Depression Augmentation Therapy Requires Clinical Judgment With Limited Evidence

Review Explores Harms Linked to Antidepressant Treatment
Review Explores Harms Linked to Antidepressant Treatment
Clinicians prescribing antidepressants may need to consider augmenting their therapy with another agent.

The definition of treatment-resistant depression can be controversial, but one widely accepted definition is a failure to respond to 2 consecutive, adequate trials of antidepressants. One- to two-thirds of patients with major depressive disorder do not achieve remission with initial monotherapy, and physicians need to consider whether the prescribed therapy requires augmentation with another agent.

That question, however, opens up many others, such as which agents to use, how much to use, when to augment rather than switch medications, and related clinical decisions. Research into augmentation that offers relevant clinical guidance remains thin, but studies are beginning to fill in the gaps, starting with which patients might be more likely to need augmented therapy.

Initial Therapy Linked to Augmentation Needs

Some research suggests that the initial monotherapy individuals receive may influence how likely they are to need augmentation. A study from June in the Journal of Clinical Psychopharmacology looked at which patients are most likely to receive augmentation based on the initial drugs they were taking for depression.

The researchers used private insurance administrative data to analyze the 2009 prescription histories of 214,705 US adults, ages 18 to 64, who were receiving treatment for a new diagnosis of major depression. Those with diagnoses of psychosis, mania, or bipolar disorders were excluded.

“There’s evidence that the use of SGAs has been on the rise since 2000 for treatment of depression either in monotherapy or as adjuvant therapy, so we thought it would be interesting to look at augmentation as an endpoint,” lead author Omid Ameli, MD, MPH, a doctoral candidate at Boston University School of Public Health, Boston, Massachusetts, told Psychiatry Advisor.

The medications in their analysis included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, second-generation (atypical) antipsychotics (SGA), serotonin agonists/antagonists, noradrenergic and specific serotonergic antidepressants, and tricyclic antidepressants.

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Ameli’s team found that 34% of their study population received augmentation, and augmentation was 2.6 times more likely among patients initially taking SGAs than among those taking SSRIs. People with severe depression were more likely to be taking SGAs than those with mild or moderate depression, but the researchers adjusted for depression severity, hospitalization, medication class switches, comorbidities, and demographic information. Even after adjustment, augmentation was 2.85 times more likely following SGAs than other drug classes.

“The SGAs are a relatively new class of drugs and there may be some incentive and interest on the provider side to prescribe them, but in an observational study, they’re not superior,” Ameli said. He emphasized the observational study’s limitations, particularly because they were only able to look at “a snapshot of the disease history,” he said.


  1. Ameli O, Soria-Saucedo R, Smith EG, Cabral HJ, Soley-Bori M, Kazis LE. Associations between medication class and subsequent augmentation of depression treatment in privately insured US adults. J Clin Psychopharmacol. 2017;37:323-331.
  2. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017;318:132-145.
  3. Marwood L, Taylor R, Goldsmith K, et al. Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study). BMC Psychiatry. 2017;17:231.