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Comparative efficacy of high-frequency repetitive transcranial magnetic stimulation to left dorsolateral prefrontal cortex as an augmentation strategy versus pharmacological augmentation in non-psychotic, unipolar, treatment-resistant depression: A randomized controlled trial
Amit Chail1, Pookala S Bhat2, Harpreet Singh3, Rajiv Kumar Saini4
1 Department of Psychiatry, Command Hospital (WC), Chandi Mandir, Haryana, India
2 Brig Med, Medical Branch MG and G Area, Mumbai, Maharashtra, India
3 Department of Psychiatry, Command (NC) Hospital, Pune, Maharashtra, India
4 Department of Psychiatry, Military Hospital, Pathankot, Punjab, India
|Date of Submission||25-Jan-2022|
|Date of Acceptance||14-Apr-2022|
|Date of Web Publication||14-Sep-2022|
Rajiv Kumar Saini,
Department of Psychiatry, Military Hospital, Pathankot, Punjab
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Depression causes significant morbidity, disability and mortality, along with socioeconomic losses. Patients with depression who don't remit even with the second trial of anti-depressants need optimization, combination or augmentation strategies. Pharmacological strategies sometimes have unacceptable adverse effects. Aim: The aim of this study is to compare the efficacy of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) to left dorsolateral prefrontal cortex (DLPFC) with that of pharmacological augmentation strategies in unipolar non-psychotic treatment-resistant depression. Method: This is a randomized controlled trial. Subjects: Cases of unipolar, non-psychotic, treatment-resistant depression between ages 20 and 60 years were taken. Period of Study: The study period was from November 2016 to May 2018. Randomization: Cases diagnosed as per ICD-10 criteria by a qualified psychiatrist. Cases of treatment-resistant depression (100) were divided into two arms by using a random number generator: rTMS arm and treatment as usual (TAU) arm. Intervention: HF-rTMS to left DLPFC (rTMS group) and pharmacological augmentation with lithium, serotonin-dopamine antagonist, buspirone or thyroxine. Results: In the rTMS arm, 44 patients and in TAU arm 41 completed the study. After 4 weeks of treatment augmentation, rTMS and TAU groups showed response rates of 52% and 46%, respectively. The difference between the two groups in terms of number of responders at the end of 4 weeks is not statistically significant. Additionally, factors associated with good response to rTMS were absence of a family history of psychiatric illness, no concomitant psychoactive substance use, being first episode of depression and mild–moderate severity of illness. Conclusion: The study did not find rTMS augmentation to be significantly better than standard pharmacological augmentation therapies.
Keywords: Depression, neuromodulation, rTMS, treatment augmentation
|How to cite this URL:|
Chail A, Bhat PS, Singh H, Saini RK. Comparative efficacy of high-frequency repetitive transcranial magnetic stimulation to left dorsolateral prefrontal cortex as an augmentation strategy versus pharmacological augmentation in non-psychotic, unipolar, treatment-resistant depression: A randomized controlled trial. Ind Psychiatry J [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.industrialpsychiatry.org/preprintarticle.asp?id=355946
Depression is a common mental health condition, characterized by sadness, reduced interest or pleasure, low self-worth, feelings of guilt, disturbed appetite or sleep, increased fatigability and poor concentration. Depression causes significant morbidity, disability and mortality, along with socioeconomic losses.
Callahan pointed out that as a disorder, depression seems to follow the '50 per cent rule,' that is, only 50% of patients having the illness are diagnosed in primary care settings, and of those diagnosed, only 50% are treated. Of the those who are treated, only 50% receive adequate treatment.
Only around one-third of patients remit with the first trial with an anti-depressant. Those who don't remit even with second trial of anti-depressant need optimization, combination or augmentation strategies. Pharmacological strategies sometimes have associated unacceptable adverse effects and also their efficacy is variable. In such a scenario, augmentation with non-invasive and relatively safer somatic treatments like rTMS (repetitive transcranial magnetic stimulation) can improve treatment response and acceptability.
