Neuroinflammatory Alterations in Treatment‐Resistant Depression Secondary to Long COVID by Repetitive Transcranial Magnetic Stimulation (rTMS): A Case Report

To the Editor:

COVID‐19 infection leads to various symptoms such as fatigue, difficulty concentrating, memory loss, anxiety, and depressed mood (1). We report the first case to our knowledge of a patient with treatment‐resistant depression secondary to COVID‐19 infection who was treated with repetitive transcranial magnetic stimulation (rTMS) and present neuroinflammatory alterations revealed by positron emission tomography (PET).

A 39‐year‐old female, without a history of SARS‐COV‐2 vaccination nor depression, had contracted the COVID‐19 2 years ago. One year later, she had no core depressive symptoms such as depressed mood or loss of interest but went to outpatient clinics because of memory loss and severe fatigue. Despite treatments, her symptoms persisted for more than a year, and furthermore, she gradually presented with depressed mood, loss of pleasure, and difficulty concentrating. Diagnosed with depression, she did not respond to antidepressants including venlafaxine 150 mg/day. She came to our hospital for rTMS treatments. No structural abnormalities were observed on head magnetic resonance imaging. rTMS was administered over the left prefrontal cortex using the NeuroStar system (Neuronetics) at a frequency of 10 Hz with 120% motor threshold. She received 29 sessions over 6 weeks. No adverse events were observed. After the treatments, depressive symptoms with Hamilton Rating Scale for Depression‐17 scores improved from 20 to 7. A PET scan utilizing the translocator protein ligand [11C] DAA1106 (2) was performed before and after rTMS, which demonstrated that the standardized uptake value ratio of the neuroinflammatory marker [11C] DAA1106 was reduced in the whole brain (see Figure S1 and Table S1 in Online Supplement). The observed changes in each volume of interest ranged from 11.0% to 22.9%.

rTMS is shown to be effective in patients with treatment‐resistant depression (3). The findings suggest that rTMS may have anti‐neuroinflammatory effects in improving depression, which is consistent with the microglial inflammatory hypothesis of depression (4). Microglial hyperactivation has been shown to be associated with persistent depressive and cognitive symptoms (5), raising the possibility that some symptoms secondary to COVID‐19 infection and subsets of treatment‐resistant depression may share a common pathophysiology. Further investigation is needed to confirm the reproducibility of the findings and elucidate the underlying mechanisms in a well‐designed study.