- Email: [email protected]
Olanzapine and risperidone effects on appetite and ghrelin in chronic schizophrenic patients
Psychiatry Research 199 (2012) 159–163
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Olanzapine and risperidone effects on appetite and ghrelin in chronic schizophrenic patients$ Robert C. Smith a,b,n,1, Saumya Rachakonda a,1, Saurabh Dwivedi c,I, John M. Davis d a
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA Department of Psychiatry, New York University Medical School, New York, NY, USA c School of Public Health, Downstate Medical Center, Brooklyn, N.Y., USA d Psychiatric Institute, University of Illinois College of Medicine, Chicago, IL, USA b
a r t i c l e i n f o
abstract
Article history: Received 28 March 2011 Received in revised form 13 December 2011 Accepted 7 March 2012
Olanzapine and other second generation antipsychotics have been associated with weight gain, which may be related to changes in appetite and food intake. However, it is unclear whether changes in appetite in response to treatment with second generation antipsychotics are persistent in patients treated chronically with these medications and the extent to which changes in appetite are related to any continuing weight gain associated with long-term treatment with these drugs. In a randomized 5-month study of the effects of olanzapine and risperidone on metabolic changes in chronic schizophrenic patients, we assessed appetite changes using two scales and correlated appetite changes with weight gain and metabolic changes. There is evidence that the hormone ghrelin is related to appetite stimulation and falls during satiation after meals, and therefore, may be a physiological concomitant indicating appetite changes. We therefore, also measured ghrelin before and after a fatty meal at baseline and after 2 months of drug treatment. Neither olanzapine nor risperidone increased appetite during the 5 months of study drug treatment, and there was a trend for a decrease in appetite over time. Weight only increased slightly during treatment and changes in appetite scores were not correlated with changes in weight or changes in glucose or lipids. Fasting ghrelin did not increase in olanzapine- or risperidone-treated patients, and there were no significant changes in ghrelin responses to a fatty meal between baseline and 2 months of drug treatment, and no differences in response in olanzapine- vs. risperidone-treated patients. Our findings suggest that in chronic schizophrenic patients treated with multiple antipsychotics in the past, olanzapine or risperidone do not induce increases in appetite and appetite changes are not related to any further small drug-induced weight gain in these chronically treated patients. However, it is possible that different relationships may exist between appetite and weight changes induced by the medications in drug naive patients newly started on olanzapine or risperidone. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Olanzapine Risperidone Appetite Weight gain Ghrelin
1. Introduction Many second generation antipsychotics are associated with an increase in weight, which may have secondary consequences resulting in metabolic disturbances and increases in diabetes and cardiovascular risk. Olanzapine and clozapine have been particularly associated with weight increase, although some studies also show considerable weight increase in patients treated with risperidone (Alvarez-Jimenez et al., 2008; Brixner et al.,
$
Clinical trials.gov registered study number NCT00287820. Correspondence to: Nathan Kline Institute Psychiatric Research, Rm 109E, Orangeburg, NY. 10962, USA. Tel.: þ 1 845 398 6531; þ1 516 569 1810; fax: þ 1 516 569 1755. E-mail addresses: [email protected], [email protected], [email protected] (R.C. Smith). 1 At the time this work was begun Dr. Smith, Dr. Dwevidi and Ms. Rachakonda were also with the Manhattan Psychiatric Center. n
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.03.011
2006). The physiological and pharmacological mechanisms associated with weight increase induced by antipsychotics have not been fully elucidated, although genetic and/or physiological changes in serotonergic, histaminic and leptin receptors or signaling have been implicated in some studies (Kim et al., 2007; Reynolds and Kirk, 2010), and one theoretical review presents evidence or multiple deficits in control of reward mechanisms associated with food intake in schizophrenia which may be exacerbated by pharmacological properties of some antipsychotics interacting with serotonergic, dopaminergic and opioid systems in the brain (Elman et al., 2006). Behaviorally, increases in appetite, hunger, and food consumption have been proposed as underlying the weight increase induced by olanzapine and other antipsychotics, but few studies have objectively measured the effects of antipsychotics on food consumption. Several cross-sectional studies have presented evidence indicating that patients treated with olanzapine or other second generation antipsychotics have greater sensitivity to food cues,
160
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
concentrate on internal food cues, or have higher scores on appetite and hunger scales than control groups or patients treated with first generation antipsychotics (Blouin et al., 2008; Sentissi et al., 2009; Treuer et al., 2009). A few studies have reported higher food consumption or caloric intake in in patients treated with antipsychotics but no difference in dietary composition (Gothelf et al., 2002; Strassnig et al., 2003). One study of clozapine-treated patients, however, reported an increase in total fat and saturated fat (Henderson et al., 2010) and another proposed a relative increase in the intake of saturated and polyunsaturated fats in schizophrenics patients compared with normative data in the U.S. population (Strassnig et al., 2005). However, the relationship of appetite changes to weight gain and metabolic changes with second generation antipsychotics is unclear, with studies showing variable relationships between appetite changes and weight gain in patients treated with olanzapine (Case et al., 2010). Ghrelin is a hormone secreted by the gut which also affects brain receptors, and this hormone appears to be strongly related to appetite in animals and man. Several studies suggest that higher ghrelin levels may be related to meal hunger stimulation in humans and a fall in ghrelin after eating may be related to satiation after feeding (Cummings et al., 2001; Hosoda et al., 2002; Wren et al., 2001). These effects of ghrelin may be mediated by its influence on receptors on hypothalamic neurons (Hosoda et al., 2002; Rosicka et al., 2002). Some studies have reported increases in ghrelin levels in patients treated with olanzapine and other second generation antipsychotics, but the results have not been uniform in different studies (Sentissi et al., 2008). However, these studies mostly utilized fasting ghrelin levels, and none tested the variability of response both at fasting and after meal ingestion. In the current experiment we assessed appetite response over 5 months of treatment with olanzapine or risperidone in chronic schizophrenic patients, and ghrelin response to a fatty meal at baseline and 2 months. We also serially assessed weight and glucose and lipid metabolic measures. On the basis of previous studies showing greater increase in weight and presumed increase in appetite in olanzapine-treated patients, we predicted that patients treated with olanzapine would show a greater increase in scores on appetite scales than patients treated with risperidone. We predicted that olanzapine-treated patients would have higher fasting baseline (pre-meal) ghrelin levels and that they would recover to baseline or even higher ghrelin levels by 4 h after meal ingestion to a greater extent than would be seen in patients treated with risperidone.
