Which augmentation combination therapies may be considered for treatment-resistant major depression (TRMD)?

Updated: Aug 06, 2020
  • Author: Jerry L Halverson, MD; Chief Editor: David Bienenfeld, MD  more...
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Augmentation combinations can include the following:

  • Bright-light therapy plus any antidepressant

  • Buspirone (BuSpar) plus a TCA or SSRI

  • Lithium (Eskalith, Lithane, Lithobid) plus any antidepressant

  • Methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) plus any antidepressant other than an MAOI

  • TCA plus an SSRI

  • Triiodothyronine (Cytomel) plus any antidepressant

The STAR*D trial found that augmentation of an SSRI with bupropion and augmentation with buspirone were equally effective after a lack of response to the SSRI. [168]

Aripiprazole (Abilify) is the first drug approved by the FDA for adjunctive treatment in major depressive disorder and the first drug to receive FDA approval for use in treatment-resistant depression. [170, 171, 172]

Esketamine nasal spray was approved by the FDA in March 2019 for treatment-resistant depression in conjunction with an oral antidepressant. It is administered in a physician’s office and the patient must be carefully monitored for at least 2 hours owing to risk of sedation, dissociation, and elevated blood pressure following the dose.

Efficacy of esketamine was evaluated in 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. In the short-term studies, patients were randomized to receive esketamine intranasal or a placebo nasal spray. Owing to the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. Primary efficacy was measured by the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) used to assess the severity of depressive symptoms. In one of the short-term studies, esketamine nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within 2 days. The 2 other short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine intranasal plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant. [173, 174]

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