Safety and Efficacy of Continuous Theta Burst "Intensive" Stimulation in Acute-Phase Bipolar Depression: A Pilot, Exploratory Study.

OBJECTIVES: Repetitive transcranial magnetic stimulation efficacy in unipolar depression is known, but its efficacy in acute-phase bipolar depression is at best modest. Citing differential right dorsolateral prefrontal cortex hyperconnectivity implicated in BD, we aimed to study the effect of novel continuous theta burst stimulation (cTBS) targeting right dorsolateral prefrontal cortex in a randomized rater blinded placebo control design. MATERIAL AND METHODS: Nineteen patients aged 18 to 59 years (baseline Hamilton Depression Rating Scale [HAM-D] 17 severity score >18) were randomly allocated to active cTBS (n = 11) and sham cTBS (n = 9) groups using block randomization method. They received 15 cTBS sessions (burst of 3 pulses delivered at 50 Hz, repeated every 200 ms at 5 Hz, 600 pulses per session), 3 sessions per day (total of 1800 pulses) for 5 days in a week at 80% resting motor threshold. The HAM-D, Beck Depression Inventory, Hamilton Anxiety Rating Scale, World Health Organization's abbreviated quality of life assessment, and Changes in Sexual Functioning Questionnaire were assessed at baseline, after the last session, and at 2 weeks after repetitive transcranial magnetic stimulation. Intention-to-treat analysis was conducted and missing values (2 patients) were replaced using the last observation carried forward method. RESULTS: On repeated measures analysis of variance, a significant within-group time effect (from pretreatment to 2 weeks after TBS) for HAM-D ( F = 15.091, P < 0.001), Beck Depression Inventory ( F = 22.376, P < 0.001), Hamilton Anxiety Rating Scale ( F = 18.290, P < 0.001), Changes in Sexual Functioning Questionnaire ( F = 9.281, P = 0.001), and World Health Organization's abbreviated quality of life assessment ( F = 24.008, P < 0.001). The integrity of the blind assessed by the guess matrix was good. When significant between group*time effect was compared, none of the variables retained statistical significance. No major adverse effects were reported, and none of the patients discontinued the trial because of adverse effects. CONCLUSIONS: Our trial concludes that although safe and well tolerated, the therapeutic efficacy of intensive intermittent TBS in acute-phase bipolar depression is inconclusive. Choice of lower total number to sessions and smaller intersession interval along with small sample size limit the study findings.

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study.

Trans-cranial magnetic stimulation (TMS) can noninvasively modulate specific brain regions to dissipate symptoms in treatment-resistant schizophrenia (TRS). Citing impaired resting state connectivity between cerebellum and prefrontal cortex in schizophrenia, we aimed to study the effect of intermittent theta burst stimulation (iTBS) targeting midline cerebellum in TRS subjects on a randomized rater blinded placebo control study design. In this study, 36 patients were randomly allocated (using block randomization method) to active and sham iTBS groups. They were scheduled to receive ten iTBS sessions, two per day (total of 1200 pulses) for 5 days in a week. The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Schizophrenia Cognition Rating Scale (SCoRS), Simpson-Angus Extrapyramidal Side Effects Scale (SAS), and Clinical Global Impression (CGI) were assessed at baseline, after last session, and at 2 weeks post-rTMS. Thirty patients (16 and 14 in active and sham groups) completed the study. Intention to treat analysis (ITT) using mixed (growth curve) model analysis was conducted. No significant group (active vs sham) × time (pretreatment-end of 10th session-end of 2 weeks post iTBS) interaction was found for any of the variable. No major side effects were reported. Our study fails to show a significant effect of intensive cerebellar iTBS (iCiTBS) on schizophrenia psychopathology, cognitive functions, and global improvement, compared with sham stimulation, in treatment resistant cases. However, we conclude that it is safe and well tolerated. Trials using better localization technique with large sample, longer duration, and better dosing protocols are needed.

Quality of life after coronary artery bypass graft & percutaneous transluminal coronary angioplasty: A follow up study from India.

Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are treatments of choice for coronary artery disease. Quality of life (QoL) is an important factor in determining optimum treatment. This study was aimed to compare changes in QoL, six months post procedure, between CABG and PTCA, and to understand the confounding effect of various contributing factors. Thirty stable angina patients each in CABG and PTCA groups, were followed up for six months. QoL was assessed with WHO-QoL-BREF. Depression was rated on the Hamilton Depression Rating Scale. Changes in QoL and depression within and between CABG and PTCA groups were compared. Multinomial logistic regression was used to measure the predictive strength of treatment type (CABG and PTCA) on QoL, controlling for significant confounders. Although scores of QoL and depression significantly changed over time in both the groups, time×group interaction did not reach to a significance. Significant confounding effects of diabetes (P<0.01), hypertension (P<0.05) and diet restriction (P<0.05) were found. Controlling for confounding effects of these factors, group distribution to PTCA, compared to CABG, significantly predicted greater improvements in QoL (P<0.01).

Safety and Efficacy of Adjunctive Θ Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study.

BACKGROUND: First-rank symptoms (FRS) in schizophrenia have been found to be associated with various cognitive and biological markers. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate such factors. We hypothesized that rTMS adjunctive to antipsychotics will be safe and effective in treatment of FRS in schizophrenia. METHODS: Schizophrenia patients with FRS randomly received either active or sham-magnetic resonance imaging navigated continuous Θ burst stimulation (cTBS)-rTMS to right inferior parietal lobule for 2 weeks; assessments were repeated. While primary outcome variables were safety profile, FRS and overall psychopathology; secondary outcomes were γ oscillatory activity, brain-derived neurotrophic factor levels, and self-monitoring function. RESULTS: No significant adverse events were reported in either group. None of the outcome measures showed sufficient power on the time by group analysis. CONCLUSIONS: This study fails to demonstrate whether or not adjunctive cTBS to right inferior parietal lobule could significantly alleviate FRS. We also fail to provide evidence for whether this protocol has any effect on brain-derived neurotrophic factor levels, self-monitoring function, and right hemispheric γ oscillations.

Evaluation of resting state gamma power as a response marker in schizophrenia.

AIMS: An abnormal activity in the electroencephalography (EEG) gamma band (>30 Hz) has been demonstrated in schizophrenia and this has been suggested to be reflecting a deficit in the development and maturation of the basic cognitive functions of attention, working memory and sensory processing. Hypothesizing gamma oscillatory activity as a potential EEG biomarker to antipsychotic response in schizophrenia, the present study aimed at measuring baseline spontaneous gamma activity in schizophrenia patients, and evaluating its response to antipsychotic treatment over 8 weeks. METHODS: Fifteen drug-free/naïve patients were recruited, compared at baseline with 15 age-, sex- and education-matched healthy controls, and were followed up for 8 weeks' treatment on antipsychotics. Resting state EEG waves were recorded using high (192-channel) resolution EEG at admission, 4 weeks and 8 weeks. Spectral power was calculated using fast Fourier transformation, Hanning window. The power was averaged region-wise over nine regions in three frequency ranges (30-50 Hz, 50-70 Hz, 70-100 Hz). RESULTS: Patients and controls differed significantly at intake in terms of left temporal and parietal high (70-100 Hz) gamma power. Consequently, no significant differences were seen over the course of antipsychotic treatment on gamma spectral power in any of the regions. CONCLUSIONS: Lack of significant effect of treatment on gamma power suggests that these gamma oscillations may be trait markers in schizophrenia.

