Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.

No abstract

Background: While cigarette smoking has plummeted in the general population, rates have stagnated in patients with schizophrenia. We tested a 3-week regimen of deep repetitive transcranial magnetic stimulation (dTMS) capable of reaching the insula, which plays an important role in maintaining smoking. Methods: Patients were assigned to active or sham stimulation. Therapeutic efficacy was assessed with cigarette self-administration (pre/post laboratory assessments); target engagement was tested with arterial spin labeling (ASL) (three MRI sessions during the trial). Of 32 enrolled patients, 20 completed the study (N¼10 active dTMS; N¼10 sham dTMS), while 12 were withdrawn. Data were analyzed with generalized estimating equations [Visit (within-person)  Group (between-person)]. Results: Number of Cigarettes Smoked during Self-Administration. Despite a nonsignificant Visit  Group interaction, the active dTMS group smoked numerically fewer cigarettes after treatment than before treatment (p¼0.15), a trend not seen for sham (p¼0.44) (exploratory posthoc comparisons). Latency to Smoke during Self-Administration. A significant Visit  Group interaction (p¼0.04) was driven by a greater probability of delayed smoking after active dTMS than sham. ASL Results. Across all participants, insula blood flow was lower after the first treatment than at baseline (Visit main effect). Notably, this Visit main effect was driven by the active dTMS group (p¼0.05) (exploratory posthoc comparisons), consistent with a greater modulation of insula activity in the patients receiving real stimulation. Conclusions: These pilot data suggest that dTMS may disrupt smoking self-administration in schizophrenia, with some indication of insula target engagement. A larger trial is warranted for confirmation. FUNDING: Lucian Manu received funding administered through Stony Brook University from 1. Janssen Pharmaceuticals to conduct clinical trials with Esketamine 2. LivaNova to conduct clinical trials with Symmetry VNS Therapy.

No abstract