Clinical studies indicate that clozapine and olanzapine carry a high risk of treatment-related metabolic dysfunction—including weight gain, hyperlipidemia, and glucose intolerance—but certain patients with high metabolic liabilities who take atypical antipsychotics do not necessarily develop these adverse effects. Though the underlying mechanism for atypical antipsychotic-related weight gain is strongly associated with central histamine H1 antagonism and increased appetite, the pharmacologic basis for other metabolic changes is not fully understood and may involve weight-independent mechanisms.
One potentially relevant research area is peptide hormones’ impact on the regulation of food intake, body weight, and other metabolic parameters. As research has elucidated the properties of 1 of these hormones—leptin—investigators have started to examine possible correlations between changes in serum levels of leptin and weight gain during atypical anti-psychotic treatment.
This article summarizes available clinical data on the interaction of atypical antipsychotics with leptin and indicates directions for future research on interactions between psychotropic medications and metabolic hormones.
Leptin’s function
Since its initial sequencing as the product of the obese (ob) gene in 1994, leptin has garnered substantial attention as a metabolic regulatory hormone.1 Leptin is produced primarily by fat cells as part of a long-term central feedback mechanism involving central control of appetite and peripheral metabolic activity regulation. Leptin is a 167 amino acid, 16-kilodalton protein that binds to cell surface receptors (the product of the diabetes [db] gene) at both central (ventromedial hypothalamic) and peripheral sites (liver, skeletal muscle, and pancreatic β-cells).2
Evidence for leptin’s activity is seen in ob/ob mice, whose genetic inability to produce leptin is manifested phenotypically in overeating and obesity. Administering recombinant leptin to these mice results in reduced appetite and weight loss.3
On average, women have greater fat mass and higher serum leptin levels than men. Humans rarely have mutations in both copies of the ob gene, but those who do are severely obese and respond to exogenous leptin. Heterozygotes are not quite as heavy.
Leptin circulates in a free form but in humans is predominantly bound to the soluble leptin receptor (sOB-R). Levels of sOB-R increase with weight loss—with concomitant decreases in leptin levels—and these effects can be seen even during 72-hour fasts.4 Leptin levels are positively correlated with fat mass, but the fact that obese individuals have chronically elevated leptin levels argues for some level of leptin insensitivity or resistance to the hormone’s appetite-suppressing effects.2
Drug effects
Clozapine and olanzapine. Literature on leptin and antipsychotic-related obesity is relatively well developed. The first papers focused on the association between clozapine and olanzapine and increases in serum leptin levels.5,6 As patients gained substantial weight on clozapine and olanzapine, serum leptin also rose, but neither weight nor leptin changes were seen in patients exposed to haloperidol or those who did not receive antipsychotics.6
Numerous subsequent prospective trials of patients treated with olanzapine4,7,8 and clozapine9-11 confirmed previousl established associations among use of these medications, weight gain, and increased serum leptin levels. Olanzapine- and clozapine-exposed subjects experienced marked increases in adiposity, weight, and serum leptin (Box 1). 5,9,12-16
Other agents. For agents associated with less weight gain liability—such as high-potency typical antipsychotics,12,17,18 sulpiride,19 quetiapine,18 or risperidone20,21—comparative trials noted modest weight gain and leptin increases. Prospective trials of weight-modifying strategies using adjunctive amantadine8 or nizatidine22 found positive effects of the adjunctive medication, with proportional decreases in leptin levels compared with antipsychotics alone.
Because the other 2 atypical antipsychotics—ziprasidone and aripiprazole—were found to be weight-neutral or have the lowest weight-gain burden, few studies have examined the relationship between leptin with weight gain in patients taking these drugs. One study reported no significant body weight or leptin level change in patients after 4-week trial of ziprasidone.23
Leptin levels increase early in antipsychotic treatment
Most of the weight gain associated with olanzapine and clozapine therapy occurs over the first 6 months of treatment and then plateaus between months 6 and 12. Leptin changes, however, do not parallel weight changes during extended antipsychotic treatment.
A prospective 10-week clozapine trial by Bromel5 found that leptin levels peaked early in treatment—at week 2—followed by a subsequent decrease and then a steady rise, though not to the peak levels seen earlier. This pattern was replicated in Monteleone’s 32-week prospective clozapine study, again with the initial peak in serum leptin levels occurring at week 2.9
Despite these fluctuations, overall leptin levels during longer-term antipsychotic treatment are highly correlated with weight and body mass index changes. Cross-sectional studies with patients on various medications generally found that those exposed to olanzapine and clozapine were heavier and had higher serum leptin levels.12-14 Younger and thinner patients—regardless of medication—have lower serum leptin levels15 and the association between the medication and leptin levels disappears when adjustments are made for differences in body mass index (BMI).16 Once BMI is accounted for, antipsychotics appear to have no effects on leptin physiology independent of their effects on adiposity.