Transcranial Magnetic Stimulation (TMS) could be recognized as one of the major breakthroughs in the translational neuroscience applied in mental health. During the year 1985, first magnetic nerve stimulator was designed which used short-pulsed magnetic fields which were used to stimulate human motor cortex to produce Motor Evoked Potentials in an experimental procedure named TMS. [1] Following the discovery of TMS in 1985, the application of this brain stimulation technique for the management of psychiatric disorders has been tested across the world. [2] Out of many target brain areas for TMS, prefrontal cortex (PFC) has been the major target site in most of the psychiatric disorders. [3] The working principle of TMS devices involves introduction of a magnetic field into the brain to induce an electric current as per Faraday’s Law of Electromagnetic Induction. [4] There are classical and non-classical therapeutic effects of TMS. Classical effects like modulation in neurotransmitter concentrations, synaptic plasticity via long-term potentiation and long-term depression are produced by the induced current. At a molecular level, TMS has been found to enhance production of substances that help in neuronal regeneration, remyelination, neuronal plasticity and protection, including production chemicals such as brain-derived neurotrophic factor, anti-apoptotic factors like Bcl-2 and Bcl-xL. [5-7] The non-classical effects of TMS could be linked directly to biophysical effects of magnetic fields including the quantum effects, the magnetic spin effects, genetic magnetoreception, and macromolecular effects. [7] Although the molecular effects of TMS were not directly studied in human subjects in both health and disease, neuroimaging techniques such as Positron Emission Tomography showed a significant change in a depressed brain before and after TMS. [8-11] Till date, a huge amount of clinical research in depression supports the fact that TMS continues to be a highly safe, non-invasive brain stimulation (NIBS) technique showing good clinical outcomes. [12-15] The basic setup of a TMS device consists of a stimulator (to generate strong alternating current pulses), coolant (to manage and nullify the heat generated from the device), connector systems that transmit the alternating currents to the coil(s), and the coil(s) (that generate magnetic field pulses from the alternating current pulses). Coil characteristics play an important role in generating magnetic fields with different strengths and directions which affect the induced electric fields measured as Volts/meter (V/m). [16-18] For instance, for a given stimulator setting, a magnetic pulse from a planar figure of 8 coil can penetrate a depth of about 0.7-1.1 cm from the cortical surface whereas from a cup-like H coil, the penetration depth can be as great as 1.8-3.5 cm, calling it as deep TMS (DTMS). [19] The thickness of human cerebral cortex is about 2-4 mm. The projection fibers from the layer 5 pyramidal cells connect multiple cortico-cortical and cortico-subcortical areas. The axons of these projection fibers are affected by the induced electric fields in TMS. The degree of stimulation in a particular axon depends on its angle to the induced resultant electric vector. Furthermore, the bend points on the axon are more susceptible to stimulation by induced threshold and suprathreshold E-fields. [20] A deeper E-field and greater volume of neuronal stimulation will therefore ensure better stimulation of projection fibers with different axial directions and bend points. A theoretical plausibility could hence exist that DTMS produces better responses as compared to conventional coils. The United States Food and Drug Administration (US-FDA) approved the usage of High Frequency Stimulation (HFS) of DTMS for Major depressive disorder (MDD), Obsessive Compulsive Disorder (OCD), and Nicotine dependence, using H1 (18Hz HFS), H7 (20Hz HFS), and H4 (10Hz HFS) coils respectively. MDD is one of the most prevalent and debilitating mental health disorders. According to WHO, about 322 million people are living with depression worldwide which increased by 18.4% between 2005 and 2015. [21] In the 2010 Global Burden of Disease report, about 85% of contribution to Years Lived with disability (YLD) and Disability Adjusted Life Years (DALY) comes from Major Depressive Disorder (MDD). The same