Effect of a brief, focal ACT protocol to accelerate repetitive TMS with theta-burst stimulation for elderly patients with depression: A randomized, blinded, controlled trial

Title

Effect of a brief, focal acceptance and commitment therapy (ACT) protocol to accelerate repetitive transcranial magnetic stimulation treatment with theta-burst stimulation (TBS) for elderly patients with depression: A randomized, blinded, controlled clinical trial

Complete Reference

Bariani, B., Pinto, B. S., Santos, L. A., Benatti, R. G., Lessa, M. M. P., Loureiro, J. C., Silva, J. F., Silva, V. A., Cardeal, H. B., Pereira, J. L., Miranda, C. S., Forlenza, O. V., Leão, C. S., Ruiz, F. J., Brunoni, A. R., & Valiengo, L. (2025). Effect of a brief, focal acceptance and commitment therapy (ACT) protocol to accelerate repetitive transcranial magnetic stimulation treatment with theta-burst stimulation (TBS) for elderly patients with depression: A randomized, blinded, controlled clinical trial. Journal of Affective Disorders, 393, 120182.

Study Type

Randomized, double-blind, sham-controlled clinical trial (RCT); two-arm design.

Context and Objectives

Major Depressive Disorder (MDD) is one of the leading causes of disability worldwide, particularly among older adults, with a prevalence of 6.6% in the population aged 60 years or older. In the elderly population, MDD is complicated by higher recurrence rates, cognitive and functional impairment, and frequent resistance to pharmacological treatments. Traditional antidepressant treatments often result in incomplete recovery and are accompanied by side effects that are particularly burdensome for this population.

Repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a non-invasive therapeutic option that modulates cortical excitability, offering a safer alternative to pharmacological treatments. Theta-Burst Stimulation (TBS) is a newer variant of rTMS that provides similar efficacy with the added advantage of shorter session durations. TBS is considered a more physiologic form of brain stimulation, as it mimics natural brain rhythms, and its shorter treatment sessions enhance patient compliance—an important consideration for elderly patients. Pivotal studies such as the THREE-D trial and Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) have demonstrated the potential of TBS in inducing antidepressant responses, leading to FDA approval of these techniques for treating MDD in adults.

However, although neuromodulation techniques such as TBS have demonstrated significant antidepressant effects, non-invasive brain stimulation (NIBS) alone may not fully address the psychological and behavioral aspects of depression. Given this, psychotherapeutic approaches remain a fundamental component of comprehensive depression treatment.

Acceptance and Commitment Therapy (ACT) emerged in the 1980s as a third wave behavioral therapy aimed at promoting psychological flexibility. According to ACT, psychological flexibility consists of being nonjudgmental, awareness of the present moment, and accepting inner experiences without attempting to change them. The patient is encouraged to behave in line with their own values, even when experiencing feelings and thoughts that conflict with value-aligned actions. The ACT Hexaflex model comprises six concepts that make up psychological flexibility: (1) contact with the present moment; (2) cognitive defusion (observing thoughts rather than looking through them); (3) acceptance (making room for what hurts); (4) self as context (perception of an observing "self" as pure perception); (5) values (an internal compass providing sense of purpose and direction); and (6) committed action (acting guided by values).

Previous studies have demonstrated that the association between ACT and rTMS leads to a strong correlation between the dorsolateral prefrontal cortex (DLPFC) and negative emotion regulation—specifically, in the (re)construction of modulation strategies in emotion processing. When dysregulated, these strategies can lead to pathological changes in anxiety and mood. Neuroimaging studies demonstrate lower levels of activity in the DLPFC of depressed individuals compared to healthy subjects. Furthermore, studies with patients with lesions in the DLPFC region indicate significantly higher levels of depression compared to non-lesioned subjects.

Study Objective: This RCT aimed to evaluate the hypothesis that the application of a brief and focal four-week psychotherapeutic protocol within the ACT approach would enhance therapeutic effects on geriatric patients receiving TBS treatment for MDD. To date, no studies have evaluated the effect of rTMS combined with ACT in the treatment of MDD.

Method

Participants

The study was approved by the Ethics Committee of Hospital das Clínicas of Faculdade de Medicina of Universidade de São Paulo (CAAE 80215117.5.0000.0068). The trial was registered nationally at ensaiosclinicos.gov.br and internationally at who.int/clinical-trials-registry-platform. The study was conducted at Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. All participants provided written, informed consent.

