Effects of second generation antipsychotics on leptin and ghrelin

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Abstract

Background

Weight gain is a major side effect of antipsychotic treatment. Some atypical antipsychotic agents have profound effects on weight. Body weight is regulated by a complex system, including both peripheral and central factors. Two of the hormones that seem to play an important role in the regulation of food intake, energy metabolism, and body weight are leptin and ghrelin. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. In this present study it is aimed to compare the effects of five different atypical antipsychotic medications on leptin and ghrelin.

Method

112 patients who were treated either with clozapine (n = 20), olanzapine (n = 28), risperidone (n = 22), quetiapine (n = 20) or amisulpride (n = 22) as monotherapy for at least one year and age, gender, and body mass index (BMI) matched control group (n = 23) were assessed cross-sectionally. Ghrelin and leptin levels were measured with enzyme-immunoassay.

Results

When fasting serum leptin levels were compared between groups, control group had the highest mean value (9.2 ± 6.7) and amisulpride group had the lowest mean value (3.7 ± 2.1) but still there was no statistically significant difference between six groups (F = 1993, p = 0.084).

In the comparison of the mean values of fasting serum ghrelin levels there was a statistically significant difference between groups (F = 11,473, p = 0.00). In post-hoc analysis it was seen that the control group had the lowest ghrelin level (194.5 ± 86.8). Quetiapine treated group (378.1 ± 260.4) had similar fasting serum ghrelin levels to control group. All the other antipsychotic treatment groups had significantly higher levels of fasting serum ghrelin compared to control group, highest in amisulpride treated group (597.0 ± 150.0).

Conclusion

The weight-gain side effect of atypical antipsychotics can be related with the orexigenic effect of elevated serum ghrelin rather than leptin deficit. Among the five widely used atypical antipsychotics quetiapine is the only one which does not elevate the ghrelin level.

Introduction

Weight gain is a major side effect of antipsychotic treatment which contributes to morbidity and poor treatment compliance. Several of the newer atypical antipsychotic agents have profound effects on weight, the greatest increases occurring with clozapine and olanzapine (Allison et al., 1999). Obesity has its inevitable consequences, which are increasingly observed in patients receiving antipsychotic drugs; such consequences may include the ‘metabolic syndrome’ of hypertension, cardiovascular disease, dyslipidaemia and impaired glucose tolerance, which may lead to type 2 diabetes (Henderson, 2002, Koponen et al., 2002).

Body weight is regulated by a complex system, including both peripheral and central factors. Two of the hormones that seem to play an important role in the regulation of food intake, energy metabolism, and body weight are leptin and ghrelin. Both originate in the periphery and signal through different pathways to the brain, particularly to the hypothalamus. In the hypothalamus, activation of the leptin or ghrelin receptor initiates different signalling cascades, such as JAK2-STAT3 and PI3K-PDE3B-cAMP pathways (Sahu, 2003, Klok et al., 2007).

Leptin is a protein which plays a major role in the regulation of appetite, adiposity and body weight. Leptin is primarily secreted by adipocytes with additional contributions from tissues including stomach, mammary epithelium, placenta and heart (Haupt et al., 2005, Klok et al., 2007). However, the majority of plasma leptin is secreted from adipose tissue, with plasma leptin strongly and positively correlated with total-body adiposity; serum and plasma leptin levels are higher in subjects with a higher body mass index (BMI) and a higher percent total total-body fat (Schwartz et al., 1996, Haupt et al., 2005). After leptin is released by the adipose tissue into the bloodstream, it crosses the blood–brain barrier and binds to the hypothalamic leptin receptors, in the arcuate nucleus, giving information about the status of the body energy stores (Schwartz et al., 1996, Sahu, 2003). Administration of leptin into the arcuate nucleus results in decreased food consumption while leptin deficiency leads to increased food intake (Haupt et al., 2005). Until several years ago, leptin had been thought only to play a significant role in long-term regulation of energy balance. More recent data indicate that leptin also seems to play a role in short-term regulation of food intake and body weight. Leptin is produced not only by adipose tissue, but also in small amount by the stomach (Sobhani et al., 2000). Therefore, it has been suggested that leptin might play a role in the control of meal size in cooperation with other satiety peptides (Pico et al., 2003).

Ghrelin, is a gastrointestinal peptide hormone that has been newly identified as an endogenous ligand for the growth hormone secretagogue receptor. Ghrelin peptide was originally isolated from the stomach, but ghrelin protein has also been identified in other peripheral tissues, such as the gastrointestinal tract, pancreas, ovary and adrenal cortex. In the brain, ghrelin-producing neurones have been identified in the pituitary, in the hypothalamic ARC, and in a group of neurones adjacent to the third ventricle between the dorsal, ventral, paraventricular and arcuate hypothalamic nuclei (Klok et al., 2007). In addition to its GH-releasing properties, ghrelin plays a role in regulating feeding behavior and energy metabolism in central nervous system; in humans ghrelin is the first hormone found to stimulate appetite and food intake (Togo et al., 2004). The concentration of circulating ghrelin is increased under conditions of negative energy balance such as starvation and anorexia nervosa while decreased under those of positive energy balance such as feeding and obesity in other words circulating ghrelin levels correlate inversely with BMI and body fat percentage (Murashita et al., 2005, Togo et al., 2004).

In rodents, central administration of ghrelin induces food intake via neuropeptide-Y (NYP) and agouti-related protein (AGRP). Ghrelin provides a peripheral signal to the hypothalamus to stimulate food intake and adiposity. Meanwhile, the adipocyte-derived circulating leptin signals the state of fat stores to the hypothalamus, inhibiting food intake and further accumulation of fat (Murashita et al., 2005). Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation (Klok et al., 2007).

It is possible that treatment with atypical antipsychotics leads to weight gain and alterations in carbohydrate and lipid metabolisms through increased appetite; leptin and ghrelin seems to play an important role in the regulation of food intake. In this present study it is aimed to compare the effects of five different atypical antipsychotic medications on leptin and ghrelin.

Section snippets

Patients

The study included patients who met the diagnostic criteria of schizophrenia or other psychotic disorders (n = 112) and healthy controls (n = 23) free from any mental or physical disorders.

Results

The whole group consisted of 135 subjects, 48.1% (n = 65) of them were male and 51.9% (n = 70) were female. There was no statistically significant difference between 6 groups in means of gender (Table 1). The mean age of the whole group was 34.3 ± 10.3. There was no statistically significant difference between 6 groups in means of age (Table 2).

There was no difference in the BMI levels among the patients treated with five different antipsychotics and control group (Table 2).

We found that fasting

Discussion

In this study the leptin and ghrelin levels of subjects treated with five different atypical antipsychotics for at least one year and healthy control groups were compared.

Conclusion

The results of our study do not support the previous hypotheses concerning impaired leptin secretion or leptin resistance in antipsychotic-treated schizophrenia patients compared to healthy controls.

But our results rather support the hypotheses that elevated fasting serum ghrelin levels can contribute to the increased food intake seen in antipsychotic-treated patients.

Among the atypical antipsychotics, quetiapine receiving patients have similar levels of ghrelin to age and BMI matched control

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