report also presents that ages between 20-44 years have highest YLDs with females having more prevalence than males. [22] Depression is a multifaceted condition which significantly affects the thoughts, emotional regulation, and behavior in an individual. The causes of depression are multifactorial such as biological, psychological, and social. The first-line treatment for depression would be pharmacotherapy with antidepressants like Selective Serotonin Reuptake Inhibitors (SSRI) and others. [23] Additionally, psychological interventions like Cognitive Behavioral Therapy (CBT) are also given. However, despite having a wide range of treatments not all patients achieve complete remission in depression. Neuroimaging studies not only identified hypofunctional left dorsolateral prefrontal cortex (dlPFC) as the major area affected in depression but also the regained functional connectivity in this area is considered as a biomarker for antidepressant response. [24, 25] Along with anterior cingulate cortex and inferior parietal lobe, dlPFC is an integral part of Central Executive Network (CEN) which is involved in cognitive and emotional functions of the brain. [26] The dlPFC plays a key role in executive functions like planning, decision making, language processing, attention, working memory, and mood regulation. [27-31] DTMS with H1 coil targeting left dlPFC with 18Hz HFS is known to produce anti-depressant effects as reflected in significant differences in response rates after a certain number of treatment sessions, which are found to be better than figure of 8 coil stimulation. [32,33] There are various factors that determine this efficacy of DTMS in depression such as, treatment regimen, motor threshold, presence of other medical and psychiatric comorbidities like hypertension, endocrinopathies, anxiety, age, sex, and duration of illness etc. These factors, called predictors of treatment response in depression, are patient-related, illness-related, and procedure-related. [34] In this context, a special emphasis must be put on the treatment regimen. The US-FDA approved standard depression regimen includes 20 daily sessions delivered over 4 weeks using 18Hz HFS (HFS18). Accelerated regimens administer more than one session per day intending to shorten the treatment duration. Although the accelerated regimens were tested for shorter treatment durations, the safety and efficacy of these regimens became an additional advantage. Interestingly, many independent studies have tried to establish the non-inferiority between accelerated and standard regimens in the past. [35-40] Accelerated regimens employed stimulation either as a HFS or intermittent Theta Burst Stimulations (iTBS). While there is no established difference in the efficacy between the stimulation type, clinically useful regimens favor iTBS over HFS for shorter session durations. Moreover, the effectiveness of an HFS is found to be non-inferior to iTBS600 stimulation. [41] Also, there are a few real-world observational studies which combine HFS and iTBS stimulations to produce composite accelerated treatment regimens. [42] While the number of pulses in a HFS remain constant as 1980/session, they can be varied from 600 to 1800 in an iTBS stimulation. It is worth nothing that the US-FDA had given approval for accelerated iTBS treatment regimen in depression in the year 2025, which consists of iTBS1800 stimulation. In addition to the treatment regimen, patient-related factors like age, sex, duration of illness etc. also appear to play a role in deciding the outcomes after DTMS treatment for depression. Although the TMS was initially advised to treat resistant patients of depression, newer clinical indications and patient selection criteria have been tried in recent days, like in achieving early functional recovery, patients denying increased doses of antidepressant medications, old, aged patients, pregnant women etc. Also, studying the effects of DTMS in a heterogenous group of patients in a naturalistic setting would help us understand the real-world efficacy of the treatment in depression. Besides establishing the clinical efficacy of accelerated DTMS (aDTMS) regimen for depression, the current study aims to investigate the impact of patient specific factors like age, sex, duration of illness and treatment specific factors like motor threshold on the clinical outcome.

