best evidence-based choice, with risperidone as an alternative if aripiprazole is not tolerated. 1, 2

Primary Recommendation: Aripiprazole

Aripiprazole has the strongest evidence base for augmenting SSRIs in both treatment-resistant OCD and depression, making it ideal for this patient with multiple comorbidities. 1, 2

Evidence Supporting Aripiprazole

• For OCD specifically: Meta-analyses demonstrate aripiprazole is one of only two antipsychotics (along with risperidone) with proven efficacy for SSRI-resistant OCD, though only approximately one-third of patients show clinically meaningful response. 1

• For MDD specifically: Multiple studies show 52-70% response rates when aripiprazole augments antidepressants in treatment-resistant depression, with significant improvement beginning as early as week 1. 3, 4

• Dosing advantage: Effective doses are low (mean 6.9-13.2 mg/day), which improves tolerability compared to other antipsychotics. 4, 5

• Side effect profile: Aripiprazole causes less metabolic dysregulation and weight gain than risperidone or olanzapine, critical for long-term tolerability. 1, 5

Practical Implementation

• Start aripiprazole at 5mg daily, titrating to 10-15mg based on response and tolerability over 2-4 weeks. 4, 5

• Expect response within 1-6 weeks if augmentation will be effective; reassess at 6 weeks minimum. 3, 4

• Monitor for akathisia (most common side effect at 20%), along with sedation, restlessness, and nausea. 3, 4

Alternative: Risperidone

Risperidone shares equivalent evidence to aripiprazole for OCD augmentation but has a less favorable metabolic profile. 1, 2

• Use risperidone if aripiprazole causes intolerable akathisia or is otherwise not tolerated. 2

• Risperidone carries higher risk of weight gain and metabolic dysregulation, requiring ongoing monitoring of the risk-benefit ratio. 1

Critical Treatment Considerations Before Augmentation

Ensure Adequate SSRI Trial

• Confirm sertraline has been at maximum dose (200mg) for at least 8-12 weeks with verified adherence before labeling as treatment-resistant. 6

• Treatment resistance requires failure of adequate trials, not just partial response to a single agent. 1, 6

Prioritize CBT with Exposure and Response Prevention

Adding CBT with ERP produces larger effect sizes than pharmacological augmentation alone and should be implemented if not already in place. 1, 6

• The combination of SSRIs with CBT showed superior outcomes compared to SSRI plus risperidone augmentation in head-to-head trials. 1

• True treatment resistance in OCD requires failure of both adequate SSRI trials AND CBT with ERP. 6

Why NOT Other Options

Bupropion Augmentation

• While bupropion augmentation showed benefit for MDD in the STAR*D trial, it has no evidence base for OCD, making it suboptimal for this patient with prominent OCD symptoms. 1

• Bupropion decreased depression severity more than buspirone but showed no difference in response or remission rates. 1

Buspirone Augmentation

• Buspirone showed similar efficacy to bupropion for MDD augmentation but had higher discontinuation rates due to adverse events (20.6% vs 12.5%) and no evidence for OCD. 1

Switching Strategies

• Switching to another SSRI or SNRI shows no superiority over augmentation strategies and would abandon the partial response already achieved. 1

• The STAR*D trial found no differences between various switch strategies (bupropion, sertraline, venlafaxine). 1

Clomipramine Augmentation

• While clomipramine plus fluoxetine was superior to fluoxetine plus quetiapine in one trial, the combination carries serious risks including seizures, cardiac arrhythmias, and serotonergic syndrome due to drug-drug interactions. 1

• This risk profile makes clomipramine augmentation inappropriate as a first augmentation choice. 1

Glutamatergic Agents (N-acetylcysteine, Memantine)

• N-acetylcysteine has the largest evidence base among glutamatergic agents, but only 3 of 5 randomized trials showed superiority to placebo, making it a weaker choice than aripiprazole. 1

• Consider these agents only after failure of antipsychotic augmentation. 1

Duration and Monitoring

• Maintain effective augmentation for 12-24 months after achieving remission due to high relapse rates after discontinuation. 6

• Approximately 50% of OCD patients fail to fully respond to first-line treatments, with even higher rates in real-world settings. 1, 6

• Ongoing monitoring of metabolic parameters is essential with any antipsychotic augmentation, though aripiprazole has the most favorable profile. 1

Key Pitfalls to Avoid

• Do not pursue augmentation without confirming adequate sertraline trial duration and adherence. 6

• Do not add pharmacological augmentation without ensuring CBT with ERP has been adequately attempted, as this combination has superior evidence. 1, 6

• Do not use bupropion or buspirone as first-line augmentation in patients with prominent OCD, as these lack evidence for OCD treatment. 1