Caution When Continuing Benzodiazepines During rTMS: Response to Hunter and Leuchter

to the editor: We thank Drs. Hunter and Leuchter for their letter regarding our recently published work characterizing the change in depressive symptom trajectories with left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) (1). Our study, which was a secondary analysis of the THREE-D clinical trial that compared high-frequency and intermittent theta burst stimulation rTMS (2), found benzodiazepine use was associated with reduced odds of membership in a “rapid response” trajectory (odds ratio=0.40, 95% CI=0.18, 0.90) and with increased odds of membership in a “nonresponse” trajectory (odds ratio=2.25, 95% CI=0.99, 5.11). Similarly, Hunter et al. (3) found a lower response rate to high-frequency left DLPFC rTMS when benzodiazepines were used concomitantly.

Despite the exploratory nature of both analyses, which generally should be regarded with caution, there exists biological plausibility for the findings of benzodiazepines interfering with rTMS treatment. Benzodiazepines exhibit their mechanism of action via allosteric modulation of the GABA_A receptor and seem to impair the ability of TMS to effectively propagate to distant regions from the stimulation site (4). The ability of left DLPFC rTMS to induce changes in sites distal to the stimulation site (i.e., the subgenual anterior cingulate cortex) has emerged as one of the potential mechanisms of action of the treatment (5, 6).

A key next step will be to disentangle the complex relationship between benzodiazepines and anxiety, both of which may interfere with treatment outcomes. Anxiety is known to be a poor predictor of treatment response in depression pharmacotherapy (7), and benzodiazepine use may be a marker of high anxiety symptom burden. Although our exploratory analyses and additional sensitivity analyses did not find a significant effect of anxiety on treatment trajectory membership, residual confounding remains a possibility.

We agree with Drs. Hunter and Leuchter that there is a need to pay close attention to concomitant pharmacotherapy when prescribing rTMS. Notwithstanding the known deleterious effects of benzodiazepines when used on a chronic basis (i.e., falls, cognitive impairment, and motor vehicle accidents [8]), there now appears to be a convergence of data suggesting that these medications may portend a poorer outcome with rTMS. Clinicians should consider the risks and benefits of tapering or ideally stopping benzodiazepines prior to a course of rTMS. This may foster a more rapid, robust response and improve long-term outcomes.