Some of the second-generation antipsychotics can be associated with weight gain and the development of metabolic syndrome and type 2 diabetes over time. Although the natural course of diabetes typically spans many years, with family history, diet, body weight, ethnicity, and other factors playing substantial roles in an individual patient’s risk, antipsychotic therapy can potentially accelerate the development of the metabolic syndrome. The bottom line is that if you gain weight and if you have pathologic adiposity, you will be at greater risk for insulin resistance, abnormal glucose levels will manifest themselves earlier, and you will experience elevations in triglycerides and in cholesterol, all of which contribute to coronary heart disease and the development of type 2 diabetes. Fortunately, there are now several second-generation antipsychotics that are more metabolically friendly, so one can consider initiating treatment with one of these agents as a first choice. 

Importantly, individual patient susceptibility to metabolic effects varies. Antipsychotic drugs with a propensity for metabolic effects can still be safely used, provided that the monitoring and follow-up are sufficient in that these effects will be recognized if they do occur. In some patients, the risk of weight gain can be mitigated by prescribing a medication such as metformin. Some clinicians may routinely take such an approach, while others may gravitate toward agents with less potential to cause weight gain and metabolic dysregulation. In patients with established cardiovascular disease, it is certainly reasonable to consider antipsychotics that are more metabolically friendly at the outset.

Endocrine considerations with antipsychotics also extend beyond metabolic syndrome, and prolactin elevation is highly relevant in the current treatment landscape. Risperidone and paliperidone are more likely than first-generation antipsychotics to promote prolactin elevation. Risks associated with these agents can be lessened to some degree by adding a low dose of a dopamine receptor partial agonist (eg, aripiprazole). Of note, lumateperone and clozapine have less of an effect on prolactin than most dopamine/serotonin antagonists because they have a lower affinity for postsynaptic dopamine D₂ receptors. Although not every patient will experience prolactin elevation with a medication that carries this risk, clinicians should carefully monitor their patients for prolactin-related adverse events such as amenorrhea, sexual dysfunction, gynecomastia, and galactorrhea.