 exclusion, as the completion of this scale was at the discretion of the sites.
A subset of the ITT sample comprised the “Completer” sample (Table 1). To ensure a minimally adequate course of TMS,44 individuals were excluded if classified as PHQ-9 nonresponders and had ended TMS after fewer than 20 sessions. Patients were also excluded if PHQ-9 and GAD-7 assessments were not conducted near the end of acute phase treatment, ie, within ± 4 days of the final session. Thus, to be included in the ITT sample, patients had to receive at least one TMS treatment and complete the PHQ-9 and GAD-7 assessments at baseline and at any point after the start of TMS. In contrast, Completers (n = 1,429, 42 sites) received at least 20 TMS sessions before classification as PHQ-9 nonresponders and had PHQ-9 and GAD-7 assessments within 4 days of the final TMS session and within 4 days of each other.
The ITT and Completer samples were subdivided into 4 TMS protocol groups (see Table 1 for the criteria used to define each protocol): (1) patients treated with high frequency (HF; 10 Hz) left DLPFC (unilateral) stimulation throughout their treatment course (HF-LUL group), (2) patients treated with sequential bilateral (SBL) TMS in at least 90% of sessions (SBL group), (3) patients who initiated treatment with HF-LUL TMS for at least 5 sessions and then switched to SBL TMS (Switch group), and (4) patients whose treatments were not otherwise classified (Other group).
The primary analyses were conducted in the total ITT sample and then repeated for confirmation in the total Completer sample and the ITT and Completer subsamples treated only with HF-LUL TMS. The anxious depression and nonanxious depression groups were compared in demographic and treatment parameters using t tests and χ2 analyses on continuous and categorical measures, respectively.
In the ITT sample, the final GAD-7 and PHQ-9 scores were the last observations obtained after baseline (last observation carried forward [LOCF]), while in the Completer sample, the final scores were obtained at the end of acute (EOA) treatment. Anxiolytic effects were defined as the change in GAD-7 scores from baseline to final observation and in terms of rates of anxiety symptom response and remission. Within the anxious and nonanxious depression groups, effect sizes (d) were calculated for the change in GAD-7 and PHQ-9 scores.54 The anxious depression and nonanxious depression groups were compared in antidepressant effects by conducting t tests on the change in PHQ-9 scores and χ2 tests on PHQ-9 response and remission rates. To confirm the findings of these bivariate analyses, analyses of covariance (ANCOVAs) and logistic regressions were conducted on the continuous change in PHQ-9 scores and the categorical outcomes, respectively. These models included as terms anxious/nonanxious depression group, baseline PHQ-9 score, age, gender, MT level, treatment level, pulse frequency, pulse train duration, interval between pulses trains (ITI), number of delivered pulses per session, and total number of treatment sessions in the acute course. In addition, to estimate the extent of covariation between anxiolytic and antidepressant effects, Pearson product-moment correlations were computed in each sample between the absolute changes in GAD-7 and PHQ-9 scores.
Descriptive statistics are reported as mean ± SD for continuous variables and frequency counts and percentages for categorical variables. For each patient, treatment parameters were averaged over all treatment sessions in their acute course. Significance values are 2-tailed with an α of.05. All P values reported are without multiplicity adjustment. Analyses were conducted using SAS v9.4 (SAS Institute Inc; Cary, North Carolina).
Table 2 presents demographic and clinical characteristics for the nonanxious and anxious depression groups in the total ITT and Completer samples and for the subsets treated only with HF-LUL TMS. More than 75% of patients had baseline GAD-7 scores of 10 or greater and were classified with anxious depression. The anxious and nonanxious depression groups did not differ in the distribution of gender. The anxious group was significantly younger than the nonanxious group by an average of approximately 5 years. In addition to the marked differences in baseline GAD-7 scores, the groups differed in baseline PHQ-9 scores. In line with reports that the severity of depressive symptoms is greater in anxious than in nonanxious depression,12,55–57 baseline PHQ-9 scores were approximately 2.5 points higher in the anxious depression group, a notable finding since the PHQ-9 does not contain items directly assessing anxiety.