Positron emission tomography studies reveal decreased metabolism in left frontal cortex patients with depression. Decreased cerebral blood and reduced glucose metabolism in regions such as the dorsolateral prefrontal cortex (DLPFC) appears to be a severity-dependent process and is correlated with difficulties inhibiting affective expression with higher cognitive processes such as abstraction and executive problem-solving skills. TMS therapy uses a computerized, electromagnetic medical device to produce and deliver non-invasive, magnetic stimulation using brief duration, rapidly alternating, or pulsed, magnetic fields to induce electrical currents directed at spatially discrete regions of the cerebral cortex.
TMS can be applied either as a single pulse or paired pulse, both of which are used in neurophysiological studies. Another method is by applying stimuli in trains (repetitive or rTMS). rTMS can be delivered either as low-frequency TMS (≤1 Hz) or HF-TMS (>1 Hz). High-frequency rTMS, which increases cortical excitability, can be applied to left DLPFC to normalize its activity., Left DLPFC can be located either by neuronavigation or by 5-cm method (corresponds to F3–F5 area of 10–20 system of EEG recording). Various coils which are available are circular (Cc), Figure-of-8 (F8c) and H-coil (Hc).
Evidence for HF-rTMS (left DLPFC) in depression
In a meta-analysis of 24 studies with more than 1000 patients, the pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively. Similarly, other meta-analytical studies also reported superior response and remission rate for rTMS as compared to sham group.,
HF-rTMS has been approved for treatment of depression by authorities in US (FDA and APA), England (NICE), Canada, Brazil, Australia, Israel, etc. and various practice guidelines like Lefaucheur et al. (2014 and 2020) and Indian Psychiatric Society Clinical Practice Guidelines (2017).,,
Need for this study
Most of initial research on use of rTMS in treatment of depression was sham controlled and rTMS has been compared with other somatic modalities like electroconvulsive therapy. There are a few studies which compared rTMS and pharmacological augmentation strategies head-to-head and most of the comparisons are indirect., Also at the time of initiation of study, the data on Indian subjects were scarce. In this background, the study was conducted.
The study aimed to compare the efficacy of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of left dorsolateral prefrontal cortex (DLPFC) as an augmentation strategy versus pharmacological augmentation in treatment of non-psychotic, unipolar treatment-resistant depression in a tertiary care hospital.
- To evaluate the efficacy of HF-rTMS as an augmentation strategy as compared to pharmacological augmentation for non-psychotic, unipolar depression.
- To find out patient (socio-demographic) and illness correlates of depression, influencing the response (variables of response) to rTMS in treatment-resistant, non-psychotic, unipolar depression.
| Material and Methods|| |
Approval for conduct of study was taken from Institutional Ethics Committee and CTRI Registration was done through the registration number CTRI/2018/02/011890.
Our study was a randomized controlled trial (RCT). The design and protocol of the study followed the CONSORT (CONsolidated Standards of Reporting Trials) guidelines. Study was conducted as per CONSORT 2010 Flow guidelines (placed at the [Appendix]).
Cases of unipolar, non-psychotic depression diagnosed as per ICD-10 criteria, F32.0, F32.1, F32.2 and F33.0, F33.1, and F33.3 by a qualified psychiatrist between age 20 and 60 years attending psychiatry OPD or admitted in psychiatry ward. Treatment-resistant depression (TRD) was defined as non-response to two adequate trials of anti-depressants from different pharmacological classes. This operational definition was given in a seminal review by Berlim et al. Non-response was defined as failure to achieve at least 50% reduction in symptom severity., Adequate duration defined as at least 4 consecutive weeks of treatment, during which the patient has had an adequate dose for at least 3 weeks. The study was conducted in a tertiary care hospital of western Maharashtra from November 2016 to May 2018. The study participants were selected as per the following criteria.
- As per study population mentioned above.
- Pass the TMS adult safety screening (TASS) test.
- Patients with suicidal ideation.
- Patients with psychoactive substance use other than alcohol and nicotine. Alcohol and nicotine use are highly prevalent among clientele. Their confounding effect was removed by random allocation.
