Evidence-Based Reviews

Weight gain with antipsychotics: What role does leptin play?

Current Psychiatry. 2009 June;8(6):26-36

References

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Other metabolic parameters

In humans, elevated serum leptin levels are associated with adverse metabolic markers, particularly those associated with insulin activity (including insulin itself) and serum triglycerides.²⁴ Several antipsychotic studies measured metabolic outcomes along with serum leptin levels but did not specifically calculate correlation coefficients between leptin and other parameters.^{7,8,11,16,17,19}

Clinical Point

Elevated serum leptin levels are associated with adverse metabolic markers, including insulin activity and serum triglycerides

Nonetheless, in many instances leptin levels increased significantly without significant changes in serum insulin or other glycemic or lipid measures.^11,25 One cross-sectional study in bipolar subjects also found no correlation between any glucose or lipid parameter and leptin levels.²⁶ A few studies reported significant correlations among leptin and serum insulin,^13,27 glucose,¹⁵ and serum triglycerides,¹⁸ although most did not control for body mass index (BMI).

Diagnosis effects

As the association was established between antipsychotic-induced weight gain and changes in serum leptin, investigators sought to understand whether disease influences modified the drug effects.

Schizophrenia. One early cross-sectional analysis of 14 olanzapine-treated schizophrenia patients noted that 57% had elevated serum leptin when compared with normal levels adjusted for BMI and gender,²⁷ but the absence of a weight-matched control group limits interpretation of these findings.

To separate diagnosis and treatment effects, Arranz²⁸ performed a cross-sectional study of 50 drug-naïve schizophrenia patients, 50 drug-free schizophrenia patients, and 50 unmatched healthy controls. Leptin levels across all cohorts were positively correlated with age and BMI, and—as found in several other studies (Box 2)^{9,12,13,20,25,28-30}—women had higher levels than men in all 3 cohorts. The antipsychotic-free patients were older and heavier than the other 2 cohorts and had higher serum leptin levels, but neuroleptic-naïve schizophrenia subjects did not differ from controls. The absence of BMI matching between the drug-free patients and other cohorts limits the ability to make definitive statements about the treatment’s impact on leptin levels.

Other studies removed these limitations by matching schizophrenia patients with controls on the basis of gender, BMI, and—in some cases—age. These studies indicate conclusively that—when matched appropriately with nonpsychiatric subjects—patients with schizophrenia do not exhibit greater-than-expected serum leptin levels, regardless of antipsychotic drug exposure.^{7,11,12,19,26,28-31}

Other diagnoses. The only controlled comparative study of medication-treated bipolar patients vs matched controls also reported no significant difference in leptin levels.²⁶ Interestingly, a 6-month prospective study of risperidone in autistic children noted no increase in serum leptin despite a 5.6-kg mean weight gain.²¹

Lastly, a single 12-week prospective trial compared the effects of antipsychotics on levodopa psychosis in Parkinson’s disease subjects treated with olanzapine (n=10), risperidone (n=10), quetiapine (n=10), or solely with antiparkinsonian medications (n=10); an unmedicated, healthy cohort (n=8) served as controls.³² Only olanzapine was associated with significant weight gain, but BMI changes were positively correlated with changes in leptin levels across all cohorts.

Box 2

Do women have higher leptin levels than men?

Most—but not all—cross-sectional studies of patients receiving antipsychotic treatment have found higher serum leptin levels in women than men, even when men had greater body mass index (BMI).^13,28,29 In several prospective trials, this gender discrepancy gradually disappeared as men’s serum leptin increased.^12,30 Data from 1 long-term study of patients treated with clozapine indicate that leptin changes were independent of gender and proportional to weight gain,⁹ but other analyses that examined both weight and fat depots continued to find significant gender effects.²⁵ One notable exception was McIntyre’s 6-month randomized adjunctive study of risperidone vs olanzapine in symptomatic bipolar patients on mood stabilizers, in which women had greater increases in serum leptin with either antipsychotic.²⁰

Clinical implications

Driven by obesity’s public health impact, researchers have achieved a basic understanding of the regulation of appetite and body weight, including identifying genetic polymorphisms and other obesity risk markers. Evidence exploring the association between peptide metabolic regulatory hormones and antipsychotic-induced weight gain and metabolic dysfunction is accumulating.

Overall, evidence strongly suggests that leptin levels increase during long-term antipsychotic treatment and are highly correlated with weight and BMI changes. Although the increase in serum leptin often parallels substantial weight gain, these changes appear to be more the result of weight gain than a direct effect of the anti-psychotic on the leptin feedback pathway.²⁹ Virtually none of the papers we reviewed examined the association between leptin and glucose-insulin measures independent of the effect of weight changes.

Clinical Point

Evidence exploring a potential link between metabolic regulatory hormones and antipsychotic-induced weight gain is accumulating

Predicting weight gain? Because increased serum leptin is likely the result of weight gain in patients taking antipsychotics, measuring leptin for clinical prediction or monitoring of weight gain may not be very useful. Measuring weight or BMI will be more feasible in most clinical settings. However, leptin level changes may help us understand the potential mechanism of hormonal feedback and its physiologic effect in weight gain.