The safety and efficacy of adjunctive 20-Hz repetitive transcranial magnetic stimulation for treatment of negative symptoms in patients with schizophrenia: A double-blinded, randomized, sham-controlled study.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment strategy for negative symptoms. However, the evidence for its efficacy is mixed, with contradictory results between studies due to lack of consensus about the optimal stimulation parameters. AIM: The present study was planned to assess the safety and efficacy of 20-Hz rTMS over left dorsolateral prefrontal cortex (Lt-DLPFC) with more robust stimulation parameters for adjunctive treatment of negative symptoms in patients with schizophrenia.
MATERIALS AND METHODS: Thirty patients with negative symptoms of schizophrenia (Positive and Negative Syndrome Scale [PANSS] negative subscore ≥15) were randomized to receive a 4-week treatment with either real-rTMS (n = 15) or sham-rTMS (n = 15). The study outcomes were assessed at baseline, after 5th and 20th rTMS sessions with PANSS, Scale for the Assessment of Negative Symptoms (SANS), Calgary Depression Scale for Schizophrenia, Clinical Global Impressions-Severity of illness scale, and rTMS side-effect checklist.
RESULTS: There was significantly greater reduction in negative symptoms assessed by SANS score in the real rTMS group, compared with the sham rTMS group. There was no significant difference in the rate of side-effects reported between the two groups. The rTMS treatment was well-tolerated by all the patients, except one seizure episode reported in the active group.
CONCLUSION: The high-frequency rTMS protocol was safe and well-tolerated, provided patients prone to developing seizure were excluded by baseline electroencephalography prior to starting of the treatment. The 20-Hz rTMS over Lt-DLPFC with more robust stimulation parameters (100% motor threshold and 40,000 pulses) might be an effective augmentation strategy for the treatment of negative symptoms in schizophrenia. Copyright:

INTRODUCTION

Negative symptoms are now recognized as one of the core symptom domains with a stable course, and an independent predictor of poor functional outcomes in patients with schizophrenia.[12] Although the newer second-generation antipsychotic drugs are effective in treating positive symptoms (e.g., delusions and hallucinations) of schizophrenia, the promise of their efficacy against negative symptoms has not been borne out.[3] Besides newer antipsychotics, meta-analytic studies on adjunctive treatment with agents, such as ginkgo biloba, oxytocin and other sex hormones, modafinil/armodafinil, minocycline, antioxidant agents, anti-glucocorticoid agents, and glutamatergic drugs, have been undertaken.[4] However, none of them have been found to have sufficient evidence in ameliorating negative symptoms of schizophrenia. The negative symptoms of schizophrenia are difficult to treat with currently available treatment options, including both pharmacological and nonpharmacological interventions such as cognitive remediation or social skills training. Thus, there is a need for exploring newer or adjunctive treatment options for their effective management.

The findings from multiple functional neuroimaging and neurophysiological studies have consistently reported hypoactivity in the dorsolateral prefrontal cortex (DLPFC) as well as impaired frontoparietal and frontostriatal brain network connectivity to be associated with the negative symptoms of schizophrenia.[56] Further, hypofrontality with a lack of dopamine release in the striatal and extrastriatal brain areas (prefrontal cortex) has been suggested as the primary abnormality responsible for negative symptoms in schizophrenia.[7] Thus, it can be hypothesized that noninvasive brain stimulation techniques such as high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over DLPFC, which can cause activation of prefrontal cortex and modulate neurotransmitter activity (e.g., dopamine) directly in the prefrontal cortex and through interconnections in the distal brain areas is likely to be an effective treatment modality for negative symptoms.

The recent evidence-based guidelines on the therapeutic use of rTMS state that HF-rTMS over left-DLPFC (Lt-DLPFC) has a probable effect in the treatment of negative symptoms of schizophrenia (Level B evidence).[8] The findings from three different meta-analyses of studies assessing the efficacy of HF-rTMS for treatment of negative symptoms also provide support for its use.[91011] The meta-analysis by Shi et al., included 13 randomized sham-controlled trials in treatment effect analysis, and reported an overall significant moderate effect size (cohen's d = 0.63).[11] Moreover, 10-Hz rTMS, at a 110% motor threshold (MT), over the Lt-DLPFC, for at least 3 consecutive weeks of duration were reported to be the best rTMS stimulation parameters for the treatment of negative symptoms. This meta-analysis also suggested that the effect of rTMS was greater in patients receiving a higher number of total pulses. However, results from a recent meta-analysis specifically including only randomized controlled studies which applied 10-Hz rTMS at Lt-DLPFC, failed to show any significant improvement in negative symptoms with active rTMS when compared to sham rTMS.[12]

