Comorbid Anxiety Lowers Accelerated Theta Burst Response in Depression

Comorbid anxiety symptoms may diminish the antidepressant efficacy of accelerated theta burst stimulation in older adults, a new study found.1

“The negative effects of comorbid anxiety may, in part, be explained by greater baseline depression severity and more frequent benzodiazepine use,” study investigator Jeanette Hui, MD, from the Temerty Center for Therapeutic Brain Intervention in Toronto, and colleagues suggested.1

Accelerated theta burst stimulation provides a faster, time-efficient alternative to conventional repetitive transcranial magnetic stimulation and has recently been investigated in older adults with depression.2 However, it was unknown how comorbid anxiety impacted the effectiveness of accelerated theta burst stimulation.

In this brief, open-label pilot trial, investigators evaluated treatment outcomes of accelerated theta burst stimulation in older adults with depression, comparing those with and without comorbid anxiety as well as varying baseline anxiety severity levels.1 The study recruited outpatients aged ≥ 60 years with a current unipolar major depressive episode. Investigators screened for other psychiatric disorders, including comorbid anxiety, via the Mini-International Neuropsychiatric Interview. The study excluded participants with psychiatric disorders more severe than their depression.

A total of 78 older adults completed a 5-day course of accelerated sequential bilateral theta burst stimulation, administered 8 times daily at 50 – 60-minute intervals. Continuous stimulation (110–120% of the resting motor threshold, 50 Hz triplet bursts repeated at 5 Hz for 600 pulses over 40 seconds) was applied to the right dorsolateral prefrontal cortex, followed by FDA-cleared intermittent stimulation (110–120% resting motor threshold, 50 Hz triplet bursts repeated at 5 Hz with 2 seconds on and 8 seconds off, 600 pulses over 3 minutes and 9 seconds) to the left dorsolateral prefrontal cortex.

Among those who completed theta burst stimulation, 62.8% had comorbid anxiety (n = 49). Comorbid anxiety disorders were linked to concurrent benzodiazepine usage (P =.03), reduced likelihood of a prior ECT trial (P <.01), and greater baseline severity of GAD-7 scores (P <.001).1

Over time, depression scores improved significantly (P<.001), but participants with an anxiety disorder had higher overall depression levels (P <.001) and showed less improvement than those without anxiety (P =.03), as seen by the mixed-model ANOVA. At every time point—before treatment, right after treatment, and 4 weeks later, participants with an anxiety disorder had significantly greater depression scores than those without an anxiety disorder (P <.001, P=.01, P<.01, respectively).1

Four weeks after treatment, participants with an anxiety disorder were much less likely to have their depression go into remission (14.3%) compared with those without anxiety (41.4%). Investigators observed no difference in remission rates immediately after treatment (P =.16).

“Interestingly, significant differences in remission only emerged after 4 weeks post-treatment and not immediately at treatment end,” investigators wrote.1 “This appears to be driven by the increase in remission rate over time only in participants with mild anxiety symptoms or without an anxiety disorder, suggesting individuals without clinically significant anxiety may experience delayed treatment benefits.”

Remission from suicidal thoughts did not differ between groups at either time point (treatment end: P =.96; 4 weeks later: P =1.00).1

“There were three main findings from this study,” investigators wrote.1 “First, [the] presence of a comorbid anxiety disorder was consistently associated with more severe depression before and after treatment. Second, individuals with a comorbid anxiety disorder or more severe anxiety symptoms were less likely to remit from depressive symptoms 4 weeks after acute treatment. Third, moderate remission rates from suicidal ideation were present across all groups, regardless of baseline anxiety levels. Overall, these findings suggest that anxiety symptoms may influence treatment outcomes for depression and suicidality in distinct ways.”

References

1. Hui J, Trevizol AP, Lee HH, et al. Effects of Comorbid Anxiety on Treatment Outcomes After Accelerated Theta Burst Stimulation for Late-Life Depression. Am J Geriatr Psychiatry. Published online September 20, 2025. doi:10.1016/j.jagp.2025.09.017

2. Hui J, Trevizol AP, Espinola C, et al. Feasibility and clinical effects of accelerated sequential bilateral theta burst stimulation in late-life depression (ACCELDER Trial). Transcranial Magnetic Stimulation. 2025. https://doi.org/10.1016/j.transm.2025.100167.