- Patients with history suggestive of delusions/hallucinations in the past. Past history was taken from patients, caregivers, and available medical records.
- Pregnant women.
Sample size was calculated to test the following hypothesis with 5% level of significance and 80% power of study.
H0: π1 − π2 = 0 against H1: π1 − π2 = 0
where π1 and π2 are proportions of patients who showed response in rTMS and treatment as usual (TAU) arms, respectively. The sample size worked out to be 38 in each arm assuming that π1 and π2 are 50% and 20%, respectively. Assuming 20–25% dropouts, a sample size of 50 in each arm was taken for the study.
At first, a list of random numbers from 1 to 100 was generated using a computer-based software. First 50 numbers were taken in intervention group and others in TAU group.
rTMS group (treatment protocol)
ATES magnetic stimulator, RTS 9000, high-frequency stimulation (10 Hz), over left DLPFC was used. The treatment protocol followed was in concordance with US FDA and NICE (UK) recommendations for use of rTMS in treatment of depression, that is, application of stimulus at 120% above MT, at 10 Hz with total of 3000 pulses in a session., Patients were given five sessions per week for 4 weeks (total 20 sessions). DLPFC was localized by the 5-cm technique and threshold energy was delivered at 120% of the MT (motor threshold). Total trains in a session were 150 with 20 pulses per train (total = 3000 pulses per session).
Treatment as usual group
Pharmacological augmentation treatment was in the form of lithium, serotonin-dopamine antagonist (SDA, buspirone or thyroxine). The choice of augmentation agent was decided by the treating psychiatrist and the patient. Psychotropic medication was not tapered off in order to avoid confounding of results by pharmacological withdrawal effects or deterioration of clinical symptoms.
Those patients who fulfilled the inclusion criteria and gave informed consent were taken up for study. They were interviewed separately and administered the following scales at the start of study:
- Socio-Demographic Questionnaire and Clinical Performa
- Patient Health Questionnaire
- Hamilton Depression Rating Scale (HAM-D): structured interview; done at baseline and 4 weeks
- Hamilton Anxiety Rating Scale (HAM-A): structured interview; done at baseline
Data analysis was done by using SPSS (Statistical Package for Social Sciences) version 22:0. Qualitative data variables were expressed using frequency and percentage (%). Quantitative data variables were expressed using mean and SD. Chi-square test/Fisher's exact test was used to compare the significant association with qualitative data variables.
Unpaired t-test is used to find the significance between two independent groups for quantitative data variables. A P value <0.05 is considered as significant. Intention to treat (ITT) analysis was applied. ITT analysis gives a real-life picture of efficacy in RCTs as it ignores protocol deviations, noncompliance, withdrawal, and any other issues that happen after randomization. Efficacy as measured by response (defined as reduction in HAM-D score ≥50%) at 4 weeks of starting treatment was the primary outcome measure. In addition, remission (defined as HAM-D score ≤7) rates were also computed. Patient and illness correlates of depression influencing the response (variables of response) to rTMS in TRD were taken as secondary outcome measures.
| Results and Observations|| |
Participants in the two groups (rTMS and TAU) were compared in terms of their mean baseline socio-demographic and clinical parameters. They were also compared for their clinical outcomes after 4 weeks of intervention.
Various socio-demographic and clinico-psychopathological factors have been studied as being associated with treatment resistance.,,,, As evident from the [Table 1], there was no statistically significant difference in the baseline socio-demographic variables among the rTMS group and the TAU group.
|Table 1: Comparison of rTMS and pharmacological treatment (TAU – treatment as usual) groups in terms of baseline (socio-demographic) variables|
Click here to view
As shown in [Table 2], there was no statistically significant difference in the baseline clinical para among the rTMS group and the TAU group. Also the mean HAM-D score for the rTMS group at baseline was 23.18 (SD 4.30) while mean HAM-D score for TAU group was 22.50 (SD 3.71). Again the difference in symptom severity scores was not statistically significant.
