TMS Tied to Antidepressant, Anxiolytic Effects in Anxious Depression

Transcranial magnetic stimulation (TMS) is associated with both anxiolytic and antidepressant effects in patients with anxious depression, new research suggests.

In an analysis of data from more than 1800 patients with a diagnosis of major depressive disorder (MDD), more than 75% also had anxiety. Following TMS, those with anxious depression showed reductions from baseline of at least 50% on anxiety and depression scores.

In addition, the anxious and nonanxious groups had equivalent absolute improvement in scores measuring depression.

"The ultimate message is that TMS is quite effective in the more difficult-to-treat and more disabled group of anxious depressives," co-investigator Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, and director of the Psychedelic Center of Excellence, Sheppard Pratt, Towson, Maryland, told Medscape Medical News.

The findings were published online January 11, 2023.

Large Cohort

Aaronson, who is also an adjunct professor at the University of Maryland School of Medicine, Baltimore, noted that between 50% and 75% of patients with depression also have significant anxiety symptoms.

"The presence of significant anxiety in a depressed person significantly increases depression symptom severity, functional impairment, chronicity, and suicidality," he said.

In general, "when patients with anxious depression are identified in a treatment study, they are less likely to respond to the index treatment and are frequently excluded from some treatment trials," he added.

Aaronson noted that previously reported outcomes from TMS for anxious depression have been "suggestive of efficacy but have not been well studied within a large cohort."

To investigate these issues, the current investigators turned to the NeuroStar Advanced Therapy System Clinical Outcomes Registry. It is the largest database of patients with difficult-to-treat depression, all of whom had undergone TMS.

This "extraordinary" database was able to provide previous insight into how often TMS works, whether some of the treatment parameters can be altered while still preserving efficacy, and whether bilateral TMS works better than unilateral TMS in patients with MDD, Aaronson said.

In the current study, researchers retrospectively analyzed data on 1820 patients with MDD. All had completed the Patient Health Questinonaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) at baseline and following at least one TMS intervention.

Most patients (n = 1514) had anxious depression, defined as a baseline GAD-7 score of 10 or higher, and 306 had nonanxious depression, defined as a GAD-7 score below that threshold.

The investigators assessed the total sample of these patients who had been treated with any TMS protocol, as well as a subsample of patients (n = 625) who had been treated only with high-frequency left dorsolateral prefrontal cortex (HF-LUL) stimulation.

Patients were also subdivided into intent-to-treat and Completer samples (n = 1820 and 1429, respectively).

Consistent Effects

There was no difference in gender distribution between the anxious and nonanxious group.

However, the anxious group was significantly younger (by about 5 years) compared with the nonanxious group. They also reported higher severity of depressive symptoms at baseline, with PHQ-9 scores approximately 2.5 points higher.

This was a "notable finding, since the PHQ-9 does not contain items directly assessing anxiety," the researchers wrote.

There were also differences between the groups in the type of TMS protocol they received, with exclusive HF-LUL more common in the nonanxious depression group compared with other types of TMS protocols or unclassified protocols in the anxious depression group.

"Anxiolytic and antidepressant effects were consistent across the ITT and Completed samples and patients who received any TMS protocol or only HF-LUL TMS," the investigators reported.

GAD-7 scores "decreased markedly" in the anxious depression group. GAD-7 response rates ranged from 47.8% to 60.6% and GAD-7 remission rates ranged from 26.4% to 38.0% (both Ps < .0001).

There were no between-group differences in PHQ-9 scores in the magnitude of change pre- to post-treatment. The anxious group scored about 2.5 points higher both pre- and post-treatment compared with the anxious group — with an effect size for change ranging from 1.46 to 1.74 in the anxious group and from 1.66 to 1.95 in the nonanxious group.

Response, Remission Rates

Notably, the anxious and nonanxious groups both showed "marked antidepressant effects," with response and remission rates in the anxious group ranging from 55.2% to 66.8% and from 24.0% to 33.2%, respectively.

However, response and remission rates were significantly higher in the nonanxious vs the anxious group.

"Thus, despite manifesting the same degree of change in the PHQ-9 scores, the higher baseline and post-TMS scores in the anxious group resulted in significantly lower response and remission rates," the investigators wrote.

They noted that the difference in post-TMS adjusted means was "small" and the groups also "did not differ in the absolute extent of symptoms improvement after multivariate adjustment."

The relationship changes in the GAD-7 and the PHQ-9 scores "covaried" for the total IT sample (r1818 = .69, P < .001), although the relation was more "robust" in the anxious depression group vs the nonanxious depression group (r1512 = .75 vs r304 = .50; both Ps < .001).

"The anxious depressed folks were sicker and had higher scores on scales capturing the severity of their illness," Aaronson said. However, their "outcomes were similar, taking into account the higher baseline scores which had the effect of lowering the percent of anxious participants who met response and remission criteria."

He reported that the average decline in depression rating scale scores was not significantly different between the groups, and the decline in depression scores tracked similarly to the decline in anxiety scores, "meaning they strongly covaried."

The authors noted that a limitation was that, although the data was prospectively gathered, the analyses were retrospective.

Settles the Debate?

Commenting for Medscape Medical News, Shan Siddiqi, MD, assistant professor of psychiatry at Harvard Medical School, Boston, Massachusetts, said clinicians know that patients with comorbid anxiety are less likely to be referred for TMS, "probably because of the longstanding perception that TMS doesn't work as well for them."

This perception "has persisted, despite several small studies to the contrary, perhaps because we know that these patients are less responsive to other treatments," said Siddiqi, who is also director of psychiatric neuromodulation research at Brigham and Women's Center for Brain Circuit Therapeutics in Boston, Massachusetts. He was not involved with the current research.

"This new study will hopefully settle that debate and let us move on to a new question: How do we optimize the treatment for this important patient population that has largely been excluded from many of our prior studies?"

The NeuroStar Advanced Therapy System Clinical Outcomes Registry, analysis of the registry data, and the drafting of this manuscript were supported by Neuronetics Inc. Aaronson serves as a scientific adviser to Genomind Inc., LivaNova PLC, Neuronetics Inc., Janssen Pharmaceuticals Inc., and Sage Therapeutics, and has received research support from Compass Pathways Inc. and Neuronetics Inc. The other investigators' disclosures are listed in the original paper. Siddiqi is a scientific consultant for Magnus Medical; a clinical consultant for Acacia Mental Health, Kaizen Brain Center, and Boston Precision Neurotherapeutics; and has received investigator-initiated research funding from Neuronetics and BrainsWay. He has also served as a speaker for BrainsWay and PsychU.org, owns stock in BrainsWay and Magnus Medical, and owns intellectual property involving the use of functional connectivity to target TMS.

J Clin Psychiatry. Published online January 11, 2023. Full article.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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