2. Method 2.1. Subjects and study design Details of subject selection, study design, randomization, drug treatment, cross-tapering, drop-outs and study flow, power analysis for primary outcome measures of the study, procedures for anthropomorphic measurements (bodymass index (BMI), waist circumference), and institutional review board approval), approval and subject consent are presented in detail elsewhere (Smith et al., 2009). In short, this was a study of 46 hospitalized chronic schizophrenic patients (45 male, 1 female) of middle age (mean age7 S.D., olanzapine patients 41.2 77.3 yr, risperidone patients 42.5 79.1 yr). All patients had been treated with multiple antipsychotics in the past, and were randomized to 5 months of treatment with either olanzapine (mean dose 25.2 mg/day, S.D. ¼10.1) or risperidone (mean dose 6.1 mg/day S.D. ¼1.8). Baseline characteristics of the patients randomized to olanzapine or risperidone are presented elsewhere (Smith et al., 2009, 2010; also see appendix Table1 for details). 2.2. Procedures 2.2.1. Metabolic Assessments and Chemical Assays Patients had glucose and lipid fasting metabolic assessments and weight assessments at baseline and during every month of treatment, and a fatty meal
test at baseline and 2 months of study drug treatment. Details of the glucose, lipid, and leptin assays and the procedures of the fatty meal test (FMT) are detailed in our previous publications from this study (Smith et al., 2009, 2010). The FMT was performed in the morning after a 9–12 h fast, at baseline and at the end of month 2 of study drug treatment. Patients ate a fatty meal (consisting of [1.2 g fat, 1.1 g carbohydrate, 0.2 g protein] BMI) for breakfast, and blood samples were drawn at baseline, 1 and 4 h post ingestion for the glucose, lipid and ghrelin measures. 2.2.2. Ghrelin Procedures and Assay In the FMT total serum ghrelin was collected and assayed at pre-meal baseline (0 h), and 1 and 4 h after ingestion of the fatty meal. Total serum ghrelin was assayed by Linco Research (now Millipore Biomarker) using Millipore Ghrelin RIA Kit with 125I-Ghrelin and Ghrelin antiserum. Intra-assay %CV is 10% and interassay %CV is 14.7%. Because of problems in shipment in one batch of ghrelin samples, data on only 30 subjects were available for ghrelin response at both baseline and 2 months of treatment (13 olanzapine, 17 risperidone) and 34 subjects (15 olanzapine, 19 risperidone) at 2 months of study drug treatment. 2.2.3. Appetite Assessment Appetite, hunger, and food craving was assessed at baseline and at months 1, 2, 3, and 5 of study drug treatment, using two scales, the Visual Analogue Scale (VAS) and the Eating Behavior Assessment (EBA), in interview assisted assessments. These are Lilly developed scales which have been described in detail in previous publications (Cavazzoni et al., 2003; Deberdt et al., 2005; Stauffer et al., 2009). The EBA is composed of nine items with each item rated from 0 (none) to 4 (extremely). The VAS has three items (hunger, interest in food, appetite) which were measured on a straight line demarked in ratings from 0 to 100 with score recorded in centimeters from the zero point. 2.3. Statistical analysis Details of statistical approach, preliminary examination of data, log transforms when appropriate, and statistical programs are described in detail in our previous report (Smith et al., 2009). In short, the primary analysis used to compare the metabolic effects of olanzapine vs. risperidone over time was a mixed model repeated measures analysis of variance (ANOVA) (SAS 8.2), with randomized drug and stay-switch (whether the randomized study drug was the same as what the patients were on at baseline or whether they were switched to the study drug) as fixed factors. For those variables which produced a significant effect of drug time, a Completer statistical analysis was also conducted using those subjects who had complete values over time for the specific appetite or weight variable. Relationships between appetite scales and weight or metabolic variables were assessed with Pearson or Spearman correlations with completer or LOCF (last observation carried forward) data.