These somewhat contradictory findings have also been replicated in two recent large double-blinded, randomized controlled trials (RCTs). A recent multicenter, double-blind RCT with a large sample size of 175 patients, failed to detect any statistically significant difference in the improvement of negative symptoms with active rTMS as compared to sham rTMS treatment.[13] The stimulation protocol used in the study consisted of 15 sessions of 10-Hz rTMS over Lt-DLPFC site, at 110% MT stimulation intensity, 5 s train and 30 s inter-train interval, with a total of 15,000 pulses delivered during the treatment. On the contrary, in another recent large double-blind RCT, 117 patients with negative symptoms were randomized to a 20-day treatment of either active rTMS applied to the Lt-DLPFC or sham rTMS.[14] The stimulation protocol used in this study consisted of 10-Hz rTMS, at 80% MT, 4 s train and 56 s inter-train interval, 20 min each day, with 800 pulses per session (16,000 pulses per treatment). They reported that treatment with HF-rTMS for 6 weeks significantly improved negative symptoms in the active stimulation group as compared to the sham group. Therefore, different rTMS protocols used in various studies may explain the contradictory findings, highlighting the importance, and need for optimizing rTMS parameters effective for the treatment of negative symptoms in schizophrenia.

Thus, the present study was planned to assess the safety and efficacy of this novel rTMS stimulation protocol with more robust stimulation parameters of higher stimulation frequency (20-Hz), a longer treatment course (4 weeks), and a higher number of total stimulation pulses (40,000 pulses) for adjunctive treatment of negative symptoms in patients with schizophrenia.

MATERIALS AND METHODS

Study design

This was a single-site, double-blinded, randomized, sham-controlled study conducted at a tertiary care general hospital in northern India. Participants were randomized to receive either active (n = 15) or sham rTMS (n = 15) treatment. Allocation concealment was done by using sequentially numbered sealed opaque envelopes, containing tokens that were randomly allocated by an independent colleague (author R.V.). The envelopes were opened just before the first treatment session by the trained rTMS technician. Only the technician administering rTMS and the doctor supervising the rTMS sessions were aware of the treatment allocation. The participants and the rater were blind to the treatment received by the participant. The study protocol was approved by the Institute Ethics Committee of the All India Institute of Medical Sciences, New Delhi, India. The trial has been registered in the Clinical Trials Registry of India (CTRI/2015/11/006397) before the recruitment of participants started. The study was conducted in accordance with ethical principles mentioned in the Declaration of Helsinki, and an informed written consent was taken from all the participants (and their legally qualified representatives) prior to their enrolment in the study.

Participants

The participants were recruited from a group of patients with a diagnosis of schizophrenia and receiving treatment at the psychiatry outpatient department of the hospital at the time of the study. Participants included in the study were right-handed, aged between 18 and 60 years, from either gender, diagnosis of schizophrenia established by a qualified psychiatrist based on the available history (from caregiver and medical records), and mental status examination of the patient as per the International Classification of Diseases-10 Diagnostic Criteria for Research (screened by the Mini-International Neuropsychiatric Interview version 7.0, Magstim, Whitland, Wales, UK),[15] stabilized for at least past 4 weeks on the same antipsychotics with significant negative symptoms (defined as Positive and Negative Syndrome Scale (PANSS) negative subscore of at least 15 points), and minimum illness duration of at least 1 year. Patients with any other psychiatric comorbidity, comorbid substance abuse or dependence (except nicotine and caffeine), history of seizures or any other neurological disease, neurosurgical metallic implant, cardiac pacemaker or inner ear prosthesis, pregnancy or unstable medical condition were excluded from the study. The medications of the participants remained the same during the study, except for the addition of anticholinergic or benzodiazepine medications allowed on as required basis. Figure 1 shows the recruitment flowchart of participants for the study and provides an overview of the clinical trial design.