This observational study presents analysis of clinical data of 445 patients, collected from multiple neuromodulation clinics during April 2022 to March 2025. All the patients were diagnosed with depression and were aged 12 to 86 years. Informed written consent was taken from all the patients to use their clinical data for analysis and publication. Additional consent was taken from parents of the adolescent patients. The diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Patients were screened for Electro-magnetic field compatibility prior to the treatment. Presence of Ferro-magnetic materials in the head and neck, previous history of Traumatic Brain Injury (TBI), substance abuse, cochlear implants, cardiovascular implants like pacemakers were the exclusion criteria. [43,44] The patient group was a mixed population with different drug prescriptions and durations of illness, and with or without medical comorbidities like Hypertension, Diabetes Mellitus, Hypothyroidism etc. Patients with psychosis and severe substance use disorders were excluded. Clinical data of all the patients satisfying the inclusion criteria was considered for analysis. The primary measure was the score of Hamilton Depression Rating Scale (HAM-D) with 17 items. [45] HAM-D was taken by a qualified psychologist after the initial assessment and screening by the psychiatrist. Day-1 HAM-D was taken at the beginning of treatment, and day-6 score was obtained after completion of 18 DTMS sessions. Response rate in depression was calculated as > 50% reduction in HAM-D score on day 6. The remission rate was calculated as HAM-D < 7 on day 6. The post treatment score was evaluated by second psychologist to rule out operator bias. Device used: BrainsWay’s 104 deep TMS system fitted with H1 coil. Pre DTMS evaluation of the patient was carried out to decide their fitness for the electromagnetic field compatibility. Before the first treatment session, resting motor threshold (RMT) was estimated using visual method. By placing the H1 coil at the location 7/8 on the grid system, a single magnetic pulse was given to stimulate the hand area of the left motor cortex which produced a visible twitch in the right hand. The intensity of the pulse was titrated up or down starting from 50% of the maximum stimulator output. The RMT was then estimated as the minimum intensity required to elicit a consistent right-hand twitch in about 50% of the 6 trials. [46] The RMT was estimated only at the beginning of the treatment. The aDTMS treatment regimen extended over 18 sessions, was administered as 3 sessions/day for 6 consecutive days. The daily treatment consisted of 3 sessions given daily with one hour gap between sessions, per day consisted of two HFS18 interspersed with one iTBS1800 stimulation. An iTBS1800 stimulation has been chosen to match the final dosage close to the US-FDA advocated 4-week treatment regimen consisting of 39,600 pulses. Keeping in view the effect of iTBS1200 in reducing cortical excitability and iTBS1800 tested successfully for treatment resistant depression, we used iTBS1800 for our patients. [47,48] A. The HFS18 stimulation delivered 55 2s trains of 18Hz and 20s interval given at 120% of RMT, accounting to 1980 pulses. Twelve such sessions were covered over 6 days at the frequency of 2 sessions/day, giving a total of 23760 pulses. B. The iTBS1800 stimulation with standard 5Hz-50Hz combination of train and burst frequencies respectively, given at 80% of RMT was given between the two HFS18 sessions with one hour gap between them. Six iTBS1800 sessions were given, accounting for 10800 pulses. The total number of pulses given by the end of the treatment period was 34560. Side effects were recorded after every session by the TMS operator. No serious adverse event was reported. Mild side effects like headache or scalp discomfort were noticed. Descriptive statistics were used first to summarize the data. Paired t-tests or Wilcoxon tests were used for HAM-D changes. Response and remission rates were analyzed with chi-squared tests. Regression models tested how patient and treatment factors affected improvement and remission. SPSS v26.0 (IBM Corp.) was used with a p=0.05 significance level.

