Self-criticism predicts antidepressant effects of intermittent theta-burst stimulation in Major Depressive Disorder

Background: Self-criticism is a risk factor for depression and depressive symptom persistence, however higher degrees of self-criticism have been associated with greater antidepressant benefits from repetitive transcranial magnetic stimulation (rTMS), suggesting that self-criticism may act as a proxy for function of the targeted circuit. We test this hypothesis using secondary data from an rTMS treatment trial where an NMDA receptor agonist (DCycloserine) was used to enhance TMS synaptic plasticity to improve efficacy. We hypothesized that selfcriticism would be more strongly associated with treatment outcome when stimulation was paired with DCycloserine than with a placebo. Methods: In a 4-week single-site double-blind randomized placebo-controlled trial, fifty adults with Major Depressive Disorder (MDD) (NCT03937596) were randomized to receive placebo or D-Cycloserine (100 mg) with daily intermittent theta-burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC). At baseline and after treatment, self-criticism was assessed using the Depressive Experiences Questionnaire as a secondary trial outcome and depressive symptoms were assessed using the clinician rated Montgomery Asberg Depression Rating scale (MADRS). Clinical response was defined as a >= 50 % decrease on the MADRS. Results: Self-criticism differentially predicted antidepressant effects when operationalized as both percent decrease on the MADRS and clinical response (>= 50 % decrease), with a statistically significantly stronger association in the iTBS+D-Cycloserine group than the iTBS+Placebo condition. Self-criticism did not significantly change in either condition over the course of treatment. Conclusions: Our data suggests that iTBS to the left DLPFC engages a circuit related to self-criticism. Higher levels of self-criticism predicted better response to iTBS with an adjuvant that enhances synaptic plasticity. This suggests that personality traits may be used to tailor non-invasive neurostimulation treatments.