Figure 1

Patient inflow in the study

Protocol for active and sham repetitive transcranial magnetic stimulation

The rTMS was administered using the Magstim Rapid2 device (Magstim Company Limited, Whitland, UK), with a 70-mm figure-of-eight air-film coil. The rTMS procedure began with the determination of the individual participant's MT and the localization of the stimulation site. The resting motor evoked potential (MEP) was determined using an electromyogram recording from the right abductor pollicis brevis (APB) in accordance with the International Federation of Clinical Neurophysiology recommendations.[16] The resting MT was defined as the minimum stimulus intensity that produced five MEP with an amplitude of at least 50 mV in ten subsequent single magnetic stimulation pulses at rest. The method followed for determining the Lt-DLPFC stimulation site as per previous studies was by measuring a point 5-cm anterior in a parasagittal line from the point of maximum stimulation of the right APB muscle.[17] This stimulation point was then marked on the patient's scalp, and its coordinates form anatomical landmarks were noted to reposition the coil for subsequent stimulation sessions. A vacuum pillow was placed around the neck to support the head and minimize head movements during the procedure. The participants in the active rTMS group received 20-Hz rTMS at 100% MT stimulation intensity, with 2000 pulses (20 trains with of 10 s duration, and 90 s of inter-train interval) per session. A total of 20 sessions of rTMS were administered for five consecutive days per week over a period of 4 weeks. Thus, a total of 40,000 pulses were delivered per treatment course. In order to decrease the risk of epileptic seizure, a slightly lesser stimulation intensity of 100% MT and a longer inter-train interval of 90 s was selected in this study (vis-à-vis 110% MT and inter-train interval of up to 60 s reported in the available literature). The sham group also underwent similar procedure including determination of resting MT and localization of Lt-DLPFC site as described for the active group. Further, sham rTMS was delivered using the same parameters and similar treatment duration to prevent unblinding. However, a purpose-built sham rTMS coil (Magstim Company Limited, Whitland, UK) that was identical in appearance to the real rTMS coil was used for stimulation. This coil generated similar sound as the real coil but has an insulated coil inside preventing delivery of any substantial magnetic field at the stimulation site. All rTMS sessions were administered by trained technicians under the medical supervision of a doctor in the rTMS laboratory. A physician was always on call and available within 5 min in case of any serious adverse events. Moreover, the provision for parenteral diazepam was kept ready in the treatment room to abort any seizure episode occurring during rTMS treatment.

Assessment of outcome measures

The clinical assessments were made by a trained researcher, who was blind to the treatment allocation. All participants were assessed in detail prior to starting of treatment at the rTMS laboratory, and relevant sociodemographic and clinical data were collected, with assessment on various different rating scales. The second and third assessments were done after the completion of 5th and 20th rTMS sessions. In addition to these three assessments, regular monitoring for any observed or spontaneously reported side-effects and adverse events related to rTMS treatment was done and documented, if any.

The PANSS was used for assessing the overall symptom severity of symptoms schizophrenia.[18] It consists of three subscales: positive symptoms, negative symptoms, and general psychopathology. These items were rated on Likert scale from 1 to 7, with higher scores representing a greater level of psychopathology. The Schedule for the Assessment of Negative Symptoms (SANS) consists of 20 items divided into five symptomatological domains: affective flattening, alogia, avolition, anhedonia, and impaired attention. These items were rated on Likert scale from 0 to 5, with higher scores representing greater severity. It is a well-validated scale and has been used as the standard scale for assessing negative symptoms in patients with schizophrenia.[19] The Calgary Depression Scale for Schizophrenia (CDSS) consists of nine items rated on a Likert scale from 0 to 3, with higher scores indicating more severe depressive symptoms. It has been extensively evaluated to assess the level of depression in schizophrenia in both relapsed and remitted patients and appears sensitive to change.[20] We used this scale to assess depressive symptoms and to disentangle them from negative symptoms in study participants. The Clinical Global Impression (CGI) is a clinician-rated 7-point Likert scale and includes three items namely: severity of illness, global improvement, and efficacy index.[21] The severity of illness item of the scale (CGI-severity [CGI-S]) was used as an additional measure to assess the overall clinical improvement in this study, with higher scores indicating greater illness severity. A checklist was prepared as per the rTMS-related side-effects reported in the available literature[22] and was used to assess the safety. These included headache, scalp discomfort, facial twitching, tearfulness, local erythema, dizziness/fainting, amnesia, increase of akathisia, and drowsiness.

