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.

Keywords: antipsychotic drugs; diabetes; dopamine; dyslipidemia; insulin; metabolism; monoamines; schizophrenia.

Figure 1

Summary of central and peripheral mechanisms contributing to deleterious effects of schizophrenia and APDs on glucose and lipid metabolism. The central nervous system,including metabolically-relevant areas in the brain such as hypothalamus, receive feedback from peripheral organs that regulate metabolism and appetite. Likewise, metabolic centers in the brain regulate metabolism throughout the body via actions on peripheral organs including GI tract, liver, pancreas, adipose tissue, and skeletal muscle. This feedback is bidirectional though non-sequential, and creates a delicate metabolic balance that is disturbed by biological changes intrinsic to schizophrenia and is further perturbed by APDs. We hypothesize that these central and peripheral target organs are linked through common molecular signaling networks involving dopaminergic, serotoninergic, histaminergic, and adipokine signaling. Since APDs act at receptors for these signaling systems, these drugs may have synergistic properties that significantly increase the risk of developing metabolic disturbances including insulin resistance and adiposity.

Figure 2

Dopaminergic modulation of insulin secretion in pancreatic beta cells. (A) Treatment of INS-IE cells, an established rat pancreatic beta cell-derived cell line, with dopamine potently inhibited glucose-stimulated insulin secretion in a dose-dependent manner (pIC₅₀ = 7.83). (B) Agonism of dopamine D₂ and D₃ receptors by bromocriptine produced a decrease in glucose-stimulated insulin secretion comparable to dopamine (pIC₅₀ = 6.87), suggesting that these receptors are important in mediating this effect in beta cells. Insulin secretion was measured via homogenous time-resolved fluorescence (HTRF) as described earlier (Farino et al., 2016). All experiments were performed in triplicate on n ≥ 3 separate experimental days. Data are represented as % maximal insulin secretion based on mean HTRF values ± SEM.