The total number of patients recruited in the study were 445 which includes 220 (49%) females and 225 (50%) males with a mean age of 41.80±15.99 years. Majority of the participants belonged to the age group of 30-44 years (mean 37.33±4.35 years) followed by 45-60 years (mean 51.57±5.01 years) [Table 1]. Table 1: Age and Sex-wise distribution of patients who received aDTMS treatment for depression Age group (years) Description Mean age (Mean ± SD) Female (N) Male (N) Total (N) 12–17 Adolescents 14.38 ± 2.56 9 5 14 18–29 Early adults 24.02 ± 3.02 58 50 108 30–44 Late adults 37.33 ± 4.35 65 76 141 45–60 Middle age 51.57 ± 5.01 60 53 113 61–89 Old age 67.96 ± 5.61 28 41 69 Total 41.80 ± 15.99 220 225 445 Table 2: Day 1 and Day 6 HAM-D scores in different disease severity groups of patients Severity Grade N Day 1 HAM-D (Mean ± SD) Day 6 HAM-D (Mean ± SD) Diff. (Mean ± SD) Diff % (Mean ± SD) Mild (8–16) 118 13.15 ± 2.39 5.84 ± 3.16 7.31 ± 3.25 55.42 ± 23.18 Moderate (17–23) 165 19.64 ± 2.01 7.81 ± 4.12 11.82 ± 4.02 60.40 ± 19.82 Severe (>24) 162 28.57 ± 4.22 11.98 ± 7.06 16.58 ± 6.42 58.74 ± 21.86 Total 445 21.09 ± 7.00 8.81 ± 5.78 12.32 ± 6.13 58.49 ± 21.58 Figure 1: Box plot showing pre- and post-aDTMS HAM-D scores by disease severity The association between disease severity, day 1 and day 6 HAM-D scores and mean reduction in HAM-D are presented in table 2 and figure 1. Overall mean reduction in HAM-D after 18 sessions was 12.32 ± 6.13 points corresponding to 58.49 ± 21.58 % reduction. Further, in patients with severe depression this reduction was greatest at 16.58 ± 6.42 points. The overall response and remission rates on day 6 were 69.66% and 47.64% respectively. The highest response rate was seen in patients with severe depression, but greatest remission was noticed in mild depression [Table 3]. Table 3: Treatment response and remission rates in subgroups with different disease severity Grade No. of Subjects (N) Fraction responded (N) Response Rate Fraction remitted (N) Remission Rate Mild (8–16) 118 76 64.40% 79 66.94% Moderate (17–23) 165 116 70.30% 88 53.33% Severe (>24) 162 118 72.83% 45 27.78% Total 445 310 69.66% 212 47.64% Figure 2: Response and Remission rates after 6 days of aDTMS treatment in depression Table 4: Reduction in HAM-D scores on day 6 compared in men and women Group day 1 – day 6 diff. (Mean ± SD) Diff. % (Mean ± SD) Males (N = 225) 11.89 ± 5.91 58.39 ± 20.99 • Mild (n = 72) 6.81 ± 3.21 53.20 ± 24.13 • Moderate (n = 76) 11.87 ± 3.71 60.84 ± 17.92 • Severe (n = 77) 16.83 ± 5.23 60.72 ± 19.80 Females (N = 220) 12.75 ± 6.32 58.59 ± 22.16 • Mild (n = 46) 8.06 ± 3.15 58.80 ± 21.20 • Moderate (n = 90) 11.79 ± 4.26 60.04 ± 21.26 • Severe (n = 84) 16.36 ± 7.33 56.93 ± 23.44 Figure 3: Initial (day 1) and final (day 6) HAM-D scores in men and women Reduction in HAM-D scores between male and female patients according to disease severity is presented in table 4. There is no significant difference between overall HAM-D reduction (p=0.21), but females (about 8-point reduction) with mild disease responded better than male (about 6-point reduction) counterparts (p<0.001). Gender-stratified analysis revealed comparable overall % reduction in HAM-D (≈58.5%) in males and females. Mean HAM-D reductions were marginally higher in females (12.75 points) than males (11.89 points), though variability was similar (p=0.04). These nuanced differences may stem from sex-related neurobiological or hormonal factors influencing cortical excitability. Table 5: Age-specific changes in HAM-D scores on day 6 and response rates Age group Description Day 1 HAM-D (Mean ± SD) Day 6 HAM-D (Mean ± SD) Diff. (Mean ± SD) Diff % (Mean ± SD) Response rate % 12–17 Adolescents 21.46 ± 6.77 9.54 ± 4.55 11.92 ± 6.44 54.94 ± 21.70 69.23% 18–29 Early adults 22.77 ± 6.49 9.81 ± 5.43 12.96 ± 5.93 56.75 ± 19.90 63.89% 30–44 Late adults 19.59 ± 6.28 7.51 ± 5.28 12.13 ± 6.19 61.41 ± 21.46 76.43% 45–60 Middle age 20.95 ± 7.94 9.25 ± 6.51 11.78 ± 6.01 57.87 ± 21.54 72.32% 61–89 Old age 21.70 ± 6.88 9.04 ± 5.76 12.65 ± 6.35 56.96 ± 23.65 63.76% Response to aDTMS varied modestly by age. Late adults (30–44 years) responded the maximum (76.4%) alongside %reduction in day 6 HAM-D (61.4%), suggesting peak neuroplastic responsiveness. Adolescents and old-age participants showed lower response rates (~69% and 63.8%, respectively) which could possibly throw light on cortical responsiveness, as elaborated in later sections. The baseline HAM-D scores did not vary significantly across the groups. Table 6: Effect of number of drugs on the HAM-D reduction and response rates No. of Drugs N % of Subjects Illness Duration (years) median [IQR] Diff. HAM-D (Mean ± SD) Response rate % 0 14 3.14% 4.5 [2.25, 6.75] 11.50 ± 6.89 71.42% 1 128 28.76% 4 [2, 7.25] 12.30 ± 6.04 75.00% 2 133 29.88% 2 [1, 5] 11.01 ± 5.41 62.30% 3 93 20.89% 3 [1, 6] 12.25 ± 5.67 69.89% 4 51 11.46% 4 [1.5, 10] 14.84 ± 6.93 70.58% ≥5 25 5.61% 6 [1, 8] 14.96 ± 7.21 