Statistical analysis

The statistical analysis was done using SPSS version 23.0 (Armonk, IBM, NY). Descriptive statistics was used to tabulate the demographic and clinical characteristics of the sample. The data were assessed for normal distribution using normality plots and using Q-Q plots and Kolmogorov–Smirnov test. The baseline demographic and clinical characteristics between the two treatment groups were compared by applying the Chi-square test and the Fisher's exact test for categorical variables and the independent t-test or Mann–Whitney U test for normal and nonnormally distributed continuous variables, respectively. Further analysis was performed in the intention-to-treat population, defined as all patients randomly assigned to a treatment group and having completed the second assessment after the 5th rTMS session. Thus, for participants completing more than five but <20 sessions of rTMS, the last observation carried forward principle was applied in the intent-to-treat analysis. Since scores obtained on some of the assessment scales were not normally distributed between the two groups, normalization of data was achieved by performing logarithmic transformation, and parametric inferential statistics was applied subsequently. The change of assessment scores within the group was examined through applying the repeated measures analysis of variance with post hoc Bonferroni test. The comparison of change in assessment scores between the two groups was performed with independent t-test. A two-tailed P < 0.05 was considered statistically significant for all the analyses.

RESULTS

A total of 66 patients were assessed for eligibility, of which 30 patients were finally enrolled into the study and randomized to receive either active (n = 15) or sham rTMS (n = 15) as shown in Figure 1. Of the 30 participants enrolled in the study, four did not receive the complete course of 20 rTMS sessions. Three patients dropped out from the active group and one from the control group. In the active group, one patient had an episode of seizure after the 6th rTMS session, following which further rTMS sessions were canceled, and two other patients stopped coming after the 6th and 13th rTMS session due to no improvement perceived in the patient's clinical condition by the caregivers and an acute febrile illness episode in the other patients, respectively. In the control group, one patient discontinued treatment after the 6th rTMS session citing difficulty in coming to rTMS laboratory daily for rTMS sessions. However, all the 30 participants received at least five rTMS sessions and had completed the second assessment after the 5th session. The scores obtained at this assessment were carried forward and analyzed in the intention-to-treat analysis as planned a priori.

Sociodemographic and clinical characteristics

The sociodemographic and clinical characteristics of the active and control group were described and compared in Table 1. There were no significant differences noted in the characteristics of participants between the two groups.

Table 1

Comparison of demographic and baseline clinical variables between the two groups

Characteristic	Active rTMS (n=15)	Sham rTMS (n=15)	P
Mean age (SD), years	33.3 (9.8)	29.8 (5.7)	0.24a
Gender (male:female)	8:7	9:6	0.99c
Mean DOI (SD), years	10.6 (7.0)	9.5 (6.5)	0.64b
Mean years of education (SD)	12.6 (3.0)	11.2 (2.9)	0.19a
Employment (employed:not employed)	0:15	1:14	0.99c
Marital status
Never married	5	9	0.37c
Married	6	3
Separated	3	1
Divorced	1	2
Antipsychotic treatment
Typical	0	0	0.70c
Atypical	9	11
Polypharmacy	6	4
Clozapine use (yes:no)	1:14	2:13	0.99c
Antidepressant use (yes:no)	4:11	2:13	0.65c
PANSS positive symptom score	10.2 (3.0)	9.9 (3.0)	0.81a
PANSS negative symptom score	25.5 (4.2)	28.2 (5.5)	0.14a
PANSS total score	69.7 (8.9)	74.8 (11.9)	0.19a
SANS score	59.0 (14.6)	70.0 (15.1)	0.054a
CDSS score	1.8 (1.3)	1.9 (1.3)	0.60b
CGI-S score	4.9 (0.7)	4.9 (0.5)	0.96b

aIndependent t-test; bMann-Whitney U-test; cChi-square and Fisher’s exact test. SD – Standard deviation; DOI – Duration of illness; PANSS – Positive and negative syndrome scale; SANS – Scale for the assessment of negative symptom; CGI-S – Clinical global impression of severity, rTMS – Repetitive transcranial magnetic stimulation

