Investigational applications of transcranial magnetic stimulation (TMS) in Mood Disorders: Studies from a tertiary care center in India.

The investigational potential of TMS in psychiatry is largely underutilized. In the current article, we present the results of five studies with similar TMS protocols that looked at the investigative applications of TMS via measuring cortical reactivity as potential biomarkers in mood disorders. The first two studies, evaluate potential of TMS parameters and Motor neuron system (MNS) as state or trait markers of BD. Third and fourth studies evaluate these as endophenotypic markers of BD. The fifth study which is an RCT evaluating add-on yoga in UD, evaluates if markers of CI can index the therapeutic response of yoga. In study one MT1 was significantly greater in the SM (symptomatic-mania) group compared to HC (healthy-control) (P=0.032). The cortical inhibition measures SICI was reduced in SM(P=0.021) and BD (remitted Bipolar) (P=0.023) groups compared to HC. LICI was increased in the SM(0.021) and BD(P=0.06) groups compared to HC. In study two, a significant group x time interaction effect was observed indicating higher putative MNS-activity mediation in patients compared to HC on SlCl(P=0.024), LlCl(P=0.033). There were no significant group differences noted in the endophenotype studies. The fifth study showed a significant time X group interaction for CSP, favoring improvement in YG (yoga-group) (p<0.01).No significant change was observed for LICI(p=0.2), SICI(p=0.5). Limitations of these studies notwithstanding, we conclude that cortical reactivity measured using TMS is a potential biomarker across the course of mood disorders, starting from state and trait markers to understanding the therapeutic mechanism of a particular treatment modality in these disorders.

Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression.

BACKGROUND: Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. METHODS: We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression. RESULTS: Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P = 0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.).

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Gender differences in the young-onset persistent delusional disorder.

We conducted a retrospective chart review to examine the gender differences in young onset Persistent Delusional Disorder (PDD) subjects (N = 236) with onset of illness before the age of 30 years. Gender differences in marital and employment status were significant (p-0.001). Delusion of infidelity and erotomania were more common in females, while males had more body dysmorphic and persecutory delusions (X2-20.45, p-0.009). Males had more substance dependence (X2-21.31, p < 0.001), as well as a family history of substance abuse and PDD (X2-18.5, p < 0.01). To conclude, gender differences in PDD comprised some psychopathology, co-morbidity, and family history among those with young onset PDD.

Multivariate Bayesian Arm-Based Network Meta-Analysis of Pharmacological Interventions for the Treatment of Acute Bipolar Mania in Adults.

Background: In a network meta-analysis (NMA), multiple treatments can be compared simultaneously by aggregating pieces of evidence from direct as well as indirect treatment comparisons in different randomized controlled trials (RCTs). Conventional NMA are performed using a normal approximation approach and can be applied for arm-level binary outcome data as well. This study aimed to estimate the treatment effects within a Bayesian framework using a binomial likelihood for a multivariate NMA model. Methods: The dataset consists of 57 RCTs comparing the effect of ten pharmacological drugs and a placebo for acute bipolar mania in adults. The binary outcomes of interest were treatment response and all-cause dropouts measured three weeks from the baseline. Binomial distribution was adopted for the number of events and the probability of event occurrence modeled on the logit scale. Jeffrey's Beta prior was considered for the heterogeneity and inconsistency of standard deviation (SD) parameters. Cholesky and spherical decomposition strategies were adopted for the between-study variance-covariance matrix. Deviance information criterion (DIC) indices were computed to determine the model fit. All results pertaining to Markov chain Monte Carlo simulations and all analyses were carried out in WinBUGS software. Results: The estimated common heterogeneity SDs were similar, and the DIC values did not provide any evidence for superiority between the two decomposition strategies. The correlation (95% credible interval) between the outcomes was estimated as -0.31 (-0.71, -0.02) and -0.37 (-0.73, -0.03) for the Cholesky and spherical decompositions, respectively. Gelman-Rubin convergence statistics were stable, and Monte Carlo errors for all the parameters were around 0.005. Overall, olanzapine, paliperidone, and quetiapine were both significantly more effective and acceptable than a placebo when both the study outcomes were considered simultaneously. Conclusions: The findings favoring olanzapine, paliperidone, and quetiapine possess an excellent concordance with the one adopted in clinical practice, and the Canadian Network for Mood and Anxiety Treatments and Royal Australian and New Zealand College of Psychiatrists guidelines recommend these as first-line drugs for treating bipolar disorder.