83.33% Subjects with greater prior pharmacotherapy burden showed variable response rates to rTMS. Those on ≥5 drugs had the highest response (83.3%). Conversely, individuals on two drugs exhibited the lowest response (62.3%). Interestingly, median illness duration did not correlate linearly with response, highlighting that drug history may override disease chronicity in predicting outcomes. The consistent HAM-D improvements across groups reinforce TMS efficacy irrespective of pharmacological background while indicating potential for even greater gains in multi-resistant cohorts. Adverse effects were generally mild and transient. Mild headache was most common (9.6%), with only 0.8% reporting severe headache. Motor-related side effects facial (4%) and jaw twitching (5.1%) occurred in a minority while systemic complaints like nausea were rare (0.2%). No serious or persistent events were documented. The low incidence of severe side effects underscores the safety of the aDTMS regimen. Monitoring and supportive care for discomfort can easily manage these transient effects, reinforcing that the risk–benefit profile of aDTMS remains highly favorable in depressed populations. Figure 4: Frequency and types of treatment-related adverse effects Table 7: Paired t-tests comparison of HAM-D scores on day 1 vs. day 6 across age groups Age Group (Years) Number of patients (N) Day 1 HAM-D Mean ± SD Day 6 HAM-D Mean ± SD t-Statistic p-Value 12–17 14 21.46 ± 6.77 9.54 ± 4.55 7.12 <0.001 18–29 108 22.77 ± 6.49 9.81 ± 5.43 15.03 <0.001 30–44 141 19.59 ± 6.28 7.51 ± 5.28 18.65 <0.001 45–60 113 20.95 ± 7.94 9.25 ± 6.51 12.48 <0.001 61–89 69 21.70 ± 6.88 9.04 ± 5.76 11.87 <0.001 All age groups demonstrated highly significant reductions in HAM-D scores from Day 1 to Day 6 (all p < 0.001). The largest t-value was observed in the 30–44-year cohort (t = 18.65), reflecting both a substantial mean change (12.08 points) and relatively low within-subject variability. Adolescents (12–17 years) had the smallest sample but still showed a strong effect (t = 7.12). Table 8: Chi-squared test association between depression severity and response rate Severity Grade Responders Non-Responders Total Expected Responders χ² (df=2) p-Value Mild (8–16) 76 42 118 82.3 Moderate (17–23) 116 49 165 115.1 3.27 0.195 Severe (>24) 118 44 162 112.6 Total 310 135 445 The chi-squared test yielded χ² = 3.27 (df = 2, p = 0.195), indicating no statistically significant association between baseline depression severity and dichotomous treatment response. Although numerically higher response rates were seen in more severe cases this difference did not exceed what might occur by chance given the sample sizes. Thus, severity grade alone does not predict likelihood of achieving ≥50% HAM-D reduction in this regimen. In the adjusted model, younger age (β = –0.09, p = 0.003), shorter illness duration (β = –0.45, p = 0.009) and fewer no. of drugs (β = –0.72, p = 0.008) independently predicted greater HAM-D reduction. Higher stimulation intensity (relative to motor threshold) and larger total pulse counts were also modest but significant positive predictors. Sex was not a significant factor. The model explained 28% of variance in symptom change, highlighting the importance of both patient history and treatment dosing in optimizing outcomes. Table 9: Multivariable linear regression predictors of reduction in HAM-D score Predictor β Coefficient Standard Error t-Value p-Value Age (years) –0.09 0.03 –3.00 0.003 Sex (1 = female) 0.12 0.85 0.14 0.886 Duration of illness (years) –0.45 0.17 –2.65 0.009 Number of drugs –0.72 0.27 –2.67 0.008 Resting Motor Threshold (%) 0.15 0.07 2.14 0.034 Model R² = 0.28 Table 10: Logistic regression predictors of remission (HAM-D ≤ 7) Predictor Odds Ratio (OR) 95% CI p-Value Age (per year increase) 0.97 0.95–0.99 0.012 Sex (female vs male) 1.05 0.70–1.56 0.811 Severity (baseline HAM-D) 0.82 0.75–0.90 <0.001 Number of Drugs Tried 0.89 0.81–0.98 0.022 Resting Motor Threshold (%) 1.03 1.00–1.06 0.045 Model Nagelkerke R² = 0.32 Figure 5: Forest plot showing the predictors of remission from depression after aDTMS treatment Remission likelihood decreased with increasing age (OR = 0.97, p = 0.012), higher baseline severity (OR = 0.82 per HAM-D point, p < 0.001) and greater number of prior drug trials (OR = 0.89, p = 0.022). Higher stimulation intensity and total pulses modestly increased odds of remission. Sex was not predictive. The model’s Nagelkerke R² of 0.32 indicates good explanatory power for identifying which patients achieve full remission under accelerated deep rTMS.

