Pharmacotherapy for Treatment-Refractory Unipolar Major Depression

Pharmacotherapy for Treatment-Refactory Unipolar Major Depression

• Patients with treatment-refractory unipolar major depression often receive an antidepressant augmented with another drug, but antidepressant monotherapy is a reasonable alternative.
• The efficacy of different antidepressants is generally comparable across and within classes, and the drug choice is based on factors such as safety and adverse effects.
• The general order of preference in choosing an antidepressant is SSRI, SNRI, atypical antidepressant, serotonin modulator, tricyclic antidepressant, and MAOI.
• For selecting augmentation agents, the general order of preference is second-generation antipsychotic, lithium, second antidepressant from a different class, and thyroid hormone.
• Second-generation antipsychotics have the best balance of efficacy and tolerability among these options, particularly in combination with first-line antidepressants such as SSRIs and SNRIs.
• Other augmentation agents that can be useful for treatment-refractory depression are intravenous ketamine and intranasal esketamine.
• The combination of a tricyclic antidepressant and an MAOI is a treatment of last resort due to potential life-threatening drug-drug interactions.
• Combining tricyclics and MAOIs requires a thorough discussion of risks and benefits, as well as careful monitoring, and the MAOI is added after a failed trial of tricyclic monotherapy.
• Low-quality evidence supporting the use of a tricyclic plus an MAOI includes a retrospective study of 62 cases.
• Complex medication regimens with ≥4 psychotropic drugs are generally avoided because there is no data supporting their utility, and patients may feel worse due to the cumulative side effects.
• The role of ketamine and esketamine in treating major depression, as well as their administration, efficacy, and adverse effects, are discussed separately.
• Additional information about choosing adjunctive pharmacotherapy, including the efficacy and tolerability of different options, is discussed separately in the context of treatment-resistant depression.