Long-term Add-on Yoga Therapy Modulates Oxidative Stress Pathway and Offers Clinical Benefits in Major Depressive Disorder: A Randomized Controlled Trial.

Background: Yoga therapy (YT) as an adjunct treatment has reportedly been demonstrated to offer clinical benefits in major depressive disorder (MDD). Although a few biological pathways are suggested to mediate the effects of yoga, the precise mechanistic basis remains unknown. Oxidative stress pathway activation has consistently been linked to the pathobiology of MDD. Whether YT has a modulatory effect on the oxidative stress pathway in MDD is not adequately understood. Aim and Objectives: In this study, we examined the impact of a course (3 months) of yoga as an add on therapy on the markers of the oxidative stress pathway in MDD patients. Methods: Thirty-three MDD patients were randomized to the YT (n = 16) and waitlist control (WC) (n = 17) groups. Colorimetric estimation of the plasma malondialdehyde (MDA) and total antioxidant (AO) levels was performed in all the study participants using commercially available kits at the baseline and after 3 months. Results: A significant reduction of plasma MDA levels was observed in MDD patients of YT group (P = 0.05) after 3 months of YT. Notably, the plasma MDA levels also decreased in MDD patients of WC group (P = 0.015) after the trial period. In addition, levels of total AO showed a trend toward significance only in MDD patients after 3 months of YT (P = 0.07). Conclusion: The current study suggests that the benefits of YT might be mediated through its modulatory role on the oxidative stress pathway in MDD.

Motor Resonance During Action Observation and Its Relevance to Virtual Clinical Consultations: Observational Study Using Transcranial Magnetic Stimulation.

BACKGROUND: Virtual clinical interactions have increased tremendously since the onset of the COVID-19 pandemic. While they certainly have their advantages, there also exist potential limitations, for example, in establishing a therapeutic alliance, discussing complex clinical scenarios, etc. This may be due to possible disruptions in the accurate activation of the human mirror neuron system (MNS), a posited physiological template for effective social communication. OBJECTIVE: This study aimed to compare motor resonance, a putative marker of MNS activity, estimated using transcranial magnetic stimulation (TMS) elicited while viewing virtual (video-based) and actual or real (enacted by a person) actions in healthy individuals. We hypothesized that motor resonance will be greater during real compared to virtual action observation. METHODS: We compared motor resonance or motor-evoked potential (MEP) facilitation during the observation of virtual (presented via videos) and real (enacted in person) actions, relative to static image observation in healthy individuals using TMS. The MEP recordings were obtained by 2 single-pulse (neuronal membrane excitability-driven) TMS paradigms of different intensities and 2 paired-pulse (cortical gamma-aminobutyric acid-interneuron-driven) TMS paradigms. RESULTS: This study comprised 64 participants. Using the repeated measures ANOVA, we observed a significant time effect for MEP facilitation from static to virtual and real observation states when recorded using 3 of the 4 TMS paradigms. Post hoc pairwise comparisons with Benjamini-Hochberg false discovery rate correction revealed significant MEP facilitation in both virtual and real observation states relative to static image observation; however, we also observed a significant time effect between the 2 action observation states (real > virtual) with 2 of the 4 TMS paradigms. CONCLUSIONS: Our results indicate that visual cues expressed via both virtual (video) or real (in person) modes elicit physiological responses within the putative MNS, but this effect is more pronounced for actions presented in person. This has relevance to the appropriate implementation of digital health solutions, especially those pertaining to mental health.

Music and neuro-cognitive deficits in depression.

Background: Cognitive deficits are one of the core features of major depressive disorder (MDD) that play crucial role in functional recovery. Studies have explored cognitive deficits in MDD, however, given inconsistent results, especially in mild-moderate MDD. Recently, studies have explored music as cognitive ability in various clinical conditions. In MDD, large focus has been on evaluating emotion deficits and just a handful on music cognition. With growing evidence on use of music based intervention to target cognitive deficits, it is imperative to explore nature of music cognitive ability in MDD. Aim: To examine musical and neuro-cognitive deficits in patients with mild-moderate MDD. Methods: Patients diagnosed with mild or moderate MDD (n = 19) and matched healthy controls (HC) (n = 18) were evaluated on selected tests from NIMHANS Neuropsychological test battery and Montreal battery for evaluation of amusia (MBEA). Results: MDD group performed significantly lower than HC on working memory (p = 0.007), verbal learning (p = 0.02) and retention (p = 0.03). Three indices were computed for a comprehensive evaluation. Groups did not differ significantly in any of the indices- focused attention, executive function, learning and memory as well as on music cognition. Focused attention and memory index predicted music cognition in HC and the combined group (MDD + HC) (p < 0.01). Attention alone contributed to 62.1% of variance in music cognition. Similarly, music cognition significantly predicted focused attention (p < 0.01). Conclusion: Individuals with mild-moderate MDD show significant deficits in working memory, verbal learning and memory, however, not in music cognition. There exists a significant relationship between music cognition and attention, which could be implicated in use of music interventions to ameliorate cognitive deficits. Limitations of study include small sample size and heterogeneity. Future studies on larger cohort examining musical emotion perception and neurocognition is imperative to have deeper understanding of this debilitating condition.

Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial.

OBJECTIVE: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. METHODS: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). RESULTS: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm. CONCLUSION: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.

A transdiagnostic evaluation of cortical inhibition in severe mental disorders using Transcranial Magnetic Stimulation.

Multiple lines of investigations suggest the presence of cortical inhibition aberrations as central to the phenotypic manifestations of severe mental disorders. Transcranial Magnetic Stimulation (TMS) combined with electromyography can characterize these inhibitory processes in the motor cortex with satisfactory temporal precision. We examined TMS-evoked short- (SICI) and long-interval intracortical inhibition (LICI) and cortical silent period (CSP) as markers of GABAA- (SICI) and GABAB-mediated (LICI and CSP) cortical neurotransmission in symptomatic individuals with mania (n = 40), schizophrenia (n = 76), unipolar depression (n = 86), and OCD (n = 43), and compared them against similar recordings in healthy subjects (n = 125). We hypothesized transdiagnostic GABAA deficits across all the clinical groups and diagnosis-specific GABAB alterations in mania (increased) and OCD (decreased). After controlling for potential confounder variables (gender, education, benzodiazepine prescription, and motor threshold) using the ANCOVA, we observed no significant group difference in SICI (F = 1.04, P = 0.38), but a significant group effect in LICI (F = 16.29, P < 0.001) and CSP (F = 3.02, P = 0.018). Post-hoc analyses revealed that LICI was significantly reduced in OCD but increased in mania and schizophrenia with reference to the healthy group. Similarly, CSP was significantly reduced in OCD and depression groups as compared to the reference group. We observed that LICI and CSP, both followed similar descending gradients from mania through schizophrenia and depression to OCD; with significant elevation in mania, and reduction in depression and OCD, as compared to the healthy group. This pattern of GABAB-mediated cortical inhibition aberrations needs independent validation as potential state-markers of distinct clinical categories.

fNIRS study of prefrontal activation during emotion recognition-A Potential endophenotype for bipolar I disorder?

BACKGROUND: Facial emotion recognition (FER) deficit is documented in many psychiatric disorders, including bipolar disorder (BD). However, its role as a risk-marker in BD is not well researched. In the present study, we investigated the role of FER and the corresponding prefrontal neurohemodynamic changes (PNHC) with functional near infra-red spectroscopy (fNIRS) in patients with BD and subjects at high risk for BD compared to healthy subject. METHODS: Using a cross-sectional case-control design we compared 14 patients with first episode mania (FEM) in remission (BD group), 14 healthy siblings of BD patients (HR group), and 13 matched healthy subjects (HC group). FER was assessed using a computer-based task called Tool for Recognition of Emotions in Neuropsychiatric Disorders (TRENDS). Simultaneously, the corresponding PNHC was recorded with fNIRS. Kruskal Wallis H test was used to analyze between-group differences and Spearman's rho for correlation analysis. RESULTS: The three groups were comparable on socio-demographics (all p>0.09) except education (p = 0.03). HR group had the most hyper-activation in the bilateral DLPFC during the TRENDS task (all p<0.05). There was no significant between-group differences in the FER performance and no significant correlation between the FER performance and the PNHC in the HR and BD groups (all p>0.35). LIMITATIONS: The potential confounding effect of medications in the BD group. CONCLUSIONS: The hyper-activation of the DLPCF in HR group during FER could indicate an increased risk for BD. However, the lack of similar findings in the BD group might reflect a possible normalizing effect of medications. It is equally likely that differences in the PNHC are detectable earlier than the differences in FER task performance during the course of the illness. This requires further exploration.

Auditory signal detection in schizophrenia: Correlates with auditory verbal hallucinations & effect of single session transcranial direct current stimulation (tDCS).