Across a large heterogenous cohort of 445 depression patients (Table 1), our 6-day aDTMS regimen has helped to achieve an overall mean reduction in HAM-D score by 12.32±6.13 points also corresponding to an overall response rate of 69.66% and a remission rate of 47.64%. This observation is in line with previous studies. [42] The discussion section will emphasize whether certain factors have affected this outcome and to what extent. We will also address the need for accelerated DTMS regimens for depression to target early functional recovery. Age of the patient: There is a significant reduction in day-6 HAM-D score (all p < 0.001 Table 9) in all age groups independently. About 57% of the total patients belonged to the age group 30-6o years, indicating a greater prevalence of depression in this group. Highest %reduction in HAM-D as well as response rate was noticed in the age group 30-44 years. Least within subject variability in this group indicates that aDTMS worked best in the middle age. Although there are a few adolescents (about 3%) selected for aDTMS, the day-6 reduction in HAM-D is significantly lesser compared to adults. This indicates that a HFS over left dlPFC is alone not sufficient to bring a clinically significant change in adolescent depression. The authors believe that a bilateral sequential stimulation that also included inhibition over right dlPFC would have been a better option in adolescents. [49, 50] Interestingly, there is no report of Treatment Emergent Manic Switch in any patient, especially younger age group establishing the safety of aDTMS. Special emphasis must be put on the impact of aDTMS in old age group, 61-89 years. 15% of the total patients belonged to old age and tolerated the aDTMS regimen and had about 57% reduction in HAM-D on par with other groups. [51] Although prior studies demonstrated a 70% response rate with HFS using H1 coil, our observation showed slightly less response probably due to the smaller sample size. [52, 53] Sex of the patient: In the present sample, males and females were in equal proportions in the entire group as well as age-wise subgroups. Factors like lower scalp-cortex distance, greater PFC gray matter density and gyrification in the prefrontal cortex, and high estradiol levels in the follicular phase were known to modulate cortical excitability and females were expected to be better responders compared to men. [54] Females with mild However, latest research from real-world sample clearly identified that sex has no significant role to play in the clinical outcomes after TMS. [55] Even in this study, we found that gender did not make any difference in how well patients responded, evidenced in either linear or logistic models (Table 11 & Table 12). Severity of depression: The overall mean day-1 HAM-D was 21.09±7.00 points. The reduction in HAM-D is proportionate to the initial score in all three severity grades, mild, moderate, and severe depression. However, patients with moderate depression, although had maximum %change in HAM-D (60.40±19.82%), chi-squared tests showed no strong association between baseline severity and response rate (χ² = 3.27, p = 0.195 Table 8) which means this treatment worked well for all levels of depression. On the other hand, high baseline HAM-D was a strong predictor of lower remission rate after the aDTMS (OR = 0.82 per HAM-D point). Number of drugs: Greater short-term efficacies have been found by combining antidepressant medications and TMS, specially focusing the accelerated regimens. [56] TMS has always been used as an adjunct to medication in depression. In our study, 3% of the patients were not on any drug, due to their choice to check with TMS first before being put on drugs. This group responded well with aDTMS. 58% of the patients who were on 1 or 2 drugs were using standard dosage of one or two SSRIs respectively. The three-drug group had an extra Benzodiazepine. There is not much difference in the outcome between 1 or 2 or 3 drug users with comparable illness duration, implying drug-TMS interactions are probably not related to drug dose or class. The highest response rate of 77% was achieved in the 4 and 5 drug (polypharmacy) groups, but their average duration of illness is above 5 years, and they constitute relatively smaller proportion of cases (17%). This group, like treatment-resistant depression, had significant reduction in HAM-D (β = –0.72, p = 0.008 Table 11) and better remission (OR = 0.89 per drug, p = 0.022 Table 12). Despite being on polypharmacy, patients with chronic depression were advised to have aDTMS because of poor clinical improvement. In