Metabolic Syndrome in Schizophrenia: Theoretical, Clinical and Translational Perspectives

Byline: Sri. Agarwal, Ganesan. Venkatasubramanian Metabolic syndrome in schizophrenia is in many ways, an epitome of the mind-body monism of modern psychiatry and medicine. The focus of this interaction has evolved over the last two decades from the viewpoint that this adverse-effect as mere collateral damage due to the newer antipsychotics' pharmacodynamic profile to a perspective that metabolic dysregulation might have complex and intrinsic link to schizophrenia pathogenesis. Interestingly, this association was indeed alluded to much earlier in Maudsley's work, [sup][1] long before atypical antipsychotics came into clinical practice. Metabolic syndrome adds significantly to the morbidity of schizophrenia and is an important cause of mortality in this population. [sup][2] In contemporary psychiatry, apart from significant clinical implications, the association between schizophrenia and metabolic syndrome has provided a fertile ground for etiological hypothesis generation and testing and has the potential toward facilitating the emergence of newer therapeutics. [sup][3] Studies have demonstrated that antipsychotic-naive patients as well as relatives of patients with schizophrenia have impaired glucose tolerance and increased insulin resistance compared with the normal controls. [sup][4],[5] An exciting development in the last few years has been the paradigm shift in understanding metabolic disorders consequent to antipsychotic use. A rapidly growing evidence base, although not unequivocal, supports the hypothesis that metabolic side-effects might be intrinsically linked to the efficacy of antipsychotic medication [sup][6] and that without these side-effects, one may not have any effects either. [sup][7],[8] Several common genetic and environmental risk factors have putatively been linked with increased risk of both schizophrenia and diabetes, which add an extra layer of complexity in understanding the interactions between these two disorders. Pathophysiological links between schizophrenia (a predominantly dopamine related condition) and metabolic diseases such as obesity, diabetes and hypertriglyceridemia (predominantly insulin related conditions) has been strengthened by independent lines of enquiry as demonstrated in recent studies. Replication of the shared genetic risk between schizophrenia and diabetes in two unrelated population samples, [sup][9],[10] both implicating the Transcription factor 7-like 2 (TCF7L2) gene (a gene that has been most consistently replicated in the risk toward type-2 diabetes mellitus [sup][11] ) have added substance to a link that was long suspected. That the gene product interacts closely with [sz]-catenin, [sup][12] a member of the Wnt pathway, which has been shown to be dysregulated in patients with schizophrenia, further underscores the biological significance of the finding. The expression of the [sz]-catenin gene itself has been shown to be decreased in patients with schizophrenia. [sup][13] The Wnt pathway is involved in cell proliferation and differentiation. Abnormalities in this pathway have been cited as evidence backing the neurodevelopmental theory of schizophrenia. Other members of the pathway like glycogen synthase kinase 3[sz] (GSK3[sz]) have direct interactions with Disruptedin schizophrenia 1, genetic abnormalities in which, consistently come up in an assessment of the genetic risk factors for schizophrenia. [sup][14] GSK3[sz] has further been shown to be involved in mediation of dopamine action and responds to antipsychotic drugs. [sup][6] Interestingly, GSK3[sz] influences inflammatory pathways [sup][15] - for example, the ones that involve Toll-like receptors, [sup][16] which are implicated in schizophrenia pathogenesis. [sup][17] This link is significant given the importance of immune-inflammatory aberrations of possible prenatal origin that connects schizophrenia and metabolic syndrome. Prenatal immune activation, due to various kinds of prenatal adversity has been shown to be associated with increase rates of both schizophrenia as well as diabetes. …