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.

Oculomotor Abnormalities and Aberrant Neuro-Developmental Markers: Composite Endophenotype for Bipolar I Disorder: Anomalies Oculomotrices et Marqueurs Neuro-Développementaux Aberrants : Endophénotype Composite du Trouble Bipolaire I.

BACKGROUND: Neurological soft signs (NSSs), minor physical anomalies (MPAs), and oculomotor abnormalities were plausible biomarkers in bipolar disorder (BD). However, specific impairments in these markers in patients after the first episode mania (FEM), in comparison with first-degree relatives (high risk [HR]) of BD and healthy subjects (health control [HC]) are sparse. AIM OF THE STUDY: This study aimed at examining NSSs, MPAs, and oculomotor abnormalities in remitted adult subjects following FEM and HR subjects in comparison with matched healthy controls. Investigated when taken together, could serve as composite endophenotype for BD. METHODS: NSSs, MPAs, and oculomotor abnormalities were evaluated in FEM (n = 31), HR (n = 31), and HC (n = 30) subjects, matched for age (years) (p = 0.44) and sex (p = 0.70) using neurological evaluation scale, Waldrop's physical anomaly scale and eye tracking (SPEM) and antisaccades (AS) paradigms, respectively. RESULTS: Significant differences were found between groups on NSSs, MPAs, and oculomotor parameters. Abnormalities are higher in FEM subjects compared to HR and HC subjects. Using linear discriminant analysis, all 3 markers combined accurately classified 72% of the original 82 subjects (79·2% BD, 56·70% HR, and 82·1% HC subjects). CONCLUSIONS: AS and SPEM could enhance the utility of NSSs, and MPAs as markers for BD. The presence of these abnormalities in FEM suggests their role in understanding the etiopathogenesis of BD in patients who are in the early course of illness. These have the potential to be composite endophenotypes and have further utility in early identification in BD.

Eye movement abnormalities and Atypical Neurodevelopmental markers as Composite Measurable components in the pathway between disease manifestation and genetics in Bipolar I Disorder.

Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses.

OBJECTIVE: Adverse childhood experiences are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of adverse childhood experiences and their relation to the age of onset of major psychiatric conditions in individuals from families that had ⩾2 first-degree relatives with major psychiatric conditions (multiplex families), identified as part of an ongoing longitudinal study. METHODS: Our sample consisted of 509 individuals from 215 families. Of these, 268 were affected, i.e., diagnosed with bipolar disorder (n = 61), obsessive-compulsive disorder (n = 58), schizophrenia (n = 52), substance dependence (n = 59) or co-occurring diagnoses (n = 38), while 241 were at-risk first-degree relatives who were either unaffected (n = 210) or had other depressive or anxiety disorders (n = 31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire and total adverse childhood experiences exposure and severity scores were calculated. RESULTS: It was seen that affected males, as a group, had the greatest adverse childhood experiences exposure and severity scores in our sample. A Cox mixed effects model fit by gender revealed that a higher total adverse childhood experiences severity score was associated with significantly increased risk for an earlier age of onset of psychiatric diagnoses in males. A similar model that evaluated the interaction of diagnosis revealed an earlier age of onset in obsessive-compulsive disorder and substance dependence, but not in schizophrenia and bipolar disorder. CONCLUSION: Our study indicates that adverse childhood experiences were associated with an earlier onset of major psychiatric conditions in men and individuals diagnosed with obsessive-compulsive disorder and substance dependence. Ongoing longitudinal assessments in first-degree relatives from these families are expected to identify mechanisms underlying this relationship.

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.

The co-occurrence of multiple sclerosis and bipolar disorder: A case series on clinical and neuroimaging correlates.

There is a dearth of studies on neuroimaging correlates of Bipolar Disorder (BD) in Multiple Sclerosis (MS). We describe the clinical profile and neuroimaging findings of four cases of MS with BD. Among them, two patients had multiple mood episodes preceding the neurological symptoms, one had concurrent manic and neurological symptoms, and one had multiple depressive episodes and an isolated steroid-induced manic episode. Frontal and temporal lobes, and Periventricular White Matter were involved in all four cases, and hence may be considered biological substrates of BD in MS. Larger studies are needed to validate the utility of these findings.

Bell's mania as a clinical presentation in a neurosurgical setting from a tertiary care neuropsychiatric hospital in India.