The anxious and nonanxious groups differed in the TMS protocols they were administered (ITT sample: χ23 = 16.22, P < .001; Completer sample: χ23 = 16.93, P < .001) (see Table 3). The exclusive use of the HF-LUL protocol was more common in the nonanxious depression group, while the anxious depression group was more likely to receive TMS protocols that were unclassified (eg, < 2,000 pulses per session, 1 Hz over right DLPFC) or protocols that involved SBL stimulation. Accordingly, outcomes for the two groups were evaluated both across all forms of TMS (total ITT and Completer samples) and when restricted to the HF-LUL protocol. The anxious and nonanxious depression groups treated with HF-LUL TMS did not differ in the duration of the TMS course or in virtually all TMS parameters. In the total sample, the nonanxious depression group received slightly more sessions over a slightly longer acute course duration. In the total sample, the difference between the anxious and nonanxious depression groups in treatment parameters reflected the fact that patients with anxiety were more likely to be started on or switched to SBL protocols than nonanxious patients.
Anxiolytic and antidepressants effects were consistent across the ITT and Completer samples and patients who received any TMS protocol or only HF-LUL TMS (Table 4). GAD-7 scores decreased markedly in the anxious depression group, with the GAD-7 response rates ranging from 47.8% to 60.6% and GAD-7 remission rates ranging from 26.4% to 38.0%. GAD-7 scores also decreased significantly in the nonanxious group (all P values < .0001). The effects size for the decrease in GAD-7 scores ranged from 1.22 to 1.47 among the anxious depression samples and from 0.39 to 0.68 among the nonanxious depression samples.
The anxious depressed group scored approximately 2.5 points higher on the PHQ-9 than the nonanxious group both before TMS and at final observation, and the groups did not differ in the magnitude of change in PHQ-9 scores. The effect size for the change in PHQ-9 scores ranged from 1.46 to 1.74 in the anxious depression samples and from 1.66 to 1.95 in the nonanxious depression samples. Both groups showed marked antidepressant effects, with response rates in the anxious depression group ranging from 55.2% to 66.8% and remission rates ranging from 24.0% to 33.2%. Nonetheless, in each comparison, response and remission rates were significantly higher in the nonanxious depression group. Thus, despite the two groups’ manifesting the same degree of change in PHQ-9 scores, the higher baseline and post-TMS scores in the anxious depression group resulted in significantly lower response and remission rates. The multivariate ANCOVA and logistic regression analyses confirmed these findings. The nonanxious group had PHQ-9 outcomes superior to those of the anxious group in all comparisons (all P values ≤ .002). However, the difference in post-TMS adjusted means was small (ITT sample: 10.2 vs 8.4 in anxious and nonanxious groups), and the groups also did not differ in the absolute extent of symptom improvement after multivariate adjustment.
Figure 1 plots absolute change in GAD-7 scores versus change in PHQ-9 scores for the total ITT sample, r1818 = 0.69, P < .001. The relationship was robust in the anxious depression group (r1512 = 0.75, P < .001) and less robust in the nonanxious depression group (r304 = 0.50, P < .001), in which patients had much lower baseline GAD-7 scores. This pattern was consistent across all the samples. In the anxious depression group, change in GAD-7 and PHQ-9 scores shared approximately 60% variance.
At the outset, we posed 4 questions to be addressed in this study. The first was, “Do providers administer different TMS protocols to patients with anxious and nonanxious depression?” We found that exclusive use of the HF-LUL TMS protocol was more likely in the nonanxious depressed group, while the SBL TMS protocol was used more commonly in the anxious depressed group.
The second question was, “Does treatment with TMS for MDD have clinically significant anxiolytic effects in patients with anxious depression?” In by far the largest sample collected to date of patients with anxious depression treated with TMS, there were marked and clinically meaningful anxiolytic and antidepressant effects in self-report