Ganesan Venkatasubramanian

Gray matter volume abnormalities and externalizing symptoms in subjects at high risk for alcohol dependence.

Reduced right amygdala volumes have been reported in young, alcohol‐naïve subjects at high risk (HR) for alcohol dependence. The differences in brain morphometry have been associated with an excess of externalizing behaviors in these subjects. This may reflect a neurobiological vulnerability to alcohol dependence. Existing Magnetic Resonance Imaging (MRI) studies on these subjects have examined only a few, pre‐selected brain regions using the manual regions of interest (ROI) approach. MRI of HR subjects (n = 20) and age, sex, and handedness‐matched low‐risk (LR) subjects (n = 21) were analyzed using optimized voxel‐based morphometry and ROI approach. The externalizing symptoms of these subjects and their fathers were measured using the Semi‐Structured Assessment for the Genetics of Alcoholism. HR subjects had significantly smaller volumes of superior frontal, cingulate and parahippocampal gyri, amygdala, thalamus and cerebellum. These gray matter volumes correlated negatively with externalizing symptoms scores. Subjects at HR for alcoholism have reduced volumes of critical areas of brain gray matter, which are associated with increased externalizing symptoms. These represent key endophenotypes of alcoholism.

Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia.

Behere RV, Arasappa R, Jagannathan A, Varambally S, Venkatasubramanian G, Thirthalli J, Subbakrishna DK, Nagendra HR, Gangadhar BN. Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia.

Automated MRI parcellation study of regional volume and thickness of prefrontal cortex (PFC) in antipsychotic-naïve schizophrenia.

Objective:  Prefrontal cortical dysfunction is considered to be critical in the pathogenesis of schizophrenia. However, structural magnetic resonance imaging (MRI) studies on the PFC have yielded inconsistent results because of various confounding factors.

Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications

Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.

Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: A longitudinal study

Neurodevelopmental pathogenesis of schizophrenia might be mediated by abnormalities in Insulin-like Growth Factor-1 (IGF-1). Developmental disturbances like obstetric complications, by themselves, as well as through the resultant hypercortisolemia due to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, can lead to deficient IGF-1 level. The relevance of IGF-1-Cortisol interactions in schizophrenia, especially in the context of antipsychotic treatment, is yet to be explored. In this study, thirty-three antipsychotic-naïve schizophrenia patients (13-men) were examined for serum IGF-1 and cortisol levels at baseline and after 3months of antipsychotic treatment. For baseline analyses, the patients were compared with 33 healthy controls matched for age, sex, socio-economic status, and physical activity. Symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS). At baseline, schizophrenia patients had significantly lower levels of IGF-1 [t=4.6; p<0.0001] and higher levels of cortisol [t=3.9; p=0.0002] in comparison with healthy controls. Following treatment, IGF-1 level increased significantly [t=4.5; p<0.0001] whereas cortisol decreased significantly [t=2.5; p=0.02] in patients. There was a significant positive correlation between magnitude of increase in IGF-1 level and the magnitude of reduction in cortisol level [r=0.52; p=0.002]. Also, the greater the increase in IGF-1 the greater was the reduction in SAPS score [r=0.39; p=0.02]. Our study findings demonstrate that antipsychotic treatment can result in significant elevation of serum IGF-1 possibly mediated by reduction in cortisol levels. These observations suggest a possible link between HPA axis abnormalities and IGF-1 deficits in the neurodevelopmental pathogenesis of schizophrenia.

Variation in the major histocompatibility complex [MHC] gene family in schizophrenia: associations and functional implications.

