Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

Abstract

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5'AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP's higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.

Keywords: G protein-coupled receptors (GPCRs); atypical antipsychotics (AAPs); clozapine; dyslipidemia; metabolic syndrome (MetS); olanzapine; type 2 diabetes; weight gain.

Figure 1

The concept of spectrum of atypia was recently introduced to classify atypical antipsychotics (AAPs). They can be divided in three categories, where risperidone is least atypical (Level I) and clozapine is most atypical (Level III), while all others fall within these two extremes of the spectrum (Level II). The molecular targets shown on the right add up, beginning with the D2 and 5-HT2A,C receptors that are common targets for all AAPs, extending to additional mechanisms such as M1 positive allosterism and GlyT (glycine transporter) activity that seem specific to clozapine. Other targets, such as H1 and α2 receptors and BDNF, are relevant to both Level II and III of atypia [7].

Figure 2

The AAPs-induced metabolic syndrome (MetS) is the consequence of a broad activity of these drugs on the central nervous system (CNS) and peripheral organs. In the CNS, the most important target is the hypothalamus, while in the periphery, the liver, pancreatic β-cells, adipose tissue and skeletal muscle are implicated in AAPs-induced MetS. By interfering with the activity of different GPCRs expressed in these regions, AAPs significantly alter glucose and lipid homeostasis.