Accelerated Intermittent Theta-Burst Stimulation and Treatment-Refractory Bipolar Depression: A Randomized Clinical Trial.

Importance: Bipolar disorder (BD) is chronic and disabling, with depression accounting for the majority of time with illness. Recent research demonstrated a transformative advance in the clinical efficacy of transcranial magnetic stimulation for treatment-resistant major depressive disorder (MDD) using an accelerated schedule of intermittent theta-burst stimulation (aiTBS), but the effectiveness of this treatment for treatment-refractory BD is unknown. Objective: To evaluate the effectiveness of aiTBS for treatment-refractory BD. Design, Setting, and Participants: This randomized clinical trial, conducted from March 2022 to February 2024, included individuals with treatment-resistant BD with moderate to severe depressive episodes referred from the Penn Bipolar outpatient clinic. Included patients had 2 or more prior failed antidepressant trials by Antidepressant Treatment History Form criteria and no other primary psychiatric diagnosis, were receiving a mood stabilizer for 4 or more weeks, and had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher. Intervention: Prior to treatment, resting-state functional magnetic resonance imaging was used to compute personalized left dorsolateral prefrontal cortex target by connectivity to subgenual anterior cingulate cortex. Patients were randomized 1:1 to 10 sessions per day of imaging-guided active or sham aiTBS for 5 days with 1 session per hour at 90% resting motor threshold for 90 000 pulses total. Main Outcome and Measures: The main outcome was repeated MADRS scores before and after treatment. Results: A total of 24 participants (12 [50%] female; 12 [50%] male; mean [SD] age, 43.3 [16.9] years) were randomized to active (n = 12) or sham (n = 12) aiTBS. All participants completed treatment and 1-month follow-up. MADRS scores were significantly lower in the active group (mean [SD], 30.4 [4.8] at baseline; 10.5 [6.7] after treatment) than in the sham group (28.0 [5.4] at baseline; 25.3 [6.7] after treatment) at treatment end (estimated difference, -14.75; 95% CI, -19.73 to -9.77; P < .001; Cohen d, -2.19). Conclusion and Relevance: In this randomized clinical trial, aiTBS was more effective than sham stimulation for depressive symptom reduction in patients with treatment-resistant BD. Further trials are needed to determine aiTBS durability and to compare with other treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT05228457.

Rates of longitudinal change in 18 F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease.

INTRODUCTION: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. METHODS: We assessed regional and interindividual variation in longitudinal change on 18 F-flortaucipir PET imaging in 24 amyloid beta (Aß)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aß- and 132 Aß+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. RESULTS: In atypical AD, 18 F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas. DISCUSSION: Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.