3. Results 3.1. Effects of olanzapine and risperidone on appetite Neither olanzapine nor risperidone increased appetite over the 5 months of drug treatment (Fig. 1), nor was there any significant difference between the effects of the two drugs. There was a trend (P’s ¼0.07–0.10) for decrease in appetite scores over time. On the EBA scale olanzapine patients had consistently higher appetite scores both at baseline and during the study, and on the VAS scale olanzapine patients had higher scores at the month 2 assessment point, but not at months 3 or 5. Completer analysis showed generally similar results. Individual items on the scale, which some previous studies have identified with weight-increase effects of olanzapine y overeating), also did not show any increase over time or a difference between olanzapine and risperidone. 3.2. Relationship of appetite changes to weight gain and metabolic changes Although there was a slight increase in patients’ weight over the 5 months of the study (mean changes in weight ranged from 2–4 kg, Time effect from mixed model, F ¼3.51, d.f. ¼5, 206, P¼0.046), there was no difference in weight increase between patients treated with olanzapine or risperidone (Drug Time effect: F ¼1.53, d.f. ¼5, 206, P¼0.1813). However, olanzapine
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
patients analyzed separately showed a small but significant increase in weight at month 5 compared to baseline (mean change 7s.e.m¼ 4.1971.59 kg, t ¼2.63, d.f. ¼206, P ¼0.0091). Changes in VAS or EBA total or component scores were not
161
correlated with weight change in the whole group, but for olanzapine patients there was a small to moderate correlation between the increase in EBA scores at month 5 compared to baseline vs. change in weight (r ¼ þ0.46, n ¼23, P¼0.028) whereas risperidone patients showed a trend for a negative correlation (r ¼ 0.34, n ¼23, P¼0.118). However, a graphical plot showed that most of the positive correlation in the olanzapine patients was accounted for by the absence of any of weight increase in patients who had no increase, or even a decrease, in EBA appetite scores at 5 months compared to baseline, rather than an increase in weight for patients who had an increase in EBA scores. There were no significant correlations between change in appetite scores on either scale and change in metabolic parameters of fasting glucose, triglycerides, cholesterol or leptin. 3.3. Ghrelin response to fatty meal A fatty meal decreased serum ghrelin 1 h after ingestion and ghrelin levels largely recovered to pre-meal baseline by 4 h. However, there was no difference in ghrelin response to a fatty meal between patients treated with olanzapine vs. risperidone for 2 months (Table 1). Fasting ghrelin levels were also not increased in the olanzapine-treated group compared with the risperidone patients. There were no correlations between lipid changes and ghrelin changes in response to the fatty meal at 2 months compared to baseline. However, in patients treated with olanzapine for 2 months there was a positive correlation (r¼ þ0.57, n¼ 14, p¼0.03) between decrease in ghrelin and rise in glucose at 1 h after ingestion of a fatty meal, whereas in risperidone-treated patients there was no significant correlation (r ¼ 0.29, n ¼18, p¼ns) between these measures.
4. Discussion
Fig. 1. Effects of 5 months of treatment with olanzapine or risperidone on appetite measures. Each point represents mean 7 s.e.m. based on mixed model repeated measures analysis (MMA) (N¼ 46). Difference in least square means between olanzapine and risperidone at indicated time point: *Po 0.05. (a) Visual Analog Scale (Sum of hunger, interest in food, appetite), MMA Month (Time) Effect: F¼ 2.27, d.f. ¼5, 206, P ¼ 0.0768, Drug Time Effect: F ¼1.84, d.f.¼ 5, 206, P ¼0.1598 of (b) Eating Behavior Assessment Scale (sum of scores on 9 items). MMA Month (Time) Effect: F¼ 2.02, d.f.¼ 5, 206, P¼ 0.1088, Drug Time Effect: F ¼1.77, d.f. ¼5, 206, P ¼0.1522. Olanzapine scores showed a trend for a decrease in least square means from baseline to month 5 (T¼1.78, d.f. ¼206, P¼ 0.08).
Contrary to our hypotheses, the main findings of our study were that olanzapine did not increase appetite more than risperidone and there was a trend for decreased appetite during the 5 months of treatment. Baseline ghrelin did not rise during 2 months of treatment with olanzapine, and ghrelin response to a fatty meal did not significantly change for either olanzapine or risperidone patients from baseline to 2 months of treatment. Thus, both the self-report appetite measure and the correlative physiological measure, putatively related to appetite, were consistent in showing a lack of increase in hunger or appetite during treatment with olanzapine or risperidone. However, the significant correlation of glucose rise with ghrelin decrease at 1 h after meal ingestion, in subjects treated for 2 months with olanzapine, may suggest that the ghrelin system in olanzapine-treated patients may be more sensitive to satiation with glucose or elevated sugar-like compounds.
Table 1 Effects of olanzapine and risperidone on ghrelin response to fatty meal. Drug and month
Olanzapine (N ¼ 13) Baseline 2 Months Risperidone (N ¼17) Baseline 2 Months
Time after fatty meal
Mixed model repeated measures analyses
Pre-meal baseline (0)
1h
4h
562.6 7 50.5 573.7 7 47.8
556.5 7 43.8 524.6 7 36.9
586.5 745.0 585.7 749.7
Time: F ¼5.75, d.f.¼2, 27, F¼0.0083 Drug Month: F¼ 0.01, d.f. ¼1, 27, P ¼0.9407
568.1 7 46.1 570.4 743.7
527.8 7 40.0 506.6 7 33.5
548.3 741.0 553.07 45.5
Drug Month Time: F¼ 0.37, d.f.¼ 4, 27, P¼ 0.8254 Month Time: F ¼1.08, de ¼2, 27, P ¼0.3549
Mixed model repeated measures ANOVA, with drug (olanzapine vs. risperidone) and switch vs. stay as fixed factors, and month and time as repeated measures. N ¼ 30. Each number represents mean 7s.e.m of total ghrelin (pg/mL).