Bell's mania is the co-occurrence of delirium and mania. We present two cases of Bell's mania in a neurosurgical setting. The first case is of a 52-year-old male who presented with holocranial headache, disorientation, and manic symptoms for five months. He was found to have suprasellar craniopharyngioma. He significantly improved with olanzapine, but re-emergence of mood symptoms was noted after surgery. The second case is of a 42-year-old male who presented with a 15-day history of seizures and disorientation. He was found to have a dural arteriovenous fistula. He developed Bell's mania in the post-procedural period, which improved with olanzapine. Compression of the hypothalamo-pituitary stalk in the first case and vascular and inflammatory changes in the second case could have led to Bell's mania. Atypical age of onset and presence of neurological symptoms in patients presenting with psychiatric symptoms should raise the suspicion of an underlying organicity. Atypical anti-psychotics can be a useful management strategy for Bell's mania.

Digital phenotyping correlates of mobile cognitive measures in schizophrenia: A multisite global mental health feasibility trial.

Traditional cognitive assessments in schizophrenia are time-consuming and necessitate specialized training, making routine evaluation challenging. To overcome these limitations, this study investigates the feasibility and advantages of utilizing smartphone-based assessments to capture both cognitive functioning and digital phenotyping data and compare these results to gold standard measures. We conducted a secondary analysis of data from 76 individuals with schizophrenia, who were recruited across three sites (one in Boston, two in India) was conducted. The open-source mindLAMP smartphone app captured digital phenotyping data and Trails A/B assessments of attention / memory for up to 12 months. The smartphone-cognitive tasks exhibited potential for normal distribution and these scores showed small but significant correlations with the results from the Brief Assessment of Cognition in Schizophrenia, especially the digital span and symbol coding tasks (r2 = 0.21). A small but significant correlation (r2 = 0.29) between smartphone-derived cognitive scores and health-related behaviors such as sleep duration patterns was observed. Smartphone-based cognitive assessments show promise as cross-cultural tools that can capture relevant data on momentary states among individuals with schizophrenia. Cognitive results related to sleep suggest functional applications to digital phenotyping data, and the potential of this multimodal data approach in research.

Topographic regulation of neuronal intermediate filaments by phosphorylation, role of peptidyl-prolyl isomerase 1: significance in neurodegeneration.

The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs.

Atypical thrombotic thrombocytopenic purpura in a middle-aged woman who presented with a recurrent stroke.

An atypical clinical presentation makes TTP diagnosis difficult, which prevents prompt management of TTP. This case highlights the importance of early recognition of TTP in patients with atypical presentations who may not have the expected clinical or laboratory findings. The level of suspicion should be especially high in young and middle-aged patients with strokes or acute coronary syndrome who do not have other risk factors for cardiovascular events. This is particularly so for those patients who have a previous episode of TTP or patients with subtle laboratory abnormalities, which may suggest the potential existence of a thrombotic microangiopathic process.

Neurocognitive Deficits in Recently Diagnosed Young Remitted Bipolar I Disorder and At-Risk Subjects: Potential Endophenotypes?

Background: Neurocognitive deficits have been reported consistently in euthymic bipolar disorder (BD) across studies. Endophenotype potential of such deficits have been reported in a few studies. However, data from the Indian subcontinent is sparse, and no studies had a sample (patients and high-risk group) aged 20-25 years, which is the actual risk period for developing BD. We studied cognitive deficits, as a potential endophenotype for BD, in recently diagnosed BD (FEM-first episode mania) in remission, young unaffected first-degree relatives (HR) of patients with BD, and healthy controls (HC). Methods: Cross-sectional study design using convenient sampling was employed. We recruited FEM (n = 25), HR (n = 25), and age-matched HC (n = 25) between 18 and 30 years. All HR subjects were <25 years of age, which is the period of vulnerability for BD. All the groups were screened using MINI Version 6. Neurocognitive assessments were done using the NIMHANS neuropsychology battery. The cognitive domains assessed were processing speed, attention, working memory, executive functions, and visual and verbal memory. Results: The three groups were comparable in age and sex (all P > 0.06). The mean (SD) age of the FEM subjects was 23.7 (3.47) years, and the mean duration of illness was 5.92 (2.94) months. Compared to the HC group, the FEM group performed poorly on multiple cognitive domains (all P < 0.05). Performance of the HR group was comparable to the FEM group, but they showed significantly poorer performance compared to HC on the verbal fluency test-controlled oral word association (COWA, F = 12.36, P = 0.001), and the visual learning and memory test-complex figure test-immediate recall (CFT-IR, F = 8.10 and p = 0.001). Conclusions: Cognition is impaired very early in the course of BD. Visual memory and executive function (verbal fluency) have endophenotypic potential. These findings are particularly important given that the HR group were still within the vulnerable period to develop BD. These findings imply a tremendous potential for early diagnosis and prevention by early interventions in BD.