Inclusion criteria: Participants were over 60 years of age, diagnosed with MDD in an acute depressive episode of at least moderate severity, defined by a Hamilton Depression Rating Scale (HDRS) score above 16. Diagnosis was confirmed by psychiatrists according to DSM-5 criteria using the Mini International Neuropsychiatric Interview (MINI).

Exclusion criteria: Individuals with other mental disorders (e.g., substance use, bipolar disorder, psychotic disorders, dementia, personality disorders) were excluded, except comorbid anxiety. Also excluded were those with serious neurological or clinical diseases, severe suicidal ideation, or contraindications to TMS.

Medication management: Antidepressants were washed out for at least 5 half-lives before the study. Benzodiazepines were allowed up to a maximum dose of 10 mg diazepam (or equivalent). Other psychotropic drugs were permitted if doses had been stable for at least 6 weeks.

Sample: A total of 29 subjects were enrolled (19 women, 65.52%; mean age 66.37 years; 9 African descent 31.0%, 19 Caucasian 65.52%, 2 Asian descent 6.90%). There was one dropout (3.45%) in the ACT group due to accidental face fracture. Analyses were conducted with available data from those who completed the study.

Design

This was a randomized, double-blind, sham-controlled clinical trial. Randomization was conducted in blocks of two, generated via www.randomization.com by an independent researcher. The randomization list was securely maintained by a third party uninvolved in the study and accessed only after all a priori hypotheses were analyzed.

The only professional directly involved in the research who had access to randomization before study findings were published was the psychologist who conducted ACT psychotherapy sessions (ACT group) and support sessions (control group). The same professional served both groups to avoid compromising patient and clinical evaluator blinding. Session duration was identical for both groups (60 minutes each across four sessions) to preserve blinding.

Intervention

TBS Intervention

Sequential bilateral TBS was administered over the dorsolateral prefrontal cortex, targeting the F3 and F4 positions as determined by the BeamF3 method. Stimulation intensity was set at 120% of the resting motor threshold (RMT). Each session consisted of right-sided continuous TBS (triplet burst pulses at 50 Hz, repeated at 5 Hz, delivering 1800 pulses over 120 s) followed by left-sided intermittent TBS (triplet burst pulses at 50 Hz, repeated at 5 Hz, with a 2-s on, 8-s off pattern, delivering 1800 pulses over 9 min 27 s).

To enhance tolerability, an adaptive titration to 120% RMT was used during the first four treatments. Motor threshold was measured daily before TMS by observing any motor twitch in the hand. There were 20 consecutive sessions, one per day except on weekends and holidays, totaling approximately 4 weeks. A day of stimulation with the same technique was performed in weeks 6, 8, and 12, totaling 23 sessions. Both groups received the identical TBS protocol; group differentiation was based on ACT intervention or non-intervention.

ACT Intervention

ACT group patients received a total of four ACT intervention sessions: an individual 60-minute session approximately once per week over the first four weeks. The ACT protocol applied in this research was developed based on the work of Steven C. Hayes, founder of ACT, and his team, as well as Francisco Ruiz, a reference in applying the approach in clinical research for brief psychotherapy. The protocol included training and clinical supervision from Caroline S. Leão.

Ruiz's study involved 48 subjects diagnosed with MDD and/or generalized anxiety disorder (GAD). Volunteers were randomly assigned to a wait-list control (WLC) group or an intervention consisting of two sessions of RNT-focused ACT. There was a four-week interval between sessions, each lasting approximately 60 minutes. The ACT intervention was efficacious in reducing emotional symptoms (d = 2.42, 95% CI [1.64, 3.19]), with 94.12% of RNT-focused ACT participants showing clinically significant change in Depression, Anxiety, and Stress Scales-21 total scores compared to 9.09% in the WLC condition. Intervention effects were maintained at 3-month follow-up.

Structure of ACT sessions in this study:

Session 1: Objective was to contextualize what a brief intervention is, investigate values, explore creative hopelessness, and begin searching for the "patriarch"—the patient's negative self-concept responsible for Repetitive Negative Thinking (RNT) patterns and counterproductive behaviors preventing value-coherent living.
Session 2: Focused mainly on closing case conceptualization by exploring experiential avoidance strategies and identifying valued actions.
Session 3: Had two main goals: (a) conduct defusion exercises to decrease the negative influence of the "patriarch" over self; and (b) teach present-moment awareness techniques through metaphors.
Session 4 (Final): Aimed mainly on the active role the patient plays facing thoughts causing suffering—encouraging them to choose not to engage with thoughts (self as context rather than content) but instead allow thoughts to happen while directing time and energy toward value-coherent actions.