these patients, aDTMS helped to bring an early recovery. This suggests that an early exposure of DTMS in these patients could have prevented long disability periods. Therefore, aDTMS with the H1-coil led to big and meaningful drops in depression for all groups, with 69.7% of patients responding and 47.6% reaching remission. The treatment was safe, well tolerated by all patients. Side effects (Table 7) were mostly minimal and transient like mild headache (9.6%) and facial or jaw twitching (4–5.1%) and there were no serious adverse events. Out of the four factors discussed, each of them had its own independent effect as elucidated. Our study explains that accelerated TMS regimens are equally safe as standard once daily regimens. Also, customized regimen by combining iTBS with HFS has been shown not to have any deleterious effects on the outcome. Pros and cons of accelerated TMS regimens used in depression have been elucidated in detail previously. [57] The current aDTMS regimen has been observed to satisfy three major determinants, efficacy, safety and tolerability. Accelerated TMS regimens produce a clinically evident Early Functional Recovery as compared to the standard protocols. The wiser safety spectrum of DTMS provides the feasibility of applying accelerated regimens in the regular clinical practice of psychiatry in managing depression. Regarding the selection of the stimulation type in accelerated regimens, a controversy exists regarding the efficacy of iTBS vs. HFS. Few studies show that HFS is superior to iTBS [58], while few animal studies on synaptic plasticity explain their similar actions. [59] Nevertheless, combination of an iTBS and HFS simulations were used in the routine clinical practice to achieve good recoveries in OCD. [60] In the same vein, the current study used a combination of iTBS and HFS to achieve early recoveries in depression. Insurance coverage for TMS treatment for depression mandates that patients must fail several antidepressant trials before they can take TMS. However, in a 2019 systematic review of the clinical efficacy of TMS in non-treatment resistant patients with depression, Voigt et al. opines that patients after <1 medication trial should also be considered for TMS, and insurance coverage policies need to be revised. [61] Also, in countries like India, insurance is not widely applied for mental health disorders like depression, especially in an out-patient clinical setup. Hence, patient selection for TMS, and counselling about advantages of TMS becomes an important duty of the consulting psychiatrist. In this context, achieving early functional recovery is beneficial both to the patient and the clinician. To make it possible, accelerated TMS regimens are no doubt very helpful. The current observational study supports the idea that aDTMS can be safely and effectively used in giving a promising outcome in depressed individuals. The authors also hope for the possibility of considering such accelerated DTMS regimens under insurance coverage for a wider application of these regimens. Lack of a control group and follow-up data are the major limitations of the study. As a future directive, we intend to establish the clinical efficacy of our aDTMS regimen through a controlled trial.

In the retrospective study in a heterogenous patient group, the aDTMS treatment regimen for depression, which included a combination of iTBS1800 and HFS18 has been found to be safe, effective, and patient compliant. The treatment outcome measured as day 6 reduction in HAM-D score did not significantly differ among men and women. The patients in their middle age (30-44 years) showed highest response. The aDTMS regimen has been well tolerated by extreme age groups as well. The effect of number of drugs the patients were on, had a functional association with duration of illness. Patients with chronic depression who were in polypharmacy showed highest response during their first aDTMS exposure. Irrespective of the number of drugs, the patients who were on 1-3 drugs had similar response. Finally, the baseline severity of depression did not affect the final treatment outcome. This out-patient based aDTMS treatment is therefore found to be useful in bringing early functional recovery in patients with acute as well as chronic depression. More studies in this area must be done to test the reproducibility of the effects. Controlled trials including sham group and animal studies to understand the synaptic mechanisms will establish the clinical and neurobiological efficacy of the accelerated regimen.

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