What is the best augmenting agent for vortioxetine (Brintellix) in treatment-resistant depression (TRD)?

Best Augmentation Agent for Vortioxetine in Treatment-Resistant Depression

Aripiprazole is the best augmentation agent for vortioxetine in treatment-resistant depression due to its FDA approval for adjunctive treatment in unipolar depression and demonstrated efficacy in clinical trials.

Understanding Treatment-Resistant Depression (TRD)

Treatment-resistant depression (TRD) is generally defined as failure to respond to at least two adequate trials of antidepressants from different classes during the current depressive episode 1. Key characteristics of TRD include:

• Inadequate response to at least two antidepressant trials at adequate dose and duration
• Each trial should be at minimum effective dosage for at least 4 weeks 1
• Medications should have different mechanisms of action 1
• Affects approximately one-third of patients with major depressive disorder 2

Augmentation Options for Vortioxetine in TRD

First-Line Option: Atypical Antipsychotics

Atypical antipsychotics have the strongest evidence base for augmentation in TRD:

1. Aripiprazole:

   • First atypical antipsychotic to receive FDA approval specifically for adjunctive treatment in unipolar, non-psychotic depression 3
   • Generally requires lower doses than those used for schizophrenia or bipolar disorder 3
   • Demonstrated efficacy in controlled clinical trials 4
   • Best supported by evidence among atypical antipsychotics 4

2. Other Atypical Antipsychotics:

   • Quetiapine: Beneficial especially when comorbid anxiety or insomnia are present 4
   • Risperidone and Olanzapine: Less studied but preliminary data indicates efficacy 4
   • Brexpiprazole and Cariprazine: Also FDA-approved for depression augmentation 2

Alternative Augmentation Strategies

If atypical antipsychotics are contraindicated or not tolerated, consider:

1. Bupropion SR:

   • STAR*D trial showed efficacy as an augmentation agent 1
   • Lower discontinuation rate due to adverse events compared to buspirone (12.5% vs. 20.6%) 1

2. Buspirone:

   • Effective augmentation option based on STAR*D data 1
   • Higher discontinuation rate due to adverse events compared to bupropion 1

3. Cognitive Therapy:

   • Similar efficacy to medication augmentation strategies in STAR*D 1
   • Lower discontinuation rate due to adverse events compared to medication augmentation (9.2% vs. 18.8%) 1

Important Considerations for Vortioxetine Augmentation

Dosing Considerations

• Ensure vortioxetine is at an adequate dose before augmentation
• Consider that supratherapeutic doses of vortioxetine (30-40 mg/day) may be effective and relatively well-tolerated in TRD patients before moving to augmentation 5
• When augmenting with aripiprazole, use lower doses than those recommended for schizophrenia or bipolar disorder 3

Monitoring and Side Effects

When using atypical antipsychotics for augmentation:

• Monitor for weight gain, metabolic changes, and akathisia 2
• Risk of tardive dyskinesia with long-term use 2
• Regular assessment of benefit-to-risk ratio is essential 1

Clinical Decision Algorithm

1. Confirm TRD diagnosis:

   • Verify at least two failed antidepressant trials at adequate dose (minimum effective dose) and duration (≥4 weeks each) 1
   • Ensure the failed medications had different mechanisms of action 1
   • Rule out bipolar depression, active substance use disorders, and personality disorders that may mimic TRD 1

2. Optimize vortioxetine dosing:

   • Consider increasing to maximum approved dose or even supratherapeutic doses (30-40 mg/day) if tolerated 5

3. Initiate augmentation with aripiprazole:

   • Start at low dose and titrate based on response and tolerability
   • Monitor for common side effects including akathisia and weight gain

4. If aripiprazole is not tolerated or ineffective:

   • Consider alternative atypical antipsychotics (quetiapine, brexpiprazole, cariprazine)
   • Or non-antipsychotic options: bupropion SR, buspirone, or cognitive therapy 1

5. Regular reassessment:

   • Evaluate response, remission, and side effects
   • Consider discontinuation of augmentation if no benefit after 4-6 weeks

Pitfalls and Caveats

• Avoid combining vortioxetine with MAOIs due to risk of serotonin syndrome
• Be cautious with high-dose strategies in elderly patients or those with hepatic impairment
• The evidence specifically for augmentation of vortioxetine is limited; recommendations are extrapolated from general TRD augmentation strategies
• Vortioxetine itself has limited evidence in TRD compared to other antidepressants 6
• Consider that switching to another antidepressant may be as effective as augmentation strategies in some cases 1