Although each of the six Hexaflex components blends together at some points, supplementary material indicates which components were evident at each moment.

Control Intervention

The control group was seen by the same psychologist as the ACT group and also had 4 weekly sessions lasting approximately 60 minutes. In these meetings, time was allocated to clarify any doubts about MDD and the TBS protocol. If any subjective demand arose, brief emotional support was provided without using psychotherapeutic techniques.

It is important to clarify that support/ACT intervention sessions occurred in parallel to the first 4 weeks of TBS—that is, the patient came for 20 consecutive days for TBS, and during this same period, once weekly, the support session/ACT intervention occurred after the TBS session.

Measurement Instruments

Study data were collected and managed using REDCap (Research Electronic Data Capture). The following clinical assessments were applied at baseline, weeks 1, 2, 4, 6, 8, and 12:

Hamilton Depression Rating Scale (HDRS) - 17-item scale measuring severity of depressive symptoms. This was the primary outcome measure.
Montgomery-Asberg Depression Rating Scale (MADRS) - depression scale sensitive to change.
Geriatric Depression Scale (GDS) - scale specifically designed for older adults.
Cumulative Illness Rating Scale (CIRS) - to evaluate medical comorbidity.
Clinical Global Impression Scale (CGI) - global clinical assessment of change.
Positive and Negative Affect Schedule (PANAS) - positive and negative affect scale (applied both by blinded evaluator and self-administered).

All clinical evaluators were certified psychiatrists who received additional training in scale application.

Primary outcome measure: Change in HDRS scores over time, specifically at week 6, assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale.

Psychological flexibility assessment: All patients completed the following self-administered questionnaires at baseline, weeks 1, 2, 3, 4, 6, 8, and 12:

Perseverative Thinking Questionnaire (PTQ) - measures Repetitive Negative Thinking (RNT).
Acceptance and Action Questionnaire-II (AAQ-II) - measures psychological inflexibility and experiential avoidance.
Valuing Questionnaire (VQ) - measures connection to personal values.
Positive and Negative Affect Schedule (PANAS) - self-administered.
Depression Anxiety Stress Scales (DASS-21) - measures depression, anxiety, and stress.

Adverse effects: Adverse and positive effects related to TBS were assessed using a commonly used TMS adverse event questionnaire at baseline, weeks 1, 2, 4, 6, 8, and 12.

Secondary outcomes: Clinical response rates (defined as ≥50% reduction in HDRS scores between baseline and endpoint) and remission (defined as HDRS score ≤7 at endpoint) were measured at baseline, weeks 1, 2, 4, 6, 8, and 12.

Data Analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) and GraphPad Prism programs. A linear mixed-effects model (LMM) was used to analyze treatment effects over time on HDRS and secondary outcomes. The model included fixed effects for group (ACT and Control), time (baseline to week 12), and their interaction (group vs. time).

The covariance structure for repeated measures was tested using Unstructured (UN), Autoregressive [AR(1)], and Toeplitz (TOEP) structures. The best-fitting structure was selected based on Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC). Model estimates were obtained using Restricted Maximum Likelihood (REML) estimation. Post hoc comparisons were adjusted using Bonferroni correction.

HDRS response and remission rates at weeks 1, 2, 4, 6, 8, and 12 were compared from baseline between groups using logistic regression. Additionally, predictive analyses were conducted with linear regressions where the outcome variable was change in HDRS from baseline to week 6.

For all statistical tests, a two-sided P value less than 0.05 was considered statistically significant.

Results

Primary Outcome

Baseline characteristics: In between-group analysis, mean baseline HDRS scores were similar (control: 17.00, SD = 3.96; ACT: 16.25, SD = 3.99; p = 0.690), indicating both groups were comparable at baseline.

HDRS change during treatment: During the first four weeks, HDRS scores decreased similarly in both groups with no significant differences (p > 0.05).

In week 4, the psychotherapeutic intervention for the ACT group ended, as did support sessions for the control group. LMM analysis between baseline and week 6 showed a significant difference between groups (group vs. week interaction p = 0.017; pairwise p = 0.007).

Trajectory graphs: The graph shows a behavioral change in groups at week 6—the control group experiences an increase in HDRS while the ACT group continues with decreasing HDRS scores (control: 11.92, SD = 4.99; ACT: 6.93, SD = 4.22; p = 0.007).