Adjuvant low-frequency rTMS in treating auditory hallucinations in recent-onset schizophrenia: a randomized controlled study investigating the effect of high-frequency priming stimulation.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been found to be effective in reducing frequency and duration of auditory verbal hallucinations (AVH). Priming stimulation, which involves high-frequency rTMS stimulation followed by low-frequency rTMS, has been shown to markedly enhance the neural response to the low-frequency stimulation train. However, this technique has not been investigated in recent onset schizophrenia patients. The aim of this randomized controlled study was to investigate whether the effects of rTMS on AVH can be enhanced with priming rTMS in recent onset schizophrenia patients. METHODS: Forty recent onset schizophrenia patients completed the study. Patients were randomized over two groups: one receiving low-frequency rTMS preceded by priming and another receiving low-frequency rTMS without priming. Both treatments were directed at the left temporo-parietal region. The severity of AVH and other psychotic symptoms were assessed with the auditory hallucination subscale (AHRS) of the Psychotic Symptom Rating Scales (PSYRATS), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI). RESULTS: We found that all the scores of these ratings significantly reduced over time (i.e. baseline through 1, 2, 4 and 6 weeks) in both the treatment groups. We found no difference between the two groups on all measures, except for significantly greater improvement on loudness of AVH in the group with priming stimulation during the follow-ups (F = 2.72; p < .05). CONCLUSIONS: We conclude that low-frequency rTMS alone and high-frequency priming of low-frequency rTMS do not elicit significant differences in treatment of overall psychopathology, particularly AVH when given in recent onset schizophrenia patients. Add on priming however, seems to be particularly better in faster reduction in loudness of AVH.

Resting State Dense Array Gamma Oscillatory Activity as a Response Marker for Cerebellar-Repetitive Transcranial Magnetic Stimulation (rTMS) in Schizophrenia.

BACKGROUND: As cerebellum and its abnormalities have been implicated in the pathophysiology of schizophrenia, repetitive transcranial magnetic stimulation (rTMS) of this alternate site has been suggested as a novel target for treating patients with this disorder. As resting state gamma activity measures functional brain connectivity, it could be used as a specific treatment marker. AIM: To investigate the effect of cerebellar-rTMS on resting state gamma activity, while studying its efficacy in recent onset schizophrenia patients. METHODS: This rater-blinded prospective study was completed by 11 schizophrenia patients. They received 10 sessions of high-frequency (theta patterned) rTMS to midline cerebellum over 2 weeks. Resting state EEG was recorded using high (192-channel) resolution EEG at baseline and post rTMS. Gamma spectral power was calculated using fast Fourier transformation, Hanning window averaged over 8 scalp segments corresponding 8 lobes. Clinical improvement rated on the Positive and Negative Syndrome Scale and depressive symptoms assessed using the Calgary Depression Scale for Schizophrenia were other outcome variables. Nonparametric statistics were used. RESULTS: Over the treatment course, significant reduction was seen on negative syndrome and depression scores. Gamma spectral power in left frontal and temporal segments reduced significantly. Spearman correlation analysis showed that percentage reduction in psychopathology scores had significant positive correlation with percentage reduction in gamma spectral power. CONCLUSIONS: Cerebellar-rTMS might be an effective adjunct to treat intricate and lingering negative and affective symptoms. Resting state gamma spectral power in frontal and temporal regions might be used as a biomarker for treatment response.

Dose-dependent olanzapine-induced myoclonus.

Second-generation antipsychotics (SGA), mainly clozapine have been reported to induce myoclonus. Although olanzapine-induced myoclonus is reported, dose-dependent response has not been described. We report dose-related olanzapine-induced myoclonus in an early onset schizophrenia patient. We also suggest certain management strategies for such adverse side effects.

Identification of youth at clinical high-risk for psychosis: A community-based study from India.

AIM: A two-stage process, wherein self-report screening precedes the structured interview, is suggested for identifying individuals at clinical high-risk for psychosis (CHR-P) in community samples. Aim of this study was to screen a community youth sample from India for CHR-P using the two-stage method. Specific objectives were to assess concordant validity of the self-report measure and predictive validity of the two-stage method. METHODS: Based on probability sampling, 2025 youth aged 15-24 years were recruited from one rural and one urban area of Telangana, a Telugu-speaking state in India. Telugu version of the PRIME Screen-Revised (PS-R) and structured interview for psychosis-risk syndromes (SIPS) were used. CHR-P positive and negative cohorts were followed-up for transition to psychosis at 3-monthly intervals. RESULTS: One hundred ten individuals screened positive on PS-R. SIPS conducted on 67 out of 110 individuals confirmed 62 (92.54%) to be CHR-P positive. PS-R showed 98.41% sensitivity and 90.74% specificity. Among CHR-P positive, three participants transitioned to psychosis in 15 months. The hazard ratio for psychosis transition was 11.4. CONCLUSIONS: Screening accuracy of PS-R in the community youth sample in Telangana is optimum. The hazard ratio for psychosis transition in the community identified CHR-P indicates good predictive validity for the two-stage method.

