Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo.

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.

BACKGROUND: The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat. OBJECTIVE: We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition. DESIGN: Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW). RESULTS: Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass. CONCLUSION: The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at clinicaltrials.gov as NCT01967563.

Examination of central body fat deposition as a risk factor for loss-of-control eating.

BACKGROUND: Elevated body mass index (BMI), higher waist-to-hip ratio, and body dissatisfaction have been investigated as risk factors for the development of bulimic symptoms. Central fat deposition may be particularly relevant to eating disorders. To our knowledge, the longitudinal relations between fat distribution, body dissatisfaction, and loss-of-control (LOC) eating development and maintenance have not been studied. OBJECTIVE: We examined body fat distribution, independent of BMI and depressive symptoms, as a unique correlate and predictor of body dissatisfaction and LOC eating cross-sectionally and over a 2-y follow-up. DESIGN: Body composition was measured by using dual-energy X-ray absorptiometry in 294 adult women at risk of weight gain at baseline, 6 mo, and 24 mo. We assessed LOC eating, body dissatisfaction, and depressive symptoms at baseline, 6 wk, 6 mo, 12 mo, and 24 mo by using the Eating Disorder Diagnostic Interview, the Multidimensional Body-Self Relations Questionnaire-Appearance Scales Body Areas Satisfaction subscale, and the Center for Epidemiologic Studies-Depression Scale, respectively. RESULTS: Independent of BMI, baseline total percentage body fat, percentage trunk fat, and percentage abdominal fat were related to greater body dissatisfaction. Total percentage body fat and trunk fat tended to be associated with greater body dissatisfaction at all subsequent time points. Women with a greater percentage trunk fat, specifically abdominal fat, were at highest risk of developing LOC eating. In the full sample, women with higher baseline percentage trunk and abdominal fat showed increases in LOC eating episode frequency over time, whereas LOC eating frequency remained stable among women with smaller percentages of fat in trunk and abdominal regions. CONCLUSION: These findings lend further support to the premise that increased central body fat deposition is associated with body image dissatisfaction and suggest that it may represent a risk and maintenance factor for LOC eating. This trial was registered at clinicaltrials.gov as NCT00456131.

Dietary energy density and diet variety as predictors of outcome in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a serious psychiatric illness associated with significant morbidity and mortality. Successful treatment results in weight restoration, but recidivism is common, and the rate of relapse is estimated to be as high as 50%. Maintenance of a healthy diet is central to the recovery process, but the relation between diet and relapse has not been investigated in AN patients. OBJECTIVE: The objective of the study was to determine whether diet energy density and diet variety in recently weight-restored women with AN predict outcome. DESIGN: After gaining weight to a body mass index (BMI; in kg/m(2)) of > or = 20, 47 hospitalized women completed 4-d food records, from which a mean diet energy density score (DEDS) and a mean diet variety score (DVS) were calculated. Outcome was determined at study end by using modified Morgan-Russell criteria, and it was dichotomized as "treatment success" or "treatment failure." Data were analyzed by using Student's t test. A logistic regression model was constructed to evaluate the effects of DEDS, DVS, and caloric intake on outcome. RESULTS: Groups did not differ significantly in mean measures of age, admission and weight-restored BMI, or caloric intake. However, DEDS and DVS were significantly higher in the success group than in the failure group. The success and failure groups were followed for a mean of 240 and 170 d, respectively. In the logistic regression model, DEDS (P = 0.016) and DVS (P = 0.048) but not caloric intake (P = 0.585) significantly predicted outcome. CONCLUSION: In recently weight-restored women with AN, lower DEDS and DVS but not caloric intake were associated with poor outcome.