INTRODUCTION: Transcranial Direct Current Stimulation (tDCS) has been beneficial for treating auditory verbal hallucinations (AVH) in schizophrenia (SZ). Aberrant auditory signal detection (ASD) is one of the pathogenetic mechanisms for AVH. We investigated the correlates of ASD with AVH and the impact of single-session tDCS on ASD in SZ patients. METHODS: The ASD performance in SZ patients was compared with matched healthy controls (HC) (N = 24). Subsequently, the effect of single-session tDCS on ASD in SZ patients (N = 24) with AVH was examined in a randomized, double-blind, sham-controlled, cross-over design. The true and sham tDCS were administered (anode at the left dorsolateral prefrontal cortex and cathode at the left temporoparietal junction) on two different days. ASD task was performed before and after each session of tDCS. RESULTS: Auditory hallucination rating scores correlated significantly with false alarm rate, discriminability index, and response bias. SZ patients had a significantly lesser discriminability index in ASD than HC. Single-session tDCS (true versus sham) did not have any significant effect on ASD in SZ patients. CONCLUSION: The study findings support the pathogenetic role of ASD in AVH in SZ. Lack of effect on ASD following single-session tDCS suggests the need for multi-session studies in the future.

Prefrontal cortex activation during working memory task in schizophrenia: A fNIRS study.

Neurocognitive cognitive deficits including working memory (WM) impairment is a key component of schizophrenia (SCZ). Though a prefrontal cortex (PFC) abnormality is recognised to contribute to WM impairment, the exact nature of its neurobiological basis in SCZ is not well established. Functional near infra-red spectroscopy (fNIRS) is an emerging low-cost neuroimaging tool to study neuro-hemodynamics. In this background, we examined the hemodynamic activity during a WM task in schizophrenia using fNIRS. fNIRS was acquired during computerised N-back (zero-, one- & two-back) task in 15 SCZ patients and compared with 22 healthy controls. Performance in N-back test were calculated using signal detection theory alongside the mean reaction times. Concentration and latencies of oxy-, deoxy-, and totalhaemoglobin, and oxygen saturation were computed from 8*8 optodes positioned over bilateral PFC. SCZ performed poorly as measured by most of the WM parameters (p < 0.05). Lesser deoxyhemoglobin concentration (two > zero, at right BA10, p = 0.006) was noted in the right frontopolar cortex in SCZ surviving multiple-comparison correction. In addition, olanzapine equivalent doses correlated negatively with right frontopolar cortex activation (two > zero back, BA10, ρ = 0.70, p = 0.004) and better performance in two back (false alarm rate, ρ = 0.61, p = 0.015). A delayed but compensatory hyperactivation of right frontopolar cortex noted in SCZ may underlie the WM deficit in SCZ. Future studies are recommended to replicate the role of right frontopolar cortex in WM using larger samples and systematically explore the effect of antipsychotics on them.

Early intervention for people at high risk of developing bipolar disorder: a systematic review of clinical trials.

Early intervention approaches are built on the premise of preventing disability, burden, and cognitive sequelae caused by bipolar disorder. The objective of this systematic review was to characterise the effectiveness of all the available psychological and pharmacological treatments for early intervention in people at high risk of developing bipolar disorder. The study was registered with PROSPERO (CRD42019133420). We did a systematic search to identify studies published in ten databases up to March 27, 2020. Randomised controlled trials and cohort studies that assessed the effect of pharmacological or psychological interventions in people at high risk of developing bipolar disorder were included. Studies of first episodes of mania were excluded. Eligible papers were assessed for quality and data were extracted. The primary outcomes were change in manic and depressive symptoms from baseline to endpoint. Of the 2856 citations retrieved by our search, 16 studies were included; five evaluated pharmacotherapeutic strategies (three randomised controlled trials and two open-label studies), ten assessed psychotherapeutic strategies (four randomised controlled trials and six open-label studies), and one randomised controlled trial assessed combination therapy; these 16 trials included a total of 755 participants at high risk of developing bipolar disorder. Quality assessment indicated fair to good quality for open-label studies, and a high risk of bias in four randomised controlled trials. Among the pharmacotherapeutic interventions, there is preliminary support for the efficacy of aripiprazole in reducing mood symptoms in people at high risk of developing bipolar disorder. Psychological interventions were effective for various outcomes. There was substantial methodological heterogeneity across studies. This systematic review underscores the need for multicentre, prospective, methodologically homogeneous studies evaluating conversion to bipolar disorder as an outcome measure.