What are effective add-on medications for treatment-resistant depression?

Effective Add-on Medications for Treatment-Resistant Depression

For patients with treatment-resistant depression, the most effective add-on medications are second-generation antipsychotics (particularly aripiprazole and quetiapine), which have demonstrated superior efficacy compared to other augmentation strategies. 1

Definition of Treatment-Resistant Depression

• Treatment-resistant depression (TRD) is defined as failure to achieve adequate response after at least 6-8 weeks of treatment with an antidepressant at an adequate dose 2
• Approximately 38% of patients do not achieve treatment response and 54% do not achieve remission with initial antidepressant therapy 2

First-Line Augmentation Options

Second-Generation Antipsychotics

• Aripiprazole and quetiapine are recommended as first-line augmentation strategies for TRD with relatively rapid onset of action 1, 3
• Aripiprazole augmentation has shown efficacy in 59% of patients with persistent depressive and anxiety disorders despite initial SSRI treatment 4
• Typical dosing for aripiprazole starts at 2-5 mg/day and can be titrated to 10-15 mg/day based on response 5
• Monitor for metabolic effects (weight gain, lipid changes, glucose abnormalities) and extrapyramidal symptoms when using antipsychotic augmentation 1, 6

Other Medication Augmentation Strategies

• Lithium augmentation has demonstrated efficacy for TRD and may be particularly beneficial for patients with suicidal ideation 3, 7
• Thyroid hormone supplementation (particularly T3/liothyronine) has shown effectiveness as an augmentation strategy 3, 7
• Buspirone can be used as an augmentation agent, though it has less robust evidence compared to antipsychotics 8
  • Caution: Buspirone should not be used with MAOIs due to risk of serotonin syndrome and elevated blood pressure 8

Non-Pharmacological Augmentation

• Adding Cognitive Behavioral Therapy (CBT) to antidepressant therapy is an effective strategy with similar benefits to medication augmentation and may provide more sustainable long-term outcomes 1
• For severe TRD, consider referral for evaluation for electroconvulsive therapy (ECT) 7, 9

Switching Strategies (Alternative to Augmentation)

• If augmentation is unsuccessful or not tolerated, switching to another antidepressant is a reasonable alternative 2, 1
• The STAR*D trial showed that approximately 25% of patients achieved remission after switching to a different antidepressant (bupropion SR, sertraline, or venlafaxine XR) with no significant difference in efficacy between these options 2
• Switching strategies avoid polypharmacy and may reduce adverse effects, but risk losing partial response achieved with initial treatment 7

Combination Antidepressant Strategies

• Combining antidepressants with different mechanisms of action can be effective:
  • Adding bupropion to an SSRI/SNRI 3
  • Adding mirtazapine to an SSRI/SNRI 3
  • Adding a tricyclic antidepressant to an SSRI (requires careful monitoring for drug interactions) 3

Duration of Treatment

• Continue augmentation strategy for at least 4-9 months after achieving satisfactory response 2, 1
• For patients with recurrent depression (≥2 episodes), longer treatment duration is beneficial 2, 1

Clinical Pearls and Pitfalls

• Ensure adequate dose and duration of initial antidepressant before concluding treatment resistance (minimum 6-8 weeks at therapeutic dose) 2
• Regularly reassess response to augmentation therapy and adjust treatment if inadequate improvement 2
• When using antipsychotic augmentation, start with low doses and titrate slowly to minimize side effects 5
• Consider potential drug interactions when combining medications (e.g., fluoxetine and paroxetine can increase aripiprazole levels due to CYP2D6 inhibition) 5