Safety and tolerability of repetitive transcranial magnetic stimulation

The common side effects reported were mild headache which was relieved with oral analgesics, and localized scalp discomfort after the rTMS session. Headache was reported by three patients in the active group (20%) and four patients in the control group (26.6%). There was no significant difference for reporting of headache between the two groups (χ2= 1.86, P = 0.66). Localized scalp discomfort was reported by five patients in active group (33.3%) and four patients in the control group (26.6%). There was no significant difference for reporting of localized scalp discomfort between the two groups (χ2= 0.68, P = 0.40). One patient in the active group experienced facial muscles twitching and had an episode of seizure during the 6th rTMS session. He was also taking clozapine at a dose of 500 mg/day. However, all other participants tolerated the rTMS sessions well and none of the participants discontinued treatment due to rTMS-related side-effects.

Change in negative symptoms between two groups

In active rTMS group, a significant reduction of SANS and PANSS negative symptoms subscale were observed between the first (baseline) and second (after 5thrTMS session) assessment scores, and between the second and third assessment scores as well. On the contrary, there was a significant reduction of SANS- and PANSS-negative symptoms subscale between first and second assessment scores, but not between second and third assessment scores. Further, the reduction in SANS score in the real rTMS group was significantly greater than sham rTMS group at the end of 20thrTMS session (third assessment), as shown in Table 2. However, there were no significant differences between PANSS negative symptoms subscale scores between the two groups at first, second, and third assessment.

Table 2

Change on various scale scores used for the assessment of clinical status of patients

Scale scores	Active rTMS group (n=15)		Sham rTMS group (n=15)		Comparison between groupsa (P)
	Mean (SD)	Change within groupb (P)	Mean (SD)	Change within groupb (P)
PANSS positive		F=4.84 (0.03)*		F=6.75 (0.02)*
1. Baseline	10.20 (3.02)	Pair 1-2 (0.96)	9.93 (3.05)	Pair 1-2 (0.03)*	0.24 (0.81)
2. After 5 rTMS	9.80 (2.85)	Pair 2-3 (0.04)*	8.53 (1.84)	Pair 2-3 (0.52)	1.44 (0.16)
3. After 20 rTMS	8.86 (2.77)	Pair 3-1 (0.10)	8.20 (1.69)	Pair 3-1 (0.07)	0.79 (0.43)
PANSS negative		F=53.66 (<0.01)**		F=30.95 (<0.01)**
1. Baseline	25.53 (4.22)	Pair 1-2 (<0.01)**	28.26 (5.58)	Pair 1-2 (<0.01)**	1.51 (0.14)
2. After 5 rTMS	23.00 (4.65)	Pair 2-3 (<0.01)**	23.93 (4.99)	Pair 2-3 (0.06)	0.52 (0.60)
3. After 20 rTMS	18.93 (4.63)	Pair 3-1 (<0.01)**	22.40 (5.12)	Pair 3-1 (<0.01)**	1.94 (0.06)
SANS		F=49.79 (<0.01)**		F=23.59 (<0.01)**
1. Baseline	59.06 (14.67)	Pair 1-2 (<0.01)**	70.00 (15.14)	Pair 1-2 (<0.01)**	2.00 (0.054)
2. After 5 rTMS	43.66 (13.14)	Pair 2-3 (<0.01)**	54.00 (21.11)	Pair 2-3 (0.11)	1.69 (0.10)
3. After 20 rTMS	35.00 (0.97)	Pair 3-1 (<0.01)**	51.73 (19.56)	Pair 3-1 (<0.01)**	2.76 (0.01)*
CDSS#		F=1.68 (0.20)		F=3.94 (0.053)
1. Baseline	1.80 (1.32)	Pair 1-2 (0.99)	1.93 (1.33)	Pair 1-2 (0.38)	0.13 (0.89)
2. After 5 rTMS	1.53 (0.91)	Pair 2-3 (0.78)	1.73 (1.27)	Pair 2-3 (0.37)	0.08 (0.93)
3. After 20 rTMS	1.33 (0.97)	Pair 3-1 (0.45)	1.33 (1.23)	Pair 3-1 (0.10)	0.33 (0.74)
CGI-S		F=28.88 (<0.01)**		F=11.87 (<0.01)**
1. Baseline	4.93 (0.79)	Pair 1-2 (0.25)	4.93 (0.59)	Pair 1-2 (0.02)*	0.08 (0.93)
2. After 5 rTMS	4.73 (0.70)	Pair 2-3 (<0.01)**	4.53 (0.74)	Pair 2-3 (0.25)	0.78 (0.43)
3. After 20 rTMS	3.66 (0.72)	Pair 3-1 (0.04)*	4.33 (0.72)	Pair 3-1 (0.002)**	2.51 (0.01)*

