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 (D-Cycloserine) was used to enhance TMS synaptic plasticity to improve efficacy. We hypothesized that self-criticism would be more strongly associated with treatment outcome when stimulation was paired with D-Cycloserine 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.