Intrinsic and antipsychotic drug-induced metabolic dysfunction in schizophrenia

Abstract

For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs) which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.Schizophrenia is a chronic psychiatric illness characterized by hallucinations, delusions, cognitive symptoms, and negative symptoms. Use of antipsychotic drugs (APDs) has been a mainstay of treatment. Though these medications effectively treat the hallucinations, APDs also cause significant metabolic side effects including insulin resistance (IR), dyslipidemia obesity and ultimately type II diabetes (T2D; Ballon et al., 2014). Consequently, a longstanding controversy in managing patients with schizophrenia has been the premorbid risk for adverse metabolic states. We therefore pose the question: is there an intrinsic metabolic risk inherent to schizophrenia or is the metabolic phenotype primarily driven by the impact of APDs?.