Continuous Theta Burst Stimulation for Generalized Anxiety Disorder

This randomized, rater-blinded clinical trial evaluates the effectiveness, safety, and tolerability of continuous theta burst stimulation (cTBS) in adults with generalized anxiety disorder (GAD). Participants will be randomly assigned in a 1:1 ratio to receive cTBS targeting either the right posterior parietal cortex (R-PPC) or the right dorsolateral prefrontal cortex (R-DLPFC). Participants may be psychotropic-medication naïve or may continue stable psychotropic medication according to the protocol-defined medication stability criteria. The primary objective is to compare changes in anxiety symptom severity, measured using the Hamilton Anxiety Rating Scale (HAM-A), from baseline to the end-of-treatment assessment. Secondary and exploratory assessments include treatment response and remission, quality of life, sleep quality, cognitive function, safety and tolerability, resting electroencephalography (EEG), and transcranial magnetic stimulation combined with EEG (TMS-EEG).

Inclusion Criteria: * Age 18 to 65 years. * Right-handed. * Diagnosis of generalized anxiety disorder (GAD) according to ICD-10 criteria (F41.1), confirmed by a psychiatrist. * GAD must be the primary diagnosis and the main reason for treatment at the time of enrollment. Current or past comorbid major depressive disorder will be identified and recorded. * Hamilton Anxiety Rating Scale (HAM-A) total score \>18 at screening/baseline. * Able and willing to provide written informed consent and comply with essential study procedures. * Participants may be psychotropic-medication naïve or may be receiving psychotropic medication. Participants currently receiving psychotropic medication must have maintained the same medication(s) and dose(s) for at least 2 weeks before randomization; for fluoxetine, the required stable period is at least 4 weeks. Exclusion Criteria: * Intracranial or head/neck metallic foreign bodies or implants that constitute a contraindication to TMS or MRI. * Implanted electronic devices such as a cardiac pacemaker, implantable cardioverter-defibrillator, or deep brain stimulator. * Untreated or clinically unstable thyroid dysfunction based on abnormal TSH and/or free T4 levels. * Clinically significant intracranial structural abnormalities that may affect TMS safety, neuropsychiatric presentation, or study neurophysiological measures. * History of epilepsy or seizures, except febrile seizures in childhood. * Bipolar disorder. * Other major psychiatric disorders, including schizophrenia, delusional disorder, or eating disorders. * Acute suicide risk, including clear suicidal ideation or behavior. * Alcohol or substance abuse or dependence within the previous 6 months. * A medical condition associated with a high seizure risk or a history of cranial surgery. * Current use of medication judged by the screening physician to substantially increase seizure risk, or rapid reduction/discontinuation of benzodiazepines, antiseizure medications, or other centrally acting medications associated with withdrawal or increased seizure risk. * Serum vitamin D level \