From the Guidelines
For treatment-resistant depression, ketamine or esketamine (Spravato) is often considered the most effective option when standard antidepressants have failed. Esketamine is administered as a nasal spray at doses of 56-84mg twice weekly for the first month, then weekly to biweekly for maintenance, under medical supervision. Alternatively, intravenous ketamine (0.5mg/kg over 40 minutes) may be used off-label in specialized clinics. Other approaches include combining an antidepressant with an atypical antipsychotic like aripiprazole (2-15mg daily) or adding lithium (600-900mg daily, targeting blood levels of 0.6-0.8 mEq/L). Transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT) are non-medication options with high efficacy. These treatments work differently than traditional antidepressants - ketamine acts rapidly on glutamate pathways rather than serotonin, providing relief within hours to days instead of weeks. Treatment-resistant depression requires professional evaluation, as medication combinations carry risks and should be closely monitored for side effects and therapeutic response.
Key Considerations
- The American College of Physicians recommends selecting second-generation antidepressants based on adverse effect profiles, cost, and patient preferences 1.
- Studies have shown that 38% of patients do not achieve a treatment response during 6 to 12 weeks of treatment with second-generation antidepressants, and 54% do not achieve remission 1.
- Mirtazapine has a faster onset of action than fluoxetine, paroxetine, or sertraline, but response rates are similar after 4 weeks 1.
- Combination therapy and alternative treatments like ketamine or esketamine may be effective for treatment-resistant depression, but require careful monitoring and professional evaluation.
Treatment Options
- Ketamine or esketamine (Spravato) for rapid relief
- Combination therapy with an antidepressant and an atypical antipsychotic like aripiprazole
- Adding lithium to an existing antidepressant regimen
- Transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT) for non-medication options
Monitoring and Evaluation
- Regular assessment of patient status, therapeutic response, and adverse effects beginning within 1 to 2 weeks of initiation of therapy 1.
- Close monitoring of medication combinations and alternative treatments for side effects and therapeutic response.
From the Research
Treatment Options for Resistant Depression
- Combining antidepressants is a common strategy for treating resistant depression, with various studies suggesting its efficacy 2, 3, 4, 5.
- The combination of venlafaxine and mirtazapine has been shown to be effective in treating treatment-refractory depression, with response rates ranging from 44% to 81.8% 2, 4.
- Other combination strategies, such as combining SSRIs with Reboxetine, Bupropion, Mirtazapine, or Tricyclics, may also be effective 5.
- However, combination therapies can also have potential safety risks due to pharmacokinetic and pharmacodynamic interactions, such as the risk of serotonin syndrome or increased toxicity 5.
Efficacy of Combination Therapies
- A review of 27 studies found an overall mean response rate of 62.2% for combination antidepressant treatment 3.
- A study of 32 patients with persistent depressive illness found a clinical response rate of 44% at 4 weeks and 50% at 8 weeks with the combination of mirtazapine and venlafaxine 4.
- Another study found a response rate of 81.8% and a remission rate of 27.3% with the combination of venlafaxine and mirtazapine 2.