Analysis through week 12: The difference between groups at week 6 in analysis through week 12 did not show statistical significance (group vs. week interaction p = 0.078; pairwise p = 0.023). However, the p-value (p = 0.078) in this later analysis is close to the significance level set for the study. This proximity, along with the statistically significant interaction observed through week 6, justifies conducting post hoc analyses to evaluate group differences in both scenarios.

Covariate control: When controlling for age and gender as covariates, p remains significant.

Post hoc power analysis: A post hoc power analysis based on the HDRS mean difference at week six (dCohen = 1.09) indicated statistical power of 80.3%, adding evidence for the observed effect at that intervention point.

Variance explained: The marginal R² of the mixed-effects model was 0.186, indicating that fixed effects accounted for 18.6% of the variance in HDRS scores. The conditional R² was 0.379, showing that the full model, including random subject-level effects, explained 37.9% of the variance.

Secondary Outcomes

Remission rates: The remission rate (HDRS ≤7) was considerably higher in the ACT group at week 6, reaching 56.3% of participants, while in the control group this percentage was 15.4% (p = 0.024, φ = 0.456). The significant difference was not maintained at week 12 (p = 0.705).

Response rates: There were no significant differences in response rate (≥50% reduction in HDRS) between groups (Table 3).

Other measures: No significant differences were found between groups in other measurements using the mixed linear model: MADRS, GDS, CIRS, CGI, PANAS, PTQ, AAQ-II, VQ, DASS-21 (see supplementary material).

Predictors: No predictors of HDRS response were found (age, sex, number of antidepressants, refractoriness, suicide risk, depression onset age, lifetime depressive episodes, months depressed in last episode).

Adverse effects: No significant differences were found between groups regarding adverse and positive effects related to TBS.

Discussion and Conclusions

Discussion

In this study, the ACT group responded earlier (at week 6) to treatment than the control group, both for continuous variables (HDRS baseline to week 6 mean difference of 8.77 for ACT and 5.08 for CG) and categorical variables (remission rate in ACT group of 56.3% compared to 15.4% in control at week 6, p = 0.024).

Notable improvement trajectory: The trajectory of improvement for the two groups is noteworthy. Both groups improve to an almost identical point at the end of week 4, but then the control group experiences temporary symptom worsening between weeks 4 and 6 (while the ACT group continues improving). It is known that TMS takes 6 weeks to work in non-accelerated protocols and longer in late-life depression (12 weeks). It was hypothesized that stopping TMS sessions, only the ACT group continued improving in week 6. As TMS can take longer to work in the elderly, it is thought that TMS began working only in week 12.

Academic literature context: Findings in the academic literature align with this research: a systematic review and meta-analysis including two systematic reviews and 15 randomized controlled trials evaluated different brief psychotherapy approaches for depression and concluded effectiveness of brief protocols involving 6 to 8 psychotherapy sessions.

A review of 17 RCTs on Acceptance and Commitment Therapy (ACT) for depression found similar findings: ACT was superior to waitlist treatment in all analyzed RCTs, with attractive beneficial effects at follow-up up to six months. Beyond reducing depressive symptoms, ACT improved patients' quality of life in multiple studies, especially compared to waitlist and usual care.

An international systematic review including 18 RCTs (totaling 1088 participants) evaluated ACT effectiveness across countries and suggests ACT significantly reduced depression symptoms compared to control groups, especially for adults with mild depression. Follow-up data also indicate ACT effects were maintained up to three months after intervention end.

An RCT with 101 outpatients investigated ACT efficacy compared to traditional Cognitive Therapy (CT) for depression or anxiety. Results indicated equivalent efficacy of both approaches. Another RCT involving 93 subjects with depressive symptoms showed significant improvement in the 8-week ACT intervention group. Another study, after 12 weeks of intervention, states that ACT presents evidence of superior efficacy in depression treatment compared to CT, explained by ACT's focus on promoting cognitive defusion.

ACT in elderly population: Studies on ACT application in older adults demonstrate noteworthy findings. First, experiential avoidance is associated with higher suffering levels in old age—engaging in mechanisms to suppress unpleasant thoughts and feelings is directly associated with loss of meaning and purpose in life.

Thus, ACT's proposal to focus on values instead of trying to modify thoughts seems to find fertile ground in the elderly population: although this period is marked by cognitive decline, paradoxically, it is also when emotional regulation ability increases.