Multiple Complement Pathway-related Proteins Might Regulate Immunopathogenesis of Major Depressive Disorder.

Objective: Exacerbated inflammatory pathway has emerged as a predominant etiological construct of major depressive disorder (MDD). Innate immune molecules like complement proteins induce inflammatory responses and also regulate key neurobiological processes. However, there is a dearth of literature on the impact of critical complement proteins in MDD. Herein, plasma profiling of seven complement proteins was carried out to obtain a better insight into the role of the complement pathway in MDD. Methods: Plasma levels of C1q, C3, C3b/iC3b, C4, Factor B, Factor H, and properdin were assayed in 22 patients with MDD and 27 healthy controls by multiplex suspension assay. The patients with MDD were diagnosed as per DSM IV-TR. Hamilton Depression Rating Scale (HAM-D), Montgomery Depression Rating Scale and Clinical Global Improvement were used for clinical assessments of the patients. The plasma levels of these complement proteins were also correlated with various clinical scores and phenotypes of MDD. Results: The patients with MDD and healthy controls did not differ in terms of age and gender (p > 0.1). The patients with MDD had a mean duration of illness of around 3 years, with average number of depressive episodes being 6 and the mean HAM-D score was 19. Of the seven complement components, the plasma levels of C1q, Factor B, and Factor H (p ≤ 0.05) were significantly elevated in MDD patients compared to healthy controls. However, the plasma levels of these complement proteins were not found to correlate with the clinical profile of MDD patients. Conclusion: Both Factor B and Factor H are crucial in the induction and regulation of the alternative pathway of complement activation. The alternative pathway also plays a critical role in inflammation. These findings suggest an important role of the alternative complement pathway in immuno-inflammation in MDD.

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.

Relapse prediction in schizophrenia with smartphone digital phenotyping during COVID-19: a prospective, three-site, two-country, longitudinal study.

Smartphone technology provides us with a more convenient and less intrusive method of detecting changes in behavior and symptoms that typically precede schizophrenia relapse. To take advantage of the aforementioned, this study examines the feasibility of predicting schizophrenia relapse by identifying statistically significant anomalies in patient data gathered through mindLAMP, an open-source smartphone app. Participants, recruited in Boston, MA in the United States, and Bangalore and Bhopal in India, were invited to use mindLAMP for up to a year. The passive data (geolocation, accelerometer, and screen state), active data (surveys), and data quality metrics collected by the app were then retroactively fed into a relapse prediction model that utilizes anomaly detection. Overall, anomalies were 2.12 times more frequent in the month preceding a relapse and 2.78 times more frequent in the month preceding and following a relapse compared to intervals without relapses. The anomaly detection model incorporating passive data proved a better predictor of relapse than a naive model utilizing only survey data. These results demonstrate that relapse prediction models utilizing patient data gathered by a smartphone app can warn the clinician and patient of a potential schizophrenia relapse.

Emotion Processing Deficit in Euthymic Bipolar Disorder: A Potential Endophenotype.