*P<0.05; **P<0.01; #Analysis was performed on logarithmic transformed variables; aComparison of scores between groups was performed with independent t-test; bChange of scores within group was examined via repeated measure ANOVA. Post hoc Bonferroni test was performed to compare scores obtained at baseline, after 5th and 20th rTMS session with each other. Bold P values indicates a significant difference in the assessment scores/variables between the active and the sham treatment groups. PANSS – Positive and negative syndrome scale; rTMS – Repetitive transcranial magnetic stimulation; SANS – Scale for the assessment of negative symptom; CDSS – Calgary depression in schizophrenia scale; CGI-S – Clinical global impression of severity; ANOVA – Analysis of variance

Change in other clinical measures between two groups

There were no significant differences in scores obtained on PANSS-positive symptoms subscale and CDSS, except for the CGI-S score between the active and control group, as shown in Table 2. There was a significant difference in the CGI-S score between two groups at the time of third assessment, with significantly greater reduction in the general severity of illness (CGI-S score) observed in the active group as compared to control group.

DISCUSSION

This randomized parallel double-blind, sham-controlled study was planned to assess the effect of 20-Hz adjunctive rTMS treatment over Lt-DLPFC on negative symptoms in patients with schizophrenia patients. To the best of our knowledge, there have been only two randomized parallel double-blind, sham-controlled studies yet assessing the effect of 20-Hz rTMS over Lt-DLPFC in patients with schizophrenia. The study by Novák et al. assessed the effect of rTMS on negative symptoms using PANSS-negative symptoms subscale and yielded negative results.[23] Another study by Barr et al. assessed the effect of rTMS on working memory performance using verbal-n-backtest, and yielded positive results.[24] There were two major aspects of this study, which could be considered as an improvement on the previous two studies and make the findings of the present study more relevant: (a) participants received a total of 40,000 stimulation pulses per rTMS treatment course under the conditions of a double-blind trial, controlled using a purpose-built sham coil, which is the highest number of pulses to be administered over one brain hemisphere for the treatment of negative symptoms in schizophrenia; (b) negative symptoms were comprehensively assessed using both PANSS negative symptoms subscale and SANS. Further, the CDSS designed to assess and delineate depression from negative symptoms in patients with schizophrenia was used in this study to differentiate the false improvement in negative symptoms secondary to improvement in depression/depressive symptoms.

In this study, compared with sham-rTMS, augmentation of antipsychotic medication with 20 sessions of active 20-Hz rTMS applied over Lt-DLPFC showed a significant reduction in negative symptoms when evaluated using SANS, but not with PANSS-negative symptoms subscale. This might be because the SANS was a more sensitive instrument for the measurement of negative symptoms than the negative subscale of the PANSS. The SANS cover multiple domains and multiple items per domain and considered to be a more extensive and reliable measure of negative symptoms than the PANSS-negative subscale.[25] Thus, the SANS provided more detailed information and might be more sensitive to detect changes in negative symptoms than the negative symptom subscale of the PANSS.[26] A recent meta-analysis also reported that the effect size generated from studies using the SANS was consistently larger than the effect size generated from studies using the PANSS in both pre-post (0.98 vs. 0.43) and sham-active (0.80 vs. 0.41) comparison of rTMS treatment.[11] Indeed, only a moderate correlation between the SANS and the negative subscale of the PANSS has been observed in available literature. This can be explained by the fact that the seven items of the PANSS-negative subscale do not seem to cover negative symptoms completely.[27] A recent RCT also confirms this finding of more sensitivity of SANS scores as compared to PANSS in determining treatment response for negative symptoms using rTMS.[28] In addition, this might also be due to low statistical power of the study, considering the relatively small sample size of 30 patients.