Exacerbation of auditory verbal hallucinations with adjunctive high-frequency cerebellar vermal repetitive transcranial magnetic stimulation in schizophrenia: a case report.

In schizophrenia, novel target sites for repetitive transcranial magnetic stimulation (rTMS), such as the cerebellum, are proposed to have a putative therapeutic role in treatment-resistant cases. We present a case of treatment-resistant schizophrenia that showed worsening of auditory verbal hallucinations after receiving high-frequency cerebellar vermal rTMS. We propose that cerebellar vermal rTMS modulates neuronal networks, causing activation in temporoparietal areas, which results in worsening of auditory verbal hallucinations.

Indian research on transcranial magnetic stimulation: A bibliometric analysis.

Background: A significant body of evidence on the role of TMS in neurology and psychiatry has emerged from Indian studies. Aims: We aimed to assess the existing and emerging trends of research on TMS as a diagnostic or therapeutic tool in India using bibliometric analysis. Results: A total of 146 publications, retrieved from various databases, were analyzed using Microsoft Excel and VOSviewer. We found a linear positive growth of publications in India in the field of TMS and neuropsychiatry, with about 3000 citations so far. The most researched diagnosis was schizophrenia. NIMHANS, Bengaluru, had the highest number of publications. The journal with the highest number of publications was the Asian Journal of Psychiatry, and that with the highest citations was the Journal of Affective disorders. Conclusion: The growth of Indian research in the field of TMS corresponds to that of the global one but also suggests the need for more studies to match the research output from other countries.

Retinal microvasculature in schizophrenia: A meta-analysis with trial sequential analysis of studies assessing vessel density using Optical Coherence Tomography Angiography.

We performed a series of random-effects meta-analyses on cross-sectional studies assessing vessel density (VD) using Optical Coherence Tomography Angiography (OCTA) in schizophrenia. Five studies with a total sample size of 410 (schizophrenia-192;healthy-218) were analysed. Supplementary Trial Sequential Analyses (TSA) was also performed. Meta-analyses revealed significantly lower VD in schizophrenia patients compared to healthy controls in the peripapillary region of the optic disc, including both superior hemisphere and inferior hemisphere. TSA validated these significant effects. We conclude that reduced VD at the peripapillary region of the optic disc as measured by OCTA may have the potential to be a schizophrenia biomarker.

Evidence from Indian studies on safety and efficacy of therapeutic transcranial magnetic stimulation across neuropsychiatric disorders- A systematic review and meta-analysis.

Repetitive transcranial magnetic stimulation (rTMS) is potentially effective as an augmentation strategy in the treatment of many neuropsychiatric conditions. Several Indian studies have been conducted in this regard. We aimed to quantitatively synthesize evidence from Indian studies assessing efficacy and safety of rTMS across broad range of neuropsychiatric conditions. Fifty two studies- both randomized controlled and non-controlled studies were included for a series of random-effects meta-analyses. Pre-post intervention effects of rTMS efficacy were estimated in "active only" rTMS treatment arms/groups and "active vs sham" (sham-controlled) studies using pooled Standardized Mean Differences (SMDs). The outcomes were 'any depression', depression in unipolar/bipolar depressive disorder, depression in obsessive compulsive disorder (OCD), depression in schizophrenia, schizophrenia symptoms (positive, negative, total psychopathology, auditory hallucinations and cognitive deficits), obsessive compulsive symptoms of OCD, mania, craving/compulsion in substance use disorders (SUDs) and migraine (headache severity and frequency). Frequencies and odds ratios (OR) for adverse events were calculated. Methodological quality of included studies, publication bias and sensitivity assessment for each meta-analyses was conducted. Meta-analyses of "active only" studies suggested a significant effect of rTMS for all outcomes, with moderate to large effect sizes, at both end of treatment as well as at follow-up. However, except for migraine (headache severity and frequency) with large effect sizes at end of treatment only and craving in alcohol dependence where moderate effect size at follow-up only, rTMS was not found to be effective for any outcome in the series of "active vs sham" meta-analyses. Significant heterogeneity was seen. Serious adverse events were rare. Publication bias was common and the sham controlled positive results lost significance in sensitivity analysis. We conclude that rTMS is safe and shows positive results in 'only active' treatment groups for all the studied neuropsychiatric conditions. However, the sham-controlled evidence for efficacy is negative from India. Conclusion: rTMS is safe and shows positive results in "only active" treatment groups for all the studied neuropsychiatric conditions. However, the sham-controlled evidence for efficacy is negative from India.