Schizophrenia is a chronic debilitating neuropsychiatric disorder with a complex genetic contribution. Although multiple genetic, immunological and environmental factors are known to contribute to schizophrenia susceptibility, the underlying neurobiological mechanism(s) is yet to be established. The immune system dysfunction theory of schizophrenia is experiencing a period of renewal due to a growth in evidence implicating components of the immune system in brain function and human behavior. Current evidence indicates that certain immune molecules such as Major Histocompatibility Complex (MHC) and cytokines, the key regulators of immunity and inflammation are directly involved in the neurobiological processes related to neurodevelopment, neuronal plasticity, learning, memory and behavior. However, the strongest support in favor of the immune hypothesis has recently emerged from on-going genome wide association studies advocating MHC region variants as major determinants of ones risk for developing schizophrenia. Further identification of the interacting partners and receptors of MHC molecules in the brain and their role in down-stream signaling pathways of neurotransmission have implicated these molecules as potential schizophrenia risk factors. More recently, combined brain imaging and genetic studies have revealed a relationship between genetic variations within the MHC region and neuromorphometric changes during schizophrenia. Furthermore, MHC molecules play a significant role in the immune-infective and neurodevelopmental pathogenetic pathways, currently hypothesized to contribute to the pathophysiology of schizophrenia. Herein, we review the immunological, genetic and expression studies assessing the role of the MHC in conferring risk for developing schizophrenia, we summarize and discuss the possible mechanisms involved, making note of the challenges to, and future directions of, immunogenetic research in schizophrenia.

Prospective comparison of course of disability in antipsychotic-treated and untreated schizophrenia patients.

Objective:  To compare the course of disability in schizophrenia patients receiving antipsychotics and those remaining untreated in a rural community.

Therapeutic efficacy of add-on yogasana intervention in stabilized outpatient schizophrenia: Randomized controlled comparison with exercise and waitlist.

Background: Schizophrenia is a highly disabling illness. Previous studies have shown yoga to be a feasible add-on therapy in schizophrenia. Aims: The current study aimed to test the efficacy of yoga as an add-on treatment in outpatients with schizophrenia. Settings and Design: The study done at a tertiary psychiatry center used a single blind randomized controlled design with active control and waitlist groups. Materials and Methods: Consenting patients with schizophrenia were randomized into yoga, exercise, or waitlist group. They continued to receive pharmacological therapy that was unchanged during the study. Patients in the yoga or exercise group were offered supervised daily procedures for one month. All patients were assessed by a blind rater at the start of the intervention and at the end of 4 months. Results: Kendall tau, a nonparametric statistical test, showed that significantly more patients in the yoga group improved in Positive and Negative Syndrome Scale (PANSS) negative and total PANSS scores as well as social functioning scores compared with the exercise and waitlist group. Odds ratio analysis showed that the likelihood of improvement in yoga group in terms of negative symptoms was about five times greater than either the exercise or waitlist groups. Conclusion: In schizophrenia patients with several years of illness and on stabilized pharmacological therapy, one-month training followed by three months of home practices of yoga as an add-on treatment offered significant advantage over exercise or treatment as usual. Yoga holds promise as a complementary intervention in the management of schizophrenia.

Fetal programming of schizophrenia: Select mechanisms

Abstract Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia.

Oxidative stress and neopterin abnormalities in schizophrenia: A longitudinal study

Oxidative stress abnormalities have been proposed to explain the pathogenesis of schizophrenia. The present study examined neopterin and oxidative stress abnormalities in schizophrenia patients before and after treatment. Serum neopterin, total anti-oxidants, nitrites and thiols in antipsychotic-naïve schizophrenia patients (n=45) were assessed at baseline before treatment in comparison with healthy controls (n=43). The schizophrenia patients on treatment were followed up for 3months and these parameters were reassessed (n=32). In comparison to healthy controls, schizophrenia patients had significantly higher levels of neopterin and nitrites and significantly lower levels of anti-oxidants before treatment. During follow-up assessments in schizophrenia patients after treatment with antipsychotics, there was a significant decrease in the neopterin levels and significant increase in anti-oxidant levels. Our study observations support increased oxidative stress in schizophrenia that improves with antipsychotic treatment.