Depressive disorders are the most common diagnosis among individuals who die by suicide, and intermittent theta-burst stimulation (iTBS) is a noninvasive treatment for those with difficult-to-treat depression who are at higher risk for suicide. Previous data suggests that pairing iTBS with D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, improves antidepressant outcomes. However, its impact on suicide risk is not known.

We examine suicidal ideation and implicit suicide risk after iTBS+D-cycloserine in two clinical trials (open-label trial [n = 12] and randomized placebo-controlled trial [RCT, n = 50]) involving adults with major depressive disorder and the acute effects of D-cycloserine on implicit suicide risk in a crossover trial (n = 18). Implicit suicide risk was assessed using the computerized death/suicide implicit association test (IAT), and depressive symptoms and suicidal ideation were assessed using the clinician-rated Montgomery–Asberg Depression Rating Scale (MADRS).

Open-label iTBS+D-cycloserine was associated with a rapid reduction in suicidal ideation, and iTBS+D-cycloserine was superior to iTBS+placebo in reducing suicidal ideation. Similarly, open-label iTBS+D-cycloserine was associated with decreased implicit suicide risk as measured by the death/suicide IAT, and iTBS+D-cycloserine was associated with greater decreases in death/suicide IAT scores compared to iTBS+placebo. A single acute dose of D-cycloserine in the absence of iTBS had no effect on implicit suicide risk.

Adjunctive D-cycloserine with iTBS is a promising strategy to reduce suicidal ideation and implicit suicide risk in depression.