The advent of atypical antipsychotics represented a significant improvement in the treatment of schizophrenia and other psychoses, with these newer drugs lacking most of the debilitating movement side effects of first generation compounds. Over the last decade it has become clear that these second generation drugs possessed other significant adverse effects with chronic treatment. The adverse effects are in the endocrine-metabolic and body weight categories. They include body weight gain, increased adiposity, insulin resistance, diabetes, and dyslipidemia 
. The close association of these metabolic sequelae with atypical antipsychotics, a popular and multi-billion dollar per year drug class, has led to efforts to further characterize the adverse events in order to discover new ways to screen or prevent the resulting obesity and diabetes, which have already reached epidemic proportions in the general population 
Understanding the mechanism of these side effects has been challenging. Most clinical studies seeking to elucidate these mechanisms have been conducted in patient samples after months to years of chronic treatment with antipsychotics. Mechanistic insights into the cause of the obesity and diabetes in such studies have to take into account the multiple potential sources of the effects including the direct actions of the drugs as well as the differential drug effects on weight gain, food intake, physical activity and other co-morbid conditions frequently associated with mental illness, e.g. 
, which may have genetic and/or lifestyle factors 
. In longer-term studies, it is more difficult to ascertain which effects are secondary to obesity and diabetes and which are primarily caused by the atypical antipsychotics. For example one finding from chronic studies has been that olanzapine decreases FFA despite its ability to also cause diabetes or insulin resistance 
. This is paradoxical because diabetes and insulin resistance are normally associated with elevated FFA not lower FFA. Despite these challenges, a considerable amount of basic and clinical research has focused on unraveling the molecular mechanisms of these adverse effects. Since the most severe diabetes and obesity in patients are observed with olanzapine and clozapine therapy, reviewed in refs: 
, these two compounds have, understandably, become the focus of much of the work in animal models.
Some of the chronic metabolic effects of these drugs, such as increased plasma glucose and decreased FFA, occur rapidly in animal models and thus imply that they could precede as opposed to follow the development of obesity. For example, several atypical antipsychotics, including olanzapine, have been shown to exhibit rather early and sustained metabolic and endocrine effects beginning within minutes to hours following drug administration 
. This time course could be important because if these effects occur early before confounding factors set in, it would improve the chances of understanding the underlying mechanism. A caveat is that recent data from animal studies have raised a number of questions about the relevance of animal models to the clinical problem. For example, in contrast to humans, drug-induced hyperphagia in response to olanzapine is sexually dimorphic in rat models, with female rats exhibiting robust increases in food intake and body weight gain in contrast to males which do not show this robust effect 
. In fact, clozapine fails to cause hyperphagia in either female or male rodents. Nevertheless, both drugs increase visceral adiposity, impair glucose tolerance, and decrease lean muscle mass in rodent models 
Clinical studies validating these acute effects are lacking, especially because of the challenge of isolating these effects in a schizophrenic population. However, such information would help us understand if animal models accurately reflect human physiology in this regard. If so, this would provide a reasonable rationale to support subsequent studies to determine the mechanisms of these effects and their relevance to the development of obesity and diabetes. This would effectively allow researchers to better define the acute metabolic effects in human subjects in hopes of validating animal studies, while at the same time focusing the direction of future laboratory efforts on biology that translates to the bedside. Therefore, we decided to examine whether some of the acute metabolic changes that have been observed in rodents treated with atypical antipsychotics also occurred in humans.
In the following report we demonstrate that acute (3 day) olanzapine administration in healthy volunteers is associated with changes in metabolic parameters, including impaired glucose tolerance, increased triglycerides, and decreased high-density lipoprotein cholesterol without changes in low-density lipoprotein or total cholesterol levels. Evidence suggests that drug-induced changes in plasma leptin concentration, whose potential decrease had been hypothesized to trigger hyperphagia in rats, may not be clinically relevant. Finally, olanzapine was associated with decreased circulating free fatty acids, a finding described in recent clinical and animal studies, which may give fresh insight to the mechanism of these metabolic side effects.