162
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
The fact that our sample consisted of chronic patients who had been treated for many years with both first and second generation antipsychotics may have been a factor attenuating our findings. The weight gain in our chronic patients was minimal and our previous studies (Smith et al., 2009, 2010) showed no change in fasting glucose or lipids over 5 months of treatment, although there was a differential response in glucose and lipids to challenge tests—glucose tolerance test (Smith et al., 2009) and fatty meal test (Smith et al., 2010). Younger patients or patients who have not previously been treated with second generation antipsychotics show more weight gain, and might have more changes in appetite related to weight gain. A study by Blouin and associates (Blouin et al., 2008) in a sample of mostly first episode patients treated with second generation antipsychotics did show higher susceptibility to hunger at baseline testing and higher hunger and lower satiation scores after a breakfast meal when compared to controls. However, previous studies of olanzapine, mostly performed in chronic patients, have shown a variable relationship between increases in appetite and weight gain on olanzapine, with some studies showing a positive relationship and others showing no significant relationships between changes in appetite and changes in weight (Case et al., 2010). Studies in rodents have generally shown some weight change or changes in feeding patterns in rodents subjected to chromic olanzapine administration, and some of these food consumption changes have been interpreted as indications of increases in appetite or changes in central regulation of the experience of satiation after feeding (Coccurello et al., 2008). Studies on the effects of antipsychotics, mostly second generation antipsychotics, on serum ghrelin in schizophrenic or psychotic patients have shown variable effects, with some studies showing increased ghrelin levels and others decreased levels or no change (Sentissi et al., 2008). The shorter term studies have generally shown decreased ghrelin levels while some longer term studies have shown increased ghrelin levels, but there are studies showing exceptions to both these trends. However, most of these studies only drew fasting ghrelin levels, and none used a provocative meal test. There are several other potential weaknesses of this study. First, we have no objective measures of food consumption in our study patients, and only subjective responses of perceived appetite. Some studies have shown that administration of olanzapine to animals leads to increases in food consumption or changes in eating patterns (Coccurello et al., 2008; Evers et al., 2010). One study in healthy men given oral olanzapine produced increased weight and increased food intake (Roerig et al., 2005), and one study in adolescent patients treated with olanzapine showed both increased caloric intake and increase in weight (Gothelf et al., 2002). Whether objective measurement of food consumption in chronic schizophrenic patients treated with these medications would show similar changes remains to be determined. Furthermore, administration of the same appetite scales, even on a oncea-month basis, may have produced decreased affective salience of the questions, and a regression of responses toward a mean lower level on repeated testing. Use of alternate forms of the appetite scales would help address this question. Although our eating behavior scales developed by Lilly researchers have been used in several studies of antipsychotic-induced weight gain and medications to treat them, they may not be as valid or standardized as some other appetite scales, such as the Three-Factor Eating Questionnaire or the Eating Behavior Inventory, which have more psychometric studies attesting to their validity and stability (Stauffer et al., 2009). Furthermore, in this study we measured total ghrelin rather than active (octanoylated) ghrelin and this part of the study had a smaller sample size. Active ghrelin may be more physiologically relevant for this hormone’s biological action and there are slightly more positive results in the literature in those studies measuring the effects of antipsychotics on active ghrelin; however, there is considerable heterogeneity of these
results, and some of the difference may depend on the radioimmunoassay kitused rather than the measurement of active ghrelin (Sentissi et al., 2008). In summary, the current study in chronically treated schizophrenic patients did not show that either olanzapine or risperidone produced a consistent increase in appetite, or a change in ghrelin response to a fatty meal. This suggests that changes in appetite and ghrelin may not be explanatory factors strongly related to any small additional weight gains in patients treated for many years with second generation antipsychotics who may have largely plateaued on the weight-gain effects of these medications. However, other studies we have cited suggest that there may be a stronger effect of second generation antipsychotics, such as olanzapine, on appetite, and a stronger relationship between changes in appetite and weight gain, in younger or neuroleptic naı¨ve patients treated with these medications.
5. Role of contributors Dr. Smith designed the study and wrote the protocol, analyzed the data, and wrote the draft of the paper and the final version submitted incorporating comments of coauthors. Dr. Davis reviewed the study design, addressed questions of additional biochemical determinations, assisted in statistical analysis, and reviewed and modified the draft of the manuscript. Dr. Dwivedi and Ms. Rachakonda helped perform statistical analyses and helped rewrite parts of the paper. All authors contributed to and have approved the final manuscript.
Conflict of interest Dr. Smith has received independent investigator grants and travel support from Eli Lilly. Dr. Smith is receiving drug supplies for a research study involving varenicline from Pfizer. Dr. Smith has received grants from the Stanley Foundation to study treatment of metabolic abnormalities in schizophrenia and received active and placebo drug supply for that study from Takeda Pharmaceuticals. The other authors report no additional financial or other relationships relevant to the subject of this article.
Acknowledgments This study was supported by an Independent Investigator Award to Dr. Smith from Eli Lilly Pharmaceuticals. Dr. Smith designed the study, and all study procedures, statistical analyses, and manuscript preparation were carried out independently by Dr. Smith and his coauthors. We wish to thank James Cornwell, Erin Kelly, Thomas F. Viviano, and Sumathi Vaidhyanathaswamy MD, for help with patient recruitment, protocol procedures and data processing.
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2012.03.011.
References Alvarez-Jimenez, M., Gonalez-Blanch, C., Crespo-Facorro, B., Hetrick, S., Rodriquez-Sanchez, M., Perez-Iglesias, R., Viaquez-Barquero, J., 2008. Antipsychotic-induced weight gain in chronic and first-episode psychotic disorders. CNS Drugs 22, 547–562.