|Table 2: Comparison of rTMS and pharmacological treatment (TAU – treatment as usual) groups in terms of baseline (illness-related and other clinical) variables|
Click here to view
[Table 3] shows the comparison of rTMS and TAU group in terms of follow-up and outcome. In terms of outcome, that is, reduction in HAM-D score at 4 weeks, the rTMS group had more responders (26/50) than TAU group (23/50), but the difference was not statistically significant. Though TAU group had more dropouts than rTMS group (9 and 6), the difference was not statistically significant [Table 3].
|Table 3: Comparison of rTMS and pharmacological treatment (TAU – treatment as usual) groups in terms of follow-up and outcome variables (at 4 weeks)|
Click here to view
Further, we compared the responders and non-responders to rTMS to find out factors associated with good response to rTMS.
In terms of socio-demographic variables [Table 4], there was no statistically significant difference between the responders and non-responders in terms of age groups, gender distribution, or education level. More patients had a family history of psychiatric illness among the responders (23/26) than non-responders (8/24). This difference in two groups was statistically significant [Table 4]. In terms of baseline clinical variables, the non-responders to rTMS had a higher baseline mean HAM-D score (more severe illness) than responders to rTMS ((24.9 and 21.5, P value = 0.004). Additionally, response to rTMS was statistically more likely to be associated with absence of alcohol or nicotine use, first episode of depression (Recurrent Depression) and lower baseline HAM-A scores [Table 5].
|Table 4: Comparison of responders and non-responders to rTMS in terms of baseline (socio-demographic) variables|
Click here to view
|Table 5: Comparison of responders and non-responders to rTMS in terms of baseline (illness-related and others) variables|
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| Discussion|| |
The present study was carried out to compare the efficacy of repetitive TMS as an augmentation strategy versus pharmacological treatment (like SDA, lithium, buspione, thyroxine) for treatment of treatment-resistant unipolar, non-psychotic depression.
Berlim et al. used a treatment protocol which was quite similar to the FDA-approved protocol. They treated 15 patients of TRD with rTMS at 120% of resting MT to F3 location of 10–20 EEG montage (corresponding to left DLPFC). They applied the stimulus at a frequency of 10 Hz with 75 trains of 4-s duration and inter-train interval of 26 s (total of 3000 pulses per session). They reported a moderate effect size (Cohen d = 0.59) at the end of 4 weeks. The results of our study also correspond with this study. The same may have been due to similar treatment protocol used in both the studies.
In a meta-analysis on the efficacy of rTMS in Psychiatric Disorders by Slotema et al., the mean weighted effect size of rTMS versus sham for depression was 0.55 (P < 0.001) which was suggestive of a moderate effect size. Our study has similar results in terms of response at 4 weeks. Liu et al. reported superior response and remission rate for rTMS. The pooled response rate for rTMS group was 46.6% as compared to sham group. Our study also yielded similar results.
| Summary and Conclusions|| |
In our study, after 4 weeks of treatment augmentation, rTMS and TAU groups showed response rates of 52% and 46%, respectively. The difference between the two groups in terms of the number of responders at the end of 4 weeks is not statistically significant.
Absence of a family history of psychiatric illness, no concomitant psychoactive substance use, first episode of depression and low baseline depression, and anxiety scores were associated with higher rates of response to rTMS as an augmentation strategy for unipolar, non-psychotic depressive episode.
An interesting finding in the study was that higher baseline levels of anxiety were associated with low response rates with rTMS. This finding warrants attention and further research to establish the extent to which baseline anxiety affects response of depressive symptoms to rTMS as augmentation strategies.
This is one of the few studies on direct comparison of rTMS as augmentation strategy versus pharmacological augmentation treatment of unipolar, non-psychotic depression. We followed US FDA-recommended treatment protocol for administering rTMS and conducted the study as per CONSORT 2010 Flow Diagram (placed at appendix). The overall number of dropout was low. We included both OPD and in-patients using stringent inclusion and exclusion criteria. Validated scales were used for symptom quantification. We attempted to account a large number of possible confounders of outcome.
