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 DisorderPlain Language SummaryWhy was the study done?Neurological soft signs, Minor physical anomalies, and eye-movement abnormalities are known disease makers of Bipolar disorder but their utility in being intermediate markers between the disease manifestation and genetics has not been studied before. Hence we took up this study with the above aim.What did the researchers do?We compared the above-mentioned biomarkers between the patients diagnosed with first-episode mania (considered as early bipolar), the high-risk population (people with a family history of bipolar), and healthy subjects (without any self or family history of any psychiatric illnesses). Each group had 30 participants. We wanted to see if these markers taken together could predict the groups or classify the subjects into the three groups accurately.What did the researchers find?We found that in all the biomarkers there was a significant group difference between the the three groups. The abnormalities showed a pattern wherein they are higher in the first episode mania group compared to at-risk, and higher in at-risk compared to healthy subjects. When all these markers were combined and linear discriminant analysis was run, we noted they accurately classified 72% of the original participants (79·2% first episode bipolar 56·70% High risk, and 82·1% Healthy Subjects).What do the findings mean?The above findings indicate that the eye-movement or oculomotor abnormalities enhance the utility of neurodevelopmental markers as biomarkers of bipolar disorder. The presence of these abnormalities fairly early in the disease also means that they have a role in the etiopathogenesis of bipolar disorder. All the markers taken together can be composite measurable components in the pathway between disease manifestation and genetics in Bipolar I Disorder, and thus help in early identification.

Effectiveness of Short-Term Lifestyle Modification on Reducing Body- Weight-Related Parameters in Persons with Severe Mental Illness: A Randomized Controlled Trial.

Background: Persons with severe mental illness (SMI) reportedly have a high mortality rate due to metabolic syndrome (MS). However, lifestyle modification (LM) offers effective management of some components of MS. This study aimed to evaluate the effectiveness of LM in reducing body-weight-related parameters in SMIs. Method: Eighty participants with SMI were assigned randomly to either LM (n = 40) or treatment as usual (TAU; n = 40) groups using block randomization (eight blocks of n = 10). The LM group and their caregivers received a structured LM package that included nutrition counselling, recommendations on a balanced diet, and physical activity. The two groups were assessed on body weight, body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and quality of life (QOL) at baseline and after three months. Thirty-one LM and 33 TAU participants completed the study. Results: The LM and TAU groups were comparable on sociodemographic and clinical characteristics and baseline variables of body weight, BMI, WC, and WHR (all P > 0.08). Repeated-measures analysis of variance (RM ANOVA) showed that the LM group had significantly reduced body weight, BMI, WC, and WHR (all P < 0.001) than the TAU group. Similarly, the LM group also showed improvement in their QOL (P < 0.001), whereas TAU showed no improvement. Conclusions: LM is an effective way to reduce body-weight-related parameters of MS and improves the QOL among persons with SMI in the short term. The caregivers' inclusion during LM contributed to the weight reduction. However, the long-term effect of the intervention could not be assessed.

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.

Neurohemodynamic correlates of BDNF gene expression in schizophrenia patients with working memory deficits: A functional MRI study.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) is involved in neuroplasticity underlying cognitive deficits, including working memory deficits (WMD), in schizophrenia. Methodological challenges and inconsistencies are reported with peripheral BDNF levels. Left dorsolateral prefrontal cortex (DLPFC) is proposed to underlie WMD, though inconsistently. We aimed to explore the correlations between brain activation during working memory task-based functional Magnetic Resonance Imaging (fMRI) and BDNF gene expression in schizophrenia patients with WMD. METHODS: 26 patients with schizophrenia with established WMD were recruited for the study. Blood samples were collected to study lymphocyte BDNF gene expression. Patients underwent task-based fMRI to examine the working memory performance and related brain activation. Whole-brain analysis was performed with 2-back > 0-back and 2-back > rest contrast. The peak intensity values of the activation were used for correlation analysis. RESULTS: Whole brain analysis with 2-back > rest contrast revealed maximum activation in left DLPFC, Brodmann area 9 (t = 10.54, FWE corrected p < 0.05). The baseline BDNF gene expression correlated positively with the peak intensity of brain activation in left DLPFC (r = 0.365, p = 0.033). Negative symptom score negatively correlated with BDNF gene expression (r = -0.499, p = 0.005) and left DLPFC fMRI activation (r = -0.393, p = 0.023) respectively. CONCLUSION: We found a significant positive association between BDNF gene expression and the activation of the DLPFC during the working memory task. This novel observation needs further systematic evaluation to establish the potential role of peripheral BDNF expression in WMD in schizophrenia.

A Systematic Chart Review of Adults with Post-Traumatic Stress Disorder: Data from a Tertiary Care Psychiatry Center in India.