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
Blouin, M., Tremblay, A., Jalbert, M.-E., Venables, H., Bouchard, R.-H., Roy, M.-A., Almras, N., 2008. Adiposity and eating behaviors in patients under second generation antipsychotics. Obesity 16, 1780–1787. Brixner, D., Said, O., Corey-Lisie, A., L’Italien, G., Stockdate, W., Wagner, T., Oderdiam, G., 2006. Naturalistic impact of second-generation antipsychotics on weight gain. Annals of Pharmacotherapy 40, 626–632. Case, M., Trejer, T., Karangianis, J., Poole, V., 2010. The potential role of appetite in predicting weight changes during treatment with olanzapine. BMC Psychiatry, 10. http://www/biomedcentral.com/1471-244X/10/72. Cavazzoni, P., Tanaka, Y., Roychowdhury, S., Breier, A., Allison, D., 2003. Nizatidine for prevention of weight gain with olanzapine: a double-blind placebocontrolled trial. European Neuropsychopharmacology 13, 81–85. Coccurello, R., D’Amato, F.R., Moles, A., 2008. Chronic administration of olanzapine affects behavioral satiety sequence and feeding behavior in female mice. Eating and Weight Disorders 13, e55–e60. Cummings, D., Purnell, J., Frayo, R.K.S., Wisse, B., Weile, D., 2001. A preprandial rise in plasma ghrelin levels suggest a role in meal initiation in humans. Diabetes 50, 1714–1719. Deberdt, W., Winokur, A., Cavazzoni, P., Trzaskoma, Q., Carlson, C., Bymaster, F., Wiener, K., Floris, M., Breier, A., 2005. Amantadine for weight gain associated with olanzapine treatment. European Neuropsychopharmacology 15, 13–21. Elman, I., Borsook, D., Lukas, S., 2006. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 31, 2091–2120. Evers, S., Calcagnoli, F., Van Dijk, C., Scheurink, A., 2010. Olanzapine causes hypothermia, inactivity, a deranged feeding pattern and weight gain in female Wistar rats. Pharmacology Biochemistry and Behavior 97 (1), 163–169. Gothelf, D., Falk, B., Singer, P., Kairi, M., Phillip, M., Zigel, L., Poraz, I., Frishman, S., Constantini, N., Zalsman, G., Weizman, A., Apter, A., 2002. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. The American Journal of Psychiatry 159, 1055–1057. Henderson, D., Sharma, B., Fan, X., Copeland, P., Borba, C., Freudenreich, O., Cather, C., Evins, A.E., Goff, D., 2010. Dietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone. Annals of Clinical Psychiatry 22, 33–42. Hosoda, H., Kojima, M., Kangawa, K., 2002. Ghrelin and the regulation of food intake and energy balance. Molecular Interventions 2, 494–503. Kim, S., Huang, A., Snowman, A., Tuescher, C., Snyder, S., 2007. Antipsychotic druginduced weight gain mediated by histamine H1 receptor-lined activation of hypothalamic AMP-kinase. Proceedings of the National Academy of Sciences of the United States of America 104, 3456–3459.
163
Reynolds, G., Kirk, S., 2010. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacology & Therapeutics 125, 169–179. Roerig, J., Mitchell, J., de Zwaan, M., Crosby, R., Gosnell, B., Steffen, K., Wonderlich, S., 2005. A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors. Journal of Clinical Psychopharmacology 25, 413–418. Rosicka, M., Krsek, M., Jarkovsk, Z., Marek, J., Schreiber, V., 2002. Ghrelin—a new endogenous growth hormone secretagogue. Physiological Research 51, 435–441. Sentissi, O., Epelbaum, J., Oli, J.-P., Poirier, M.-F., 2008. Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a review. Schizophrenia Bulletin 34, 1189–1199. Sentissi, O., Viala, A., Bourdel, M., Kaminski, F., Bellisle, F., Oli, J., Poirier, M., 2009. Impact of antipsychotic treatments on the motivation to eat: preliminary results in 153 schizophrenic patients. International Clinical Psychopharmacology 24, 257–264. Smith, R., Lindenmayer, J.-P., Hu, Q., Kelly, E., Viviano, T., Cornwell, J., Vaidhyanathaswamy, S., Marcovina, S., Davis, J., 2010. Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with longterm antipsychotic treatment: a randomized five month study. Schizophrenia Research 120, 204–209. Smith, R., Lindenmayer, J., Davis, J., Kelly, E., Viviano, T., Cornwell, J., Hu, Q., Khan, A., Vaidhyanathaswamy, S., 2009. Effects of olanzapine and risperidone on glucose metabolism and insulin sensitivity in chronic schizophrenic patients with longterm antipsychotic treatment: a randomized five month study. Journal of Clinical Psychiatry 70, 1501–1513. Stauffer, V.L., Lipovich, I., Hoffman, V.P., Heinloth, A., McGregor, H.S., Kinon, B.J., 2009. Predictors and correlates for weight changes in patients treated with olanzapine and weight mitigating agents: a post-hoc analysis. BMC Psychiatry 9. Strassnig, M., Brar, J., Ganguli, R., 2003. Nutritional assessment of patients with schizophrenia: a preliminary study. Schizophrenia Bulletin 29, 393–397. Strassnig, M., Singh Brar, J., Ganguli, R., 2005. Dietary fatty acid and antioxidant intake in community-dwelling patients suffering from schizophrenia. Schizophrenia Research 76, 343–351. Treuer, T., Hoffmann, V., Chen, A., Irimia, V., Ocampo, M., Wang, G., Singh, P., Holt, S., 2009. Factors associated with weight gain during olanzapine treatment in patients with schizophrenia or bipolar disorder: results from a six-month prospective, multinational, observational study. The World Journal of Biological Psychiatry 10, 729–740. Wren, A., Seal, L., Cohen, M., Brynes, A., Frost, G., Murphy, K., Dhillo, W., Ghatei, M., Bloom, S., 2001. Ghrelin enhances appetite and increases food intake in humans. Journal of Clinical Endocrinology and Metabolism 86, 5992–5995.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Olanzapine and risperidone effects on appetite and ghrelin in chronic schizophrenic patients$ Robert C. Smith a,b,n,1, Saumya Rachakonda a,1, Saurabh Dwivedi c,I, John M. Davis d a
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA Department of Psychiatry, New York University Medical School, New York, NY, USA c School of Public Health, Downstate Medical Center, Brooklyn, N.Y., USA d Psychiatric Institute, University of Illinois College of Medicine, Chicago, IL, USA b
a r t i c l e i n f o
abstract
Article history: Received 28 March 2011 Received in revised form 13 December 2011 Accepted 7 March 2012