Association Between Post-COVID Pulmonary Dysfunction and New-Onset Anxiety and Depression and the Impact of Incentive Spirometer-Based Exercises.

Objective: To determine the rates of new-onset anxiety and depression in patients with restrictive or obstructive lung disease after COVID-19 infection and to assess the improvement in pulmonary functions and anxiety/depression scores after prescribing incentive spirometer-based breathing exercises.Methods: A 2-phase study with a cross-sectional and open-label randomized interventional design evaluated anxiety (Generalized Anxiety Disorder-7 [GAD-7] and Hamilton Anxiety Rating Scale [HARS]), depression (Patient Health Questionnaire-9 [PHQ-9]), and pulmonary function tests (PFTs) of 100 COVID-19 patients within 8 weeks of acute illness. Patients with pulmonary dysfunction were randomized (incentive spirometry vs controls), and anxiety/depression scores and lung function were reevaluated after 4 weeks.Results: The results revealed 35% (35/100) of mild-moderate COVID-19 patients had abnormal PFTs. Anxiety/depression was higher in patients with abnormal PFTs than in those with normal lung function (prevalence ratio: 1.8 [20% vs 11%]). The median HARS, GAD-7, and PHQ-9 scores decreased significantly with 4 weeks of incentive spirometry exercises (2 [0-5.5, P = .013], 2 [0-3.5, P = .006], and 2 [0-3.5, P = .006], respectively) compared to standard of care alone. More patients with incentive spirometry had normalization of pulmonary functions compared to controls (50% [8/16] vs 33% [6/18]). The mean age of patients with anxiety/depression was significantly higher than those without anxiety/depression (42 ± 11 vs 30 ± 7, P = .04).Conclusions: While the rates of new-onset anxiety/depression were higher in patients with pulmonary dysfunction, these rates were reduced with incentive spirometer-based exercises. Greater age may be a risk factor for abnormal pulmonary functions and greater anxiety or depression.Trials Registry: Clinical Trials Registry-India identifier: CTRI/2022/11/047183.Prim Care Companion CNS Disord 2023;25(5):23m03490. Author affiliations are listed at the end of this article.

Brief intervention to enhance cessation of smokeless tobacco use in newly diagnosed patients with head and neck cancers: A randomized controlled trial in patient-relative dyads.

Introduction: Tobacco use is a major causative factor for head and neck cancers (HNC). Continued use of tobacco even after cancer diagnosis is common and is associated with all-cause and cancer-specific mortality, cancer recurrence and poor treatment response. Evidence suggests that behavioral interventions, help achieve greater smoking cessation rates in HNC patients. However, intervention studies focussed on HNC patients using smokeless tobacco, which is more common than smoking in India, are sparse. Materials and Methods: We conducted a parallel arm randomized controlled trial (RCT) on dyads of patients with recently diagnosed HNC and a close relative. The experimental arm received a brief tobacco cessation intervention (BTCI) and the control arm received treatment as usual (TAU); 27 and 25 dyads in each arm completed the trial. Results: Overall for the dyads using SLT, the relative risk of continuing to use SLT was 3.23 times higher (odds ratio = 7.01) if BTCI was not undertaken at one-month follow-up and 4.43 times higher (odds ratio = 8.65) at 3-months follow-up. For patients only, the relative risk of continuing to use SLT at one-month and 3-months follow-ups was 4.99 and 12.04 times higher, respectively, if BTCI was not undertaken. For relatives only, the corresponding relative risk values were 2.14 and 2.2. Conclusion: We conclude that BTCI delivered to patient-relative dyads, compared to TAU, is effective in enhancing the discontinuation rates of the use of SLT in newly diagnosed patients with HNC. This form of intervention is significantly effective for discontinuing SLT use in the relatives too.