Effectiveness of a Combined High-Definition tDCS-Primed Intermittent Theta Burst Stimulation Protocol Targeting the Cerebellar Vermis in Treatment-Resistant Schizophrenia: a Randomized Sham-Controlled Trial.

Around 60% of treatment-resistant schizophrenia (TRS) patients fail conventional therapies. This study aimed to evaluate the safety and effectiveness of a combined high-definition transcranial direct current stimulation (HD-tDCS)-primed intermittent theta burst stimulation (iTBS) protocol targeting the cerebellar vermis using a randomized, sham-controlled design. Thirty-six right-handed TRS patients (aged 18-59 years) were randomized to active (n = 18) and sham (n = 18) groups. The active group received cathodal HD-tDCS (2 mA for 15 min) at the cerebellar vermis, followed by iTBS per session. Sessions were daily for 5 days/week over 2 weeks (total 10 sessions), 30 min apart. The sham group received sham HD-tDCS (0.2 mA) followed by sham iTBS. Assessments occurred at baseline, Day 14, and Day 28 using the Positive and Negative Syndrome Scale (PANSS), Schizophrenia Cognition Rating Scale (SCoRS), Modified Simpson-Angus Extrapyramidal Side Effects Scale (MSAS), CGI-S, and WHOQOL-BREF. Intention-to-treat analysis revealed significant between-group time × group interactions favored the active group for PANSS total (F = 6.196, p = 0.018, partial η²=0.170), PANSS-negative (F = 5.06, p = 0.031, partial η²=0.130), and SCoRS (F = 4.149, p = 0.049, partial η²=0.109). No significant effects for PANSS-positive (p = 0.107), PANSS-general (p = 0.175), CGI-S (p = 0.174), WHOQOL-BREF (p = 0.088), or MSAS (p = 0.935). Minor side effects reported; no dropouts from adverse events. The combined HD-tDCS-primed iTBS protocol targeting the cerebellar vermis is safe and modestly effective for overall psychopathology, negative symptoms, and cognition in treatment-resistant schizophrenia. Due to simultaneous sham control of both modalities, the specific contribution of HD-tDCS priming cannot be isolated. Future 2 × 2 factorial trials with neuronavigation are required.