Olanzapine and other second generation antipsychotics have been associated with weight gain, which may be related to changes in appetite and food intake. However, it is unclear whether changes in appetite in response to treatment with second generation antipsychotics are persistent in patients treated chronically with these medications and the extent to which changes in appetite are related to any continuing weight gain associated with long-term treatment with these drugs. In a randomized 5-month study of the effects of olanzapine and risperidone on metabolic changes in chronic schizophrenic patients, we assessed appetite changes using two scales and correlated appetite changes with weight gain and metabolic changes. There is evidence that the hormone ghrelin is related to appetite stimulation and falls during satiation after meals, and therefore, may be a physiological concomitant indicating appetite changes. We therefore, also measured ghrelin before and after a fatty meal at baseline and after 2 months of drug treatment. Neither olanzapine nor risperidone increased appetite during the 5 months of study drug treatment, and there was a trend for a decrease in appetite over time. Weight only increased slightly during treatment and changes in appetite scores were not correlated with changes in weight or changes in glucose or lipids. Fasting ghrelin did not increase in olanzapine- or risperidone-treated patients, and there were no significant changes in ghrelin responses to a fatty meal between baseline and 2 months of drug treatment, and no differences in response in olanzapine- vs. risperidone-treated patients. Our findings suggest that in chronic schizophrenic patients treated with multiple antipsychotics in the past, olanzapine or risperidone do not induce increases in appetite and appetite changes are not related to any further small drug-induced weight gain in these chronically treated patients. However, it is possible that different relationships may exist between appetite and weight changes induced by the medications in drug naive patients newly started on olanzapine or risperidone. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Olanzapine Risperidone Appetite Weight gain Ghrelin
1. Introduction Many second generation antipsychotics are associated with an increase in weight, which may have secondary consequences resulting in metabolic disturbances and increases in diabetes and cardiovascular risk. Olanzapine and clozapine have been particularly associated with weight increase, although some studies also show considerable weight increase in patients treated with risperidone (Alvarez-Jimenez et al., 2008; Brixner et al.,
$
Clinical trials.gov registered study number NCT00287820. Correspondence to: Nathan Kline Institute Psychiatric Research, Rm 109E, Orangeburg, NY. 10962, USA. Tel.: þ 1 845 398 6531; þ1 516 569 1810; fax: þ 1 516 569 1755. E-mail addresses: [email protected], [email protected], [email protected] (R.C. Smith). 1 At the time this work was begun Dr. Smith, Dr. Dwevidi and Ms. Rachakonda were also with the Manhattan Psychiatric Center. n
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.03.011
2006). The physiological and pharmacological mechanisms associated with weight increase induced by antipsychotics have not been fully elucidated, although genetic and/or physiological changes in serotonergic, histaminic and leptin receptors or signaling have been implicated in some studies (Kim et al., 2007; Reynolds and Kirk, 2010), and one theoretical review presents evidence or multiple deficits in control of reward mechanisms associated with food intake in schizophrenia which may be exacerbated by pharmacological properties of some antipsychotics interacting with serotonergic, dopaminergic and opioid systems in the brain (Elman et al., 2006). Behaviorally, increases in appetite, hunger, and food consumption have been proposed as underlying the weight increase induced by olanzapine and other antipsychotics, but few studies have objectively measured the effects of antipsychotics on food consumption. Several cross-sectional studies have presented evidence indicating that patients treated with olanzapine or other second generation antipsychotics have greater sensitivity to food cues,
160
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
concentrate on internal food cues, or have higher scores on appetite and hunger scales than control groups or patients treated with first generation antipsychotics (Blouin et al., 2008; Sentissi et al., 2009; Treuer et al., 2009). A few studies have reported higher food consumption or caloric intake in in patients treated with antipsychotics but no difference in dietary composition (Gothelf et al., 2002; Strassnig et al., 2003). One study of clozapine-treated patients, however, reported an increase in total fat and saturated fat (Henderson et al., 2010) and another proposed a relative increase in the intake of saturated and polyunsaturated fats in schizophrenics patients compared with normative data in the U.S. population (Strassnig et al., 2005). However, the relationship of appetite changes to weight gain and metabolic changes with second generation antipsychotics is unclear, with studies showing variable relationships between appetite changes and weight gain in patients treated with olanzapine (Case et al., 2010). Ghrelin is a hormone secreted by the gut which also affects brain receptors, and this hormone appears to be strongly related to appetite in animals and man. Several studies suggest that higher ghrelin levels may be related to meal hunger stimulation in humans and a fall in ghrelin after eating may be related to satiation after feeding (Cummings et al., 2001; Hosoda et al., 2002; Wren et al., 2001). These effects of ghrelin may be mediated by its influence on receptors on hypothalamic neurons (Hosoda et al., 2002; Rosicka et al., 2002). Some studies have reported increases in ghrelin levels in patients treated with olanzapine and other second generation antipsychotics, but the results have not been uniform in different studies (Sentissi et al., 2008). However, these studies mostly utilized fasting ghrelin levels, and none tested the variability of response both at fasting and after meal ingestion. In the current experiment we assessed appetite response over 5 months of treatment with olanzapine or risperidone in chronic schizophrenic patients, and ghrelin response to a fatty meal at baseline and 2 months. We also serially assessed weight and glucose and lipid metabolic measures. On the basis of previous studies showing greater increase in weight and presumed increase in appetite in olanzapine-treated patients, we predicted that patients treated with olanzapine would show a greater increase in scores on appetite scales than patients treated with risperidone. We predicted that olanzapine-treated patients would have higher fasting baseline (pre-meal) ghrelin levels and that they would recover to baseline or even higher ghrelin levels by 4 h after meal ingestion to a greater extent than would be seen in patients treated with risperidone.
