What is the treatment for treatment-resistant depression?

Treatment for Treatment-Resistant Depression

For treatment-resistant depression (TRD), the most effective approach is augmentation with atypical antipsychotics, particularly quetiapine, which has demonstrated superior clinical effectiveness and cost-effectiveness compared to other augmentation strategies. 1

Definition of Treatment-Resistant Depression

• TRD is generally defined as failure to respond to at least two adequate trials of antidepressants with different mechanisms of action in the current depressive episode 2
• An adequate trial requires the minimal approved dosage administered for at least four weeks 2
• Discontinuation of treatment before completing four weeks due to side effects should not be considered a treatment failure for establishing TRD 2

First-Line Treatment Options for TRD

Pharmacological Augmentation Strategies

• Atypical antipsychotic augmentation has the most extensive and rigorous evidence base of all pharmacological approaches for TRD 3

  • Quetiapine shows greater reduction in depressive symptoms over 52 weeks compared to lithium and is more cost-effective 1
  • Aripiprazole, brexpiprazole, cariprazine, and olanzapine-fluoxetine combination are also FDA-approved for depression augmentation 4
  • Consider metabolic side effects when using olanzapine-fluoxetine combination 5

• Lithium augmentation is effective but may be less effective than quetiapine based on recent evidence 1, 5

• Thyroid hormone augmentation with liothyronine (T3) has shown efficacy, while evidence for levothyroxine (T4) is insufficient 5

Antidepressant Strategies

• Combining antidepressants with different mechanisms of action (e.g., adding bupropion, tricyclics, or mirtazapine to existing therapy) 5
• Switching antidepressants is generally less effective than augmentation strategies 6, 5

Second-Line Treatment Options

• Anticonvulsant augmentation with lamotrigine has shown efficacy 5

• Non-pharmacological interventions:

  • Electroconvulsive therapy (ECT) is effective for TRD patients who have failed multiple medication trials 6, 3
  • Transcranial magnetic stimulation (TMS) can be considered for patients who have failed medication trials 2, 3
  • Psychotherapy, particularly cognitive behavioral therapy, can be used in conjunction with pharmacotherapy 2, 3

Third-Line Treatment Options

• Esketamine/ketamine appears effective for TRD 5

• Experimental options for refractory cases:

  • Psychostimulants (e.g., lisdexamfetamine) 3
  • Vagus nerve stimulation (VNS) for patients who have failed at least four adequate treatments 6

Treatment Algorithm

1. Confirm TRD diagnosis:

   • Verify failure of at least two adequate antidepressant trials with different mechanisms of action 2
   • Ensure each trial was at minimum effective dosage for at least 4 weeks 2

2. First treatment choice:

   • Add quetiapine to current antidepressant (strongest recent evidence for effectiveness and cost-efficiency) 1
   • If contraindicated, consider aripiprazole or brexpiprazole (less metabolic risk) 4

3. If first augmentation fails:

   • Try alternative augmentation with lithium or T3 5
   • Consider antidepressant combinations (e.g., adding bupropion or mirtazapine) 5

4. If pharmacological approaches fail:

   • Refer for ECT evaluation 6
   • Consider TMS if ECT is refused or contraindicated 3

5. For highly refractory cases:

   • Consider esketamine/ketamine 5
   • Evaluate for VNS in patients who have failed ≥4 treatments 6

Important Considerations

• Patients with TRD who have failed multiple medications should not be excluded from treatment trials 2
• Previous failure of psychotherapy should not alter the pharmacological treatment approach 2
• All depression specifiers (melancholic, atypical, anxious, psychotic, mixed) should be considered within TRD, except bipolar depression 2
• Carefully monitor for side effects with atypical antipsychotics, including weight gain, metabolic changes, akathisia, and risk of tardive dyskinesia 4