Inflammatory Cytokines and Antipsychotic-Induced Weight Gain: Review and Clinical Implications

Abstract

Antipsychotic medications (APs), particularly second-generation APs, are associated with significant weight gain in schizophrenia patients. Recent evidence suggests that the immune system may contribute to antipsychotic-induced weight gain (AIWG) via AP-mediated alterations of cytokine levels. Antipsychotics with a high propensity for weight gain, such as clozapine and olanzapine, influence the expression of immune genes, and induce changes in serum cytokine levels to ultimately down-regulate neuroinflammation. Since inflammatory cytokines are normally involved in anorexigenic responses, reduced inflammation has been independently shown to mediate changes in feeding behaviours and other metabolic parameters, resulting in obesity. Genetic variation in pro-inflammatory cytokines is also associated with both general obesity and weight change during AP treatment, and thus, may be implicated in the pharmacogenetics of AIWG. At this time, preliminary data support a cytokine-mediated model of AIWG which may have clinical utility in developing more effective metabolic monitoring guidelines and prevention measures. However, further research is still needed to clearly elucidate the validity of this immune model. This article reviews the evidence implicating inflammatory cytokines in AIWG and its potential clinical relevance.

Keywords: Antipsychotic-induced weight gain; Cytokines; Inflammation; Schizophrenia; Side effect.

Fig. 1

Weight change propensities of antipsychotic treatments. Antipsychotics are categorized according to a low, moderate, or high propensity to induce weight gain in patients. The varying propensities of antipsychotics to induce AIWG may depend on differences in their immunomodulatory profiles. Drugs are listed in the order from highest to lowest weight-inducing potential per category. Asterisk indicates SGA.

Fig. 2

Cytokine involvement in adiposity signalling. The adiposity signalling pathway of inflammatory cytokines is shown. Cytokines, which are elevated during fat accumulation, act within the hypothalamus to initiate anorexigenic pathways, to ultimately decrease food intake and increase energy expenditure. Once caloric restriction is achieved, cytokine levels are reduced. Antipsychotics may perturb adiposity signalling by reducing central cytokine levels, thereby blocking the illustrated pathway at the level of the hypothalamus, and shifting weight outcomes back toward fat accumulation.