2. Method 2.1. Subjects and study design Details of subject selection, study design, randomization, drug treatment, cross-tapering, drop-outs and study flow, power analysis for primary outcome measures of the study, procedures for anthropomorphic measurements (bodymass index (BMI), waist circumference), and institutional review board approval), approval and subject consent are presented in detail elsewhere (Smith et al., 2009). In short, this was a study of 46 hospitalized chronic schizophrenic patients (45 male, 1 female) of middle age (mean age7 S.D., olanzapine patients 41.2 77.3 yr, risperidone patients 42.5 79.1 yr). All patients had been treated with multiple antipsychotics in the past, and were randomized to 5 months of treatment with either olanzapine (mean dose 25.2 mg/day, S.D. ¼10.1) or risperidone (mean dose 6.1 mg/day S.D. ¼1.8). Baseline characteristics of the patients randomized to olanzapine or risperidone are presented elsewhere (Smith et al., 2009, 2010; also see appendix Table1 for details). 2.2. Procedures 2.2.1. Metabolic Assessments and Chemical Assays Patients had glucose and lipid fasting metabolic assessments and weight assessments at baseline and during every month of treatment, and a fatty meal
test at baseline and 2 months of study drug treatment. Details of the glucose, lipid, and leptin assays and the procedures of the fatty meal test (FMT) are detailed in our previous publications from this study (Smith et al., 2009, 2010). The FMT was performed in the morning after a 9–12 h fast, at baseline and at the end of month 2 of study drug treatment. Patients ate a fatty meal (consisting of [1.2 g fat, 1.1 g carbohydrate, 0.2 g protein] BMI) for breakfast, and blood samples were drawn at baseline, 1 and 4 h post ingestion for the glucose, lipid and ghrelin measures. 2.2.2. Ghrelin Procedures and Assay In the FMT total serum ghrelin was collected and assayed at pre-meal baseline (0 h), and 1 and 4 h after ingestion of the fatty meal. Total serum ghrelin was assayed by Linco Research (now Millipore Biomarker) using Millipore Ghrelin RIA Kit with 125I-Ghrelin and Ghrelin antiserum. Intra-assay %CV is 10% and interassay %CV is 14.7%. Because of problems in shipment in one batch of ghrelin samples, data on only 30 subjects were available for ghrelin response at both baseline and 2 months of treatment (13 olanzapine, 17 risperidone) and 34 subjects (15 olanzapine, 19 risperidone) at 2 months of study drug treatment. 2.2.3. Appetite Assessment Appetite, hunger, and food craving was assessed at baseline and at months 1, 2, 3, and 5 of study drug treatment, using two scales, the Visual Analogue Scale (VAS) and the Eating Behavior Assessment (EBA), in interview assisted assessments. These are Lilly developed scales which have been described in detail in previous publications (Cavazzoni et al., 2003; Deberdt et al., 2005; Stauffer et al., 2009). The EBA is composed of nine items with each item rated from 0 (none) to 4 (extremely). The VAS has three items (hunger, interest in food, appetite) which were measured on a straight line demarked in ratings from 0 to 100 with score recorded in centimeters from the zero point. 2.3. Statistical analysis Details of statistical approach, preliminary examination of data, log transforms when appropriate, and statistical programs are described in detail in our previous report (Smith et al., 2009). In short, the primary analysis used to compare the metabolic effects of olanzapine vs. risperidone over time was a mixed model repeated measures analysis of variance (ANOVA) (SAS 8.2), with randomized drug and stay-switch (whether the randomized study drug was the same as what the patients were on at baseline or whether they were switched to the study drug) as fixed factors. For those variables which produced a significant effect of drug time, a Completer statistical analysis was also conducted using those subjects who had complete values over time for the specific appetite or weight variable. Relationships between appetite scales and weight or metabolic variables were assessed with Pearson or Spearman correlations with completer or LOCF (last observation carried forward) data.
