The use of second generation antipsychotics (SGAs) for the treatment of psychiatric illnesses in children and adolescents is increasing. Adverse effects of SGAs include weight gain, dyslipidemia, insulin resistance, and glucose intolerance that can subsequently progress to diabetes. In an already at-risk population, SGA-related metabolic effects further increase the risk for cardiovascular disease. Literature also shows that these effects adversely impact adherence, quality of life, and emotional status.

Data suggest that the metabolic effects of SGAs may be more severe in children and adolescents than in adults.¹ The number of pediatric patients at risk for adverse health outcomes related to metabolic and hormonal effects of SGAs has been shown to increase by more than twofold after six months of SGA therapy.² A retrospective study reported that 53% of children and adolescents with prior exposure to SGAs were overweight and that 16% were at risk for becoming overweight. In addition, triglycerides were elevated in 51% of these patients and 48% had decreased high density lipoproteins.³ Independent of adverse medication effects, patients with neuropsychiatric disorders are more likely to have impaired glucose regulation and type 2 diabetes as compared to the general population.⁴ The risk of glucose intolerance is augmented by SGA treatment.

Recommendations for treatment of individuals at risk for metabolic syndrome include lifestyle changes and/or switching to an SGA with lesser risk of weight gain.⁵ However, studies report lifestyle changes in patients with neuropsychiatric disorders are often unachievable⁶ and switching SGAs may worsen clinical symptoms. Moreover, switching SGAs may not positively influence weight change.⁷

The relative risks for weight gain among SGAs are summarized in Table 1. While clozapine is not a first-line treatment option, olanzapine may be considered as an initial treatment for pediatric patients with bipolar disorder or schizophrenia. However, olanzapine prescribing information specifically cautions, "Compared to patients from adult clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin, and hepatic transaminase level. The increased potential (in adolescents compared with adults) for weight gain and hyperlipidemia may lead clinicians to consider prescribing other drugs first in adolescents."¹² The newest SGAs — asenapine, iloperidone, and lurasidone — have not been included in recent studies.

Table 1: Relative risk for weight gain among second generation antipsychotics^8–10

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The mechanism of SGA-related weight gain is not fully understood and almost certainly due to a combination of factors. The anti-diabetic drug, metformin, has been reported to reduce the magnitude of weight gain associated with SGA therapy. Twelve trials and seven meta-analyses examined weight gain and glucose dysregulation in patients treated with metformin and SGAs.¹³ These reports provide evidence that metformin is effective, presumably from effects on insulin sensitivity. An additional study reported metformin is safe and effective in preventing SGA-related weight gain, decreased insulin sensitivity, and abnormal glucose metabolism in adolescents.¹⁴ Data from the Diabetes Prevention Program also support that, along with lifestyle changes, metformin decreases weight and prevents progression from impaired glucose tolerance to diabetes in SGA-treated patients. A recent meta-analysis reported that metformin yielded greater weight loss compared with other agents, and in SGA-treated individuals who experienced weight gain, weight loss from metformin was significant.⁹ Metformin improves blood glucose control, increases insulin sensitivity, and reduces waist circumference in addition to weight loss. Metformin use in younger or first episode patients resulted in three times greater weight loss than in older, more chronic patients.¹⁵

Adult^16–18 and pediatric¹⁹ studies suggest safety is not monitored consistently despite a 2003 FDA-mandated warning for diabetes risk and 2004 consensus statement recommendation for metabolic monitoring.⁵ Nevertheless, more aggressive monitoring has been proposed.⁸ A vital first step to minimize risk and long-term adverse outcomes from SGA treatment is to implement consistent metabolic monitoring. As new data become available, practitioners may recognize risk factors for weight gain and identify candidates most likely to benefit from early metformin treatment and/or other interventions to mitigate SGA-related metabolic complications.