Besides, there is also evidence that psychotherapy is beneficial for older adults with depression in different contexts, including chronic illnesses, heart problems, Parkinson's disease, and several conditions involving cognitive impairment and suicide risk.

Integration of rTMS with psychotherapy: A study by Russo et al. (2018) specifically investigating rTMS treatment integration with psychotherapy for MDD was conducted with 11 subjects combining Behavioral Activation therapy with rTMS over six weeks. The integration of both techniques proved feasible and well tolerated. Additionally, patients showed significant improvement: average reductions of 47%, 55%, and 39% in Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Patient Health Questionnaire-9 (PHQ-9), and Snaith-Hamilton Pleasure Scale (SHAPS) scores, respectively. However, this study did not have a control group.

Furthermore, there is evidence that combining TMS with psychotherapy enhances MDD treatment, as both neurobiological and psychosocial depression aspects are addressed. However, there is still need for studies specifying psychotherapeutic protocol guidelines.

A study with 220 MDD patients and 110 healthy subjects investigated whether different brain region connectivity patterns related to different symptoms and treatment responses. Using magnetic resonance imaging, the study suggests that MDD from a neurophysiological perspective is not a single condition but rather characterized by several subtypes of different neurobiological functions.

All these findings reinforce that each individual's neurophysiology plays a crucial role in MDD treatment response. Given evident neurobiological heterogeneity, it is essential to consider integrated approaches combining psychotherapy with drug treatments and/or neuromodulation techniques.

Aligned with this, this study has accelerated depression treatment in the elderly with four ACT sessions. This is important because in older adults the antidepressant effect of rTMS is similar but occurs later than in younger adults. The mechanism of action of both treatments—both modulating the prefrontal cortex—may explain this. Besides, ACT and TMS can enhance cognitive functions, such as executive and attention functions decreased in MDD.

Limitations

Study limitations include: small sample size with MDD, use of a brief ACT intervention protocol (4 sessions), absence of a TMS control group, and no biomarker use. It is important to emphasize that the small sample size limits research power; therefore, this study is configured as a pilot. Additionally, an individualized ACT protocol was not used for each participant. The same (unblinded) therapist delivered both active and control interventions. Although this can add advantages as being the same person trying to blind patients, it may have led to allegiance bias.

Although previous studies used brief ACT protocols and suggest advantages of 4 psychotherapy sessions, 4 sessions are considered brief for the population studied and could have led to less response than expected.

Another limitation is the low number of TMS sessions used in this study. Twenty-three sessions were used; recent findings showed that at least 30 sessions are needed to optimize TMS response.

Noteworthy Findings Despite Limitations

Although the study has limitations, some findings are worth highlighting: first, this is an unprecedented study—to date, no other RCTs integrating TMS and ACT combination effects have been published. Second, the ACT approach led to significant improvement in the primary outcome measurement in a shorter time period compared to the control group, demonstrating that meaningful change can be achieved with a reduced number of sessions. Although sample size was small, post hoc power analysis estimated statistical power at 80.3% for the significant HDRS score difference observed at week 6, suggesting the study had sufficient sensitivity to detect this clinically relevant effect. This model appears to fit public health limitations in investing in long-term psychotherapies; brief psychotherapy becomes an option.

Conclusion

Both groups demonstrated clinical improvement; however, participants receiving ACT in combination with TBS experienced significantly greater reductions in depressive symptoms at week six (HDRS: 6.93 vs. 11.92; p = 0.007) and higher remission rates (56.3% vs. 15.4%; p = 0.024) compared to the control group. Although statistical significance was not sustained in subsequent weeks, lower HDRS scores persisted in the ACT group through week 12. These findings point to the potential of ACT combined with TBS as a promising therapeutic approach for late-life depression. Nonetheless, the absence of a TBS-specific control group and the limited sample size highlight the need for further research to confirm and expand upon these preliminary results.

Significance and contribution

This study contributes to the treatment of major depression in older adults by demonstrating that a brief acceptance and commitment therapy protocol can accelerate response to repetitive transcranial magnetic stimulation (rTMS). The research provides evidence that brief psychological interventions can produce clinically meaningful benefits when combined with established neuromodulatory treatments. The ACT protocol emphasizes processes such as cognitive defusion and emotion regulation, processes relevant to treatment-resistant depression. The findings expand the literature on psychological interventions as complements to the treatment of geriatric depression, a particularly vulnerable population.