Background: Post-traumatic stress disorder (PTSD) is an understudied construct in the psychiatric setting. The majority of existing Indian studies on PTSD focus on the general population or disaster-stricken communities. Here, we present data from a five-year retrospective chart review from a tertiary care psychiatric center in India. Methods: Medical records of adult patients (≥18 years) who had attended psychiatry outpatient services between April 1, 2015 and March 31, 2020 (five years) and were diagnosed with PTSD, as per ICD-10 criteria, were reviewed (n = 113). The relevant sociodemographic and clinical details were extracted using a semistructured pro-forma. Results: The percentage of adult patients with PTSD diagnosis in the five years was 0.22%. PTSD was more common in females (n = 65, 57.5%). Most patients had interpersonal trauma (n = 85, 75.2%), specifically sexual abuse (n = 47, 41.6%). The median age of onset was 22 years. All the patients had re-experiencing symptoms, with an equally high rate of avoidance (n = 109, 96.5%) and arousal symptoms (n = 110, 97.3%). 82%(93) had a comorbid psychiatric disorder, with mood disorder being the most common (n = 44, 38.9%). Males had a higher rate of comorbid substance use disorder (n = 14, 29.2%) and depression (n = 20,42%), and females had a higher rate of comorbid dissociative disorder (n = 13,20%). Most of the patients received non-trauma-focused psychological interventions, and only 18% (20) received evidence-based trauma-focused psychological interventions. Conclusion: Interpersonal trauma, specifically sexual abuse, largely contributes to PTSD among adults attending psychiatric services. The need for trauma-focused psychological interventions is underscored.

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.

Clinical efficacy and neurobiological correlates of electroconvulsive therapy in patients with clozapine-resistant/intolerant schizophrenia: study protocol of multi-site parallel arm double-blind randomized sham-controlled study.

Background: A substantial proportion of patients with treatment resistant schizophrenia do not respond well or partially to clozapine, with a subset that does not tolerate an adequate trial of clozapine. Electroconvulsive therapy (ECT) is regarded as one of the augmenting options, but there is a lack of high-quality evidence for this practice. This protocol describes a double-blind randomised sham-controlled modified-ECT trial to evaluate its efficacy in patients with clozapine resistant/intolerant schizophrenia. The study also involves multimodal investigations to identify the response predictors and the mechanistic basis of modified ECT in this population. Methods: One hundred consenting schizophrenia patients with resistance/intolerance to clozapine referred by clinicians for ECT would be randomly assigned to receive true ECT or sham ECT at three study centers. Sham ECT would mimic all the procedures of modified ECT including anaesthesia and muscle relaxation, except the electrical stimulation. After a blinded course, non-responders to sham ECT would be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging [MRI], electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphism) would be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial would evaluate the improvement in positive symptoms (scale for assessment of positive symptoms) of schizophrenia as the primary outcome measure with prediction of this change by resting-state functional-MRI based brain-connectivity as the second primary objective. Registration: Clinical Trial Registry of India (Reg no: CTRI/2021/05/033775) on 24 th May 2021.

Clinical Research Center for Neuromodulation in Psychiatry: A Multi-Center Initiative to Advance Interventional Psychiatry in India.

This manuscript introduces a unique program titled "Clinical Research Center (CRC) for Neuromodulation in Psychiatry" supported by the prestigious CRC/Public Health Research Center Grant of the DBT Wellcome Trust India Alliance. This multi-institutional research program will be led by NIMHANS (Bengaluru) in collaboration with the Central Institute of Psychiatry (Ranchi), and Kasturba Medical College (Manipal). The goal of this CRC is in alignment with the editorial titled "Need to Develop "Interventional Psychiatry" as a subspecialty in India" published in the January 2020 issue of the Indian Journal of Psychiatry. The translational research studies and the training programs envisaged through this center will facilitate the development of cost-effective, advanced interventional psychiatry tailored to resource-limited Indian clinical settings and similar other countries as well.

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.

Cross-diagnostic evaluation of minor physical anomalies in psychiatric disorders.

BACKGROUND: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer's dementia). METHODS: Modified Waldrop's MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO). RESULTS: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders. CONCLUSION: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders.

Evaluating schema modes and cognitive distortions in borderline personality disorder: A mixed-method approach.

OBJECTIVES: Cognitive processes, such as schema modes and cognitive distortions, may play a role in the genesis and maintenance of affective, interpersonal, and behavioral difficulties in individuals with Borderline Personality Disorder (BPD). This study aimed at exploring the schema modes and cognitive distortions in individuals with BPD. METHODS: Using a mixed-method approach, 30 individuals with BPD and 30 healthy participants were assessed on the Borderline Personality Questionnaire, the Schema Mode Inventory, the Cognitive Distortions Scale, and a semi-structured interview schedule. RESULTS: The BPD group had higher scores than the control group on all the maladaptive schema modes and cognitive distortions subscales. The child modes were the commonest and were also the strongest correlate of BPD symptomatology. Qualitative analysis of the content of the semi-structured interview also corroborated these findings. CONCLUSIONS: There could be many schema modes and cognitive distortions operating behind the diverse psychopathology seen in BPD.

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.