However, our study has several limitations. Despite our best efforts, certain confounding variables may have been unaccounted for. Novelty effect or placebo effect of rTMS may have contributed to response and remission rates. However, the outcome (efficacy) measures were similar to international studies using similar protocols. Like medication dosages tend to be lower in Asian population, specific rTMS protocols may also be required for our population. More research in Indian subjects is needed to develop specific protocols better suited for Indian subjects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep 2018;8:2861.
World Health Organization. Depression in India: Lets Talk. New Delhi: World Health Organization, Country Office for India; 2017.
Callahan CM, Berrios GE. Reinventing Depression: A History of the Treatment of Depression in Primary Care, 1940–2004. New York: Oxford University Press; 2005.
Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th
ed. Cambridge: Cambridge Univ Press; 2013.
Sadock VA, Sadock BJ. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. 10th
ed. Philadelphia: LWW; 2017.
Chail A, Saini R, Bhat P, Srivastava K, Chauhan V. Transcranial magnetic stimulation: A review of its evolution and current applications. Ind Psychiatry J 2018;27:172-80.
] [Full text]
Rossi S, Hallett M, Rossini PM, Pascual-leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120:2008-39.
Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, et al
. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150-206.
Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: A systematic review and metaanalysis. Can J Psychiatry 2008;53:621-31.
Liu B, Zhang Y, Zhang L, Li L. Repetitive transcranial magnetic stimulation as an augmentative strategy for treatment-resistant depression, a meta-analysis of randomized, double-blind and sham-controlled study. BMB Med Ress Methodol 2014;14:342.
Slotema CW, Blom JD, Hoek HW, Sommer IEC. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry 2010;71:873-84.
Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al
. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol 2020;131:474-528.
Gautam S, Jain A, Gautam M, Vahia VN, Grover S. Clinical practice guidelines for the management of depression. Indian J Psychiatry 2017;59(Suppl 1):S34-50.
Chen J-J, Zhao L-B, Liu Y-Y, Fan S-H, Xie P. Comparative efficacy and acceptability of electroconvulsive therapy versus repetitive transcranial magnetic stimulation for major depression: A systematic review and multiple-treatments meta-analysis. Behav Brain Res 2017;320:30-6.
Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N. Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: A systematic review and network meta-analysis. Curr Med Res Opin 2017;33:701-11.
Moher D, Schulz KF, Altman DG. The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191-4.
Berlim M, Gustavo T. Definition, assessment, and staging of treatment-resistant refractory major depression: A review of current concepts and methods. Can J Psychiatry 2007;52:46-54.
Al-Harbi KS. Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Prefer Adherence 2012;6:369-88.
Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Screening questionnaire before TMS: An update. Clin Neurophysiol 2011;122:1686.
Gupta S. Intention-to-treat concept: A review. Perspect Clin Res 2011;2:109.
] [Full text]
Kautzky A, Dold M, Bartova L, Spies M, Kranz GS, Souery D, et al
. Clinical factors predicting treatment resistant depression: Affirmative results from the European multicenter study. Acta Psychiatr Scand 2019;139:78-88.
Cepeda MS, Reps J, Ryan P. Finding factors that predict treatment-resistant depression: Results of a cohort study. Depress Anxiety 2018;35:668-73.
Nuñez NA, Comai S, Dumitrescu E, Ghabrash MF, Tabaka J, Saint-Laurent M, et al
. Psychopathological and sociodemographic features in treatment-resistant unipolar depression versus bipolar depression: A comparative study. BMC Psychiatry 2018;18:68.
Balestri M, Calati R, Souery D, Kautzky A, Kasper S, Montgomery S, et al
. Socio-demographic and clinical predictors of treatment resistant depression: A prospective European multicenter study. J Affect Disord 2016;189:224-32.
Bennabi D, Aouizerate B, El-Hage W, Doumy O, Moliere F, Courtet P, et al
. Risk factors for treatment resistance in unipolar depression: A systematic review. J Affect Disord 2015;171:137-41.
Berlim MT, McGirr A, Beaulieu MM, Turecki G. High frequency repetitive transcranial magnetic stimulation as an augmenting strategy in severe treatment-resistant major depression: A prospective 4-week naturalistic trial. J Affect Disord 2011;130:312-7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]