Antipsychotics, which are frequently used for psychotic and nonpsychotic conditions, are associated with substantially increased appetite and weight gain, as well as increased risk for obesity and metabolic abnormalities. Taken together, the available data suggest that cardiometabolic pathology and risk factors in mentally ill patients result from several interactive factors, including i) the patient’s genetic background; ii) the underlying illness; iii) unhealthy lifestyle behaviors; and iv) psychotropic medication effects.
Despite the importance of weight gain, obesity and metabolic abnormalities, the mechanisms underlying antipsychotic-related cardiometabolic adverse effect are still poorly characterized. This has interfered with the development of targeted and successful interventions for antipsychotic weight gain. In addition, because antipsychotics highly likely link to innate satiety, energy homeostasis and metabolic pathways, the lack of a detailed mechanistic understanding of antipsychotic-related cardiometabolic effects has also hampered a further unraveling of the mechanisms underlying the development and maintenance of idiopathic obesity. However, recent data support the view that antipsychotics affect key mechanisms that regulate appetite, satiety and energy homeostasis and involve hypothalamic serotonin 5HT2C
, histamine H1 and cannabinoid receptors, dopamine and alpha-adrenergic transmission, as well as central and/or peripheral orexigenic and anorexigenic hormones and peptides and/or their receptors. Nevertheless, despite this body of work, many basic questions remain unresolved and should be addressed in future studies (Box 1
Box 1. Outstanding questions
- What are the relative contributions of illness, environmental and treatment related effects for weight gain and obesity associated with antipsychotics?
- Can antipsychotic action be entirely separated from weight gain?
- What are the reliable pretreatment and early intratreatment predictors of clinically relevant, antipsychotic-related weight gain?
- What are the exact biological and environmental mechanisms of antipsychotic-related weight gain?
- Can understanding mechanisms of antipsychotic-related weight gain lead to the development of novel antiobesity drugs for idiopathic obesity in nonmentally ill populations?
- What are the most promising molecular and genetic targets for the development of preventive and ameliorative interventions for antipsychotic-induced weight gain?
- To what degree are direct effects of antipsychotics that do not require weight gain responsible for metabolic complications?
- What are the antipsychotic-related mechanisms that are uncoupled from weight gain that are responsible for glucose and lipid abnormalities?
- Can understanding the mechanisms responsible for antipsychotic-related metabolic abnormalities that are unrelated to weight gain lead to the development of novel antidiabetic and/or lipid-lowering drugs for nonmedication-induced diabetes or dyslipidemia?
However, notwithstanding these unresolved questions, the potential for significant antipsychotic-related cardiometabolic effects has been established [3
]; this risk differs across both FGAs and SGAs [3
], and patients as well as behavioral factors are relevant [3
]. Based on these findings, clinicians should: i) select antipsychotics with the least cardiometabolic liability whenever possible [3
]; ii) council patients about, strongly encourage and proactively monitor healthy diet and exercise behaviors [4
]; iii) monitor all patients treated with antipsychotics for the presence and emergence of cardiometabolic risk factors or disorders [3
]; iv) be vigilant about the possibility of metabolic abnormalities in the absence of relevant weight gain or obesity; v) consider behavioral and pharmacologic interventions to mitigate antipsychotic cardiometabolic effects [4
]; and vi) collaborate as part of an integrated care model with medical health care providers when cardiometabolic disorders emerge that require more complex medical interventions [3
Future research is needed that takes advantage of the enhanced power obtained by studying antipsychotic-naïve individuals for proximal/early cardiometabolic effects. Likewise, for the study of distal/late effects, such as diabetes and cardiovascular events, sample enrichment strategies for the outcome under investigation should be used . Although this strategy runs counter to the general procedures of excluding severely ill and metabolically compromised patients, focusing on such samples allows the focused and accelerated study of mechanisms of and risk factors for effects that take years to emerge. Furthermore, in addition to mechanistic proof of concept studies in highly selected samples, large pharmacoepidemiologic studies in generalizable samples are needed that have sufficient power to differentiate between different agents and to control for relevant confounding variables, such as prior treatment history, degree of weight gain, comedications, lifestyle, illness type and phase, comorbidities, cotreatments, etc.
Moreover, given the lack of conclusive evidence that current genetic candidates are actual susceptibility polymorphisms for antipsychotic-related cardiometabolic side effects, next generation, exploratory genomic approaches should be pursued. These hypothesis-generating studies will need to be followed by second-step hypothesis-testing of significant findings in enriched and in generalizable replication samples. Additionally, studies that go beyond the traditional weight gain approach need to be pursued. This includes the investigation of mechanisms involved in the reversal of antipsychotic-induced weight gain, focusing on peptide and hormonal changes as well as genetic factors affecting the variance in the observed weight loss after antipsychotic treatment discontinuation, after the switch to a lower risk medication, or after adding a weight loss intervention.
Finally, any novel leads from the study of antipsychotic-related cardiometabolic adverse effects should be translated into the field of idiopathic obesity research and vice versa. For example, medications tested in the idiopathic obesity field should prompt investigations of these agents in patients undergoing antipsychotic treatment [5
]. Testing such agents in patients with antipsychotic-related obesity as well as in those with idiopathic obesity followed in the same study could further elucidate shared and unique pathways involved in the maintenance or reductions of abnormally elevated body weight and lipid and glucose metabolism. Given the importance of obesity and cardiometabolic risk factors, in general, and given the prevalence of antipsychotic use, in particular, the current lack of any decisive knowledge about mechanisms and best preventive treatment options should prompt an increase in the study of this important side effect cluster.