Background: Emotion processing deficits have been described in patients with bipolar disorder (BD) and are considered one of the core cognitive abnormalities in BD with endophenotype potential. However, the literature on specific impairments in emotion processing cognitive strategies (directive/cortical/higher versus intuitive/limbic/lower) in euthymic adult BD patients and healthy first-degree relatives/high-risk (HR) subjects in comparison with healthy controls (HCs) is sparse. Methods: We examined facial emotion recognition deficits (FERD) in BD (N = 30), HR (N = 21), and HC (N = 30) matched for age (years), years of education, and sex using computer-administered face emotions-Matching And Labeling Task (eMALT). Results: The three groups were significantly different based on labeling accuracy scores for fear and anger (FA) (P < 0.001) and sad and disgust (SD) (P < 0.001). On post-hoc analysis, HR subjects exhibited a significant deficit in the labeling accuracy of FA facial emotions (P < 0.001) compared to HC. The BD group was found to have significant differences in all FA (P = 0.004) and SD (P = 0.003) emotion matching as well as FA (P = 0.001) and SD (P < 0.001) emotion labeling accuracy scores. Conclusions: BD in remission exhibits FERD in general, whereas specific labeling deficits of fear and anger emotions, indicating impaired directive higher order aspect of emotion processing, were demonstrated in HR subjects. This appears to be a potential endophenotype. These deficits could underlie the pathogenesis in BD, with possible frontolimbic circuitry impairment. They may have potential implications in functional recovery and prognosis of BD.

Smartphone digital phenotyping, surveys, and cognitive assessments for global mental health: Initial data and clinical correlations from an international first episode psychosis study.

Objective: To examine feasibility and acceptability of smartphone mental health app use for symptom, cognitive, and digital phenotyping monitoring among people with schizophrenia in India and the United States. Methods: Participants in Boston, USA and Bhopal and Bangalore, India used a smartphone app to monitor symptoms, play cognitive games, access relaxation and psychoeducation resources and for one month, with an initial clinical and cognitive assessment and a one-month follow-up clinical assessment. Engagement with the app was compared between study sites, by clinical symptom severity and by cognitive functioning. Digital phenotyping data collection was also compared between three sites. Results: By Kruskal-Wallis rank-sum test, we found no difference between app activities completed or digital phenotyping data collected across the three study sites. App use also did not correlate to clinical or cognitive assessment scores. When using the app for symptom monitoring, preliminary findings suggest app-based assessment correlate with standard cognitive and clinical assessments. Conclusions: Smartphone app for symptom monitoring and digital phenotyping for individuals with schizophrenia appears feasible and acceptable in a global context. Clinical utility of this app for real-time assessments is promising, but further research is necessary to determine the long-term efficacy and generalizability for serious mental illness.

Adjunct yoga therapy: Influence on heart rate variability in major depressive disorder - A randomized controlled trial.

HRV is inversely proportional to severity of depression. Effect of 12-weeks adjunct yoga therapy on HRV in patients with MDD was assessed through a randomized controlled trial. Sixty-eight subjects (40 females) with mean age 31.58 ± 8.79 years, scoring ≥ 18 on HDRS were randomized to either (YG; n = 35) or (WG; n = 33). Linear mixed model analysis showed no significant difference between groups. On comparing change in mean percentage, substantial more decrease could be elicited only for LF/HF ratio in YG compared to WG, while being comparable for other variables across the groups. Findings suggest Yoga therapy may help in bringing parasympathetic dominance in patients with MDD.

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.

Childhood abuse and intimate partner violence among women with mood disorders.

BACKGROUND: Mild to moderate association between childhood abuse (CA) and intimate partner violence (IPV) is reported among women from community samples. CA and IPV in clinical samples have shown strong association with adult psychopathology. METHODS: We investigated the association between CA and IPV among women with mood disorders (MD), in comparison with healthy women (HW), at a tertiary mental health centre in India. Women diagnosed with mental health disorders (n=609) and healthy volunteers (n=100), between the ages of 18 to 50 years, were assessed as part of a larger study. For the purpose of this analysis, we have taken a sample of women with MD (n=251) this includes 121 women with unipolar depression, 130 with Bipolar disorder and HW (n=72), with intimate partners. RESULTS: Incidences of childhood emotional abuse (χ2 =4.200, p=<0.05) and IPV [Severe combine abuse (t=3.924, p<0.01), Emotional abuse (t=3.895, p<0.01), Physical abuse (t=2.333, p<0.05)] were higher in women with MD as compared to HW. We noted a positive correlation between CA and IPV, in women with MD. And also CA came out as a predictor for IPV in later life among women with MD on regression analysis. LIMITATIONS: No information about the total number of depressive and manic episodes, and also the mood ratings at the entry point. CONCLUSIONS: CA and IPV have an additive effect which might lead to the expression of severe mental disorders like MD and these factors might also have an impact on course and outcome of mood disorder which needs further studies.