In the present study, we applied the maximum number of pulses delivered per hemisphere (40,000 per treatment course) so far in any of the published rTMS studies for the treatment of negative symptoms in schizophrenia. Three RCTs applied a total amount of 30,000 pulses to the Lt-DLPFC and reported a significant improvement in negative symptoms of schizophrenia.[293031] Two other RCTs applying HF-rTMS with 30,000 pulses delivered over each hemisphere sequentially reported negative findings.[3233] All other available studies had administered fewer number of pulses. Of these studies, four RCTs found a significant improvement in negative symptoms,[14343536] and seven RCTs found no significant effect.[13233738394041] Thus, applying a greater amount of unilateral pulses might indeed enhance rTMS treatment effects.

There was also a significant improvement observed in the overall clinical condition of patients in the active group compared to control group at the end of 20 sessions of rTMS, evaluated using CGI scores for severity of illness. Therefore, improvement in SANS score is also seconded by improvement in CGI-S scores over study duration, with differences perceived among the groups. Thus, the statistical significance in the improvement of negative symptoms is also in concordance to significant improvement in the overall severity of the clinical symptoms of schizophrenia. Further, low CDSS scores among the study participants at baseline suggested the absence of any significant contribution of depressive symptoms within the framework of the negative symptoms assessed among the study sample. In the present study, after 20 sessions of rTMS, there was no significant improvement in the mean CDSS scores in both active and control groups, showing that the improvement of the SANS scores was not related with improvement in depressive symptoms.

All the study participants tolerated the rTMS treatment well with no serious side-effect, or adverse event reported except for one patient in the active group, who developed facial muscles twitching followed by a seizure episode during the sixth rTMS session, which ended spontaneously in about 5 s and was followed by postictal drowsiness. The patient was assessed by a doctor available in the rTMS laboratory and was administered intramuscular diazepam (5 mg) and kept under observation for another 2 h to prevent any further seizure episodes. Further, on-call neurologist examined the patient for any signs or symptoms of hypoxic insult on regaining consciousness. The subsequent rTMS sessions were stopped and the patient was referred to neurology for further assessment of seizure episode. The patient had no past or family history of seizures in any of his first-degree family members. However, he was on a relatively high dose of clozapine (500 mg/day), which lowers the threshold for seizures in a dose-dependent manner. There has been a report of spontaneous seizures occurring during any stage of treatment with clozapine even in nonepileptic persons. The incidence of clozapine-induced seizures varies from 4% to 22% in studies evaluating the risk of seizures associated with clozapine use.[42] Although electroencephalography (EEG) was not done prior to the inclusion of participants in the present study.

A recent systematic review on the safety of clozapine use among patients undergoing adjunctive treatment with different brain stimulation techniques and reported that HF-rTMS over the DLPFC could be safely administered.[43] In three previous RCTs assessing the effect of HF-rTMS on negative symptoms, which also included a small number of schizophrenia patients receiving clozapine, no instances of seizure were reported.[243236] However, future studies should conduct a baseline EEG to exclude participants with any epileptiform activity prior to initiating treatment with HF-rTMS to avoid the potential risk of seizures, especially among patients taking concomitant medications with seizurogenic potential like clozapine.

The results should be interpreted keeping in mind the certain limitations of the present study. Although the current study had a larger sample size than two previous studies using 20-Hz rTMS, the sample size was still small resulting in lower statistical power of the study and limiting the generalizability of study findings. The use of classical method for localizing the site of stimulation, instead of the more accurate method of neuronavigation-guided localization of DLPFC. There was no long-term follow-up, which leaves open the question of prospective effects of rTMS over time in terms of decline, stabilization, or amplification.

CONCLUSION

The use of adjunctive higher frequency (20-Hz) rTMS over Lt-DLPFC with more robust stimulation parameters (100% MT and 40,000 pulses) might be an effective augmentation strategy for the treatment of difficult to treat negative symptoms of schizophrenia. However, future studies with a multicentric study design, larger sample size, and follow-up assessments should be conducted to confirm the findings of the present study and better characterize the optimum rTMS stimulation parameters. The HF-rTMS protocol was safe and well-tolerated in majority of the patients. However, to prevent rTMS-induced seizures, patients prone to developing seizure may be excluded by baseline EEG prior to starting of the treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.