3. Results 3.1. Effects of olanzapine and risperidone on appetite Neither olanzapine nor risperidone increased appetite over the 5 months of drug treatment (Fig. 1), nor was there any significant difference between the effects of the two drugs. There was a trend (P’s ¼0.07–0.10) for decrease in appetite scores over time. On the EBA scale olanzapine patients had consistently higher appetite scores both at baseline and during the study, and on the VAS scale olanzapine patients had higher scores at the month 2 assessment point, but not at months 3 or 5. Completer analysis showed generally similar results. Individual items on the scale, which some previous studies have identified with weight-increase effects of olanzapine y overeating), also did not show any increase over time or a difference between olanzapine and risperidone. 3.2. Relationship of appetite changes to weight gain and metabolic changes Although there was a slight increase in patients’ weight over the 5 months of the study (mean changes in weight ranged from 2–4 kg, Time effect from mixed model, F ¼3.51, d.f. ¼5, 206, P¼0.046), there was no difference in weight increase between patients treated with olanzapine or risperidone (Drug Time effect: F ¼1.53, d.f. ¼5, 206, P¼0.1813). However, olanzapine
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
patients analyzed separately showed a small but significant increase in weight at month 5 compared to baseline (mean change 7s.e.m¼ 4.1971.59 kg, t ¼2.63, d.f. ¼206, P ¼0.0091). Changes in VAS or EBA total or component scores were not
161
correlated with weight change in the whole group, but for olanzapine patients there was a small to moderate correlation between the increase in EBA scores at month 5 compared to baseline vs. change in weight (r ¼ þ0.46, n ¼23, P¼0.028) whereas risperidone patients showed a trend for a negative correlation (r ¼ 0.34, n ¼23, P¼0.118). However, a graphical plot showed that most of the positive correlation in the olanzapine patients was accounted for by the absence of any of weight increase in patients who had no increase, or even a decrease, in EBA appetite scores at 5 months compared to baseline, rather than an increase in weight for patients who had an increase in EBA scores. There were no significant correlations between change in appetite scores on either scale and change in metabolic parameters of fasting glucose, triglycerides, cholesterol or leptin. 3.3. Ghrelin response to fatty meal A fatty meal decreased serum ghrelin 1 h after ingestion and ghrelin levels largely recovered to pre-meal baseline by 4 h. However, there was no difference in ghrelin response to a fatty meal between patients treated with olanzapine vs. risperidone for 2 months (Table 1). Fasting ghrelin levels were also not increased in the olanzapine-treated group compared with the risperidone patients. There were no correlations between lipid changes and ghrelin changes in response to the fatty meal at 2 months compared to baseline. However, in patients treated with olanzapine for 2 months there was a positive correlation (r¼ þ0.57, n¼ 14, p¼0.03) between decrease in ghrelin and rise in glucose at 1 h after ingestion of a fatty meal, whereas in risperidone-treated patients there was no significant correlation (r ¼ 0.29, n ¼18, p¼ns) between these measures.
4. Discussion
Fig. 1. Effects of 5 months of treatment with olanzapine or risperidone on appetite measures. Each point represents mean 7 s.e.m. based on mixed model repeated measures analysis (MMA) (N¼ 46). Difference in least square means between olanzapine and risperidone at indicated time point: *Po 0.05. (a) Visual Analog Scale (Sum of hunger, interest in food, appetite), MMA Month (Time) Effect: F¼ 2.27, d.f. ¼5, 206, P ¼ 0.0768, Drug Time Effect: F ¼1.84, d.f.¼ 5, 206, P ¼0.1598 of (b) Eating Behavior Assessment Scale (sum of scores on 9 items). MMA Month (Time) Effect: F¼ 2.02, d.f.¼ 5, 206, P¼ 0.1088, Drug Time Effect: F ¼1.77, d.f. ¼5, 206, P ¼0.1522. Olanzapine scores showed a trend for a decrease in least square means from baseline to month 5 (T¼1.78, d.f. ¼206, P¼ 0.08).
Contrary to our hypotheses, the main findings of our study were that olanzapine did not increase appetite more than risperidone and there was a trend for decreased appetite during the 5 months of treatment. Baseline ghrelin did not rise during 2 months of treatment with olanzapine, and ghrelin response to a fatty meal did not significantly change for either olanzapine or risperidone patients from baseline to 2 months of treatment. Thus, both the self-report appetite measure and the correlative physiological measure, putatively related to appetite, were consistent in showing a lack of increase in hunger or appetite during treatment with olanzapine or risperidone. However, the significant correlation of glucose rise with ghrelin decrease at 1 h after meal ingestion, in subjects treated for 2 months with olanzapine, may suggest that the ghrelin system in olanzapine-treated patients may be more sensitive to satiation with glucose or elevated sugar-like compounds.
Table 1 Effects of olanzapine and risperidone on ghrelin response to fatty meal. Drug and month
Olanzapine (N ¼ 13) Baseline 2 Months Risperidone (N ¼17) Baseline 2 Months
Time after fatty meal
Mixed model repeated measures analyses
Pre-meal baseline (0)
1h
4h
562.6 7 50.5 573.7 7 47.8
556.5 7 43.8 524.6 7 36.9
586.5 745.0 585.7 749.7
Time: F ¼5.75, d.f.¼2, 27, F¼0.0083 Drug Month: F¼ 0.01, d.f. ¼1, 27, P ¼0.9407
568.1 7 46.1 570.4 743.7
527.8 7 40.0 506.6 7 33.5
548.3 741.0 553.07 45.5
Drug Month Time: F¼ 0.37, d.f.¼ 4, 27, P¼ 0.8254 Month Time: F ¼1.08, de ¼2, 27, P ¼0.3549
Mixed model repeated measures ANOVA, with drug (olanzapine vs. risperidone) and switch vs. stay as fixed factors, and month and time as repeated measures. N ¼ 30. Each number represents mean 7s.e.m of total ghrelin (pg/mL).
162
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
The fact that our sample consisted of chronic patients who had been treated for many years with both first and second generation antipsychotics may have been a factor attenuating our findings. The weight gain in our chronic patients was minimal and our previous studies (Smith et al., 2009, 2010) showed no change in fasting glucose or lipids over 5 months of treatment, although there was a differential response in glucose and lipids to challenge tests—glucose tolerance test (Smith et al., 2009) and fatty meal test (Smith et al., 2010). Younger patients or patients who have not previously been treated with second generation antipsychotics show more weight gain, and might have more changes in appetite related to weight gain. A study by Blouin and associates (Blouin et al., 2008) in a sample of mostly first episode patients treated with second generation antipsychotics did show higher susceptibility to hunger at baseline testing and higher hunger and lower satiation scores after a breakfast meal when compared to controls. However, previous studies of olanzapine, mostly performed in chronic patients, have shown a variable relationship between increases in appetite and weight gain on olanzapine, with some studies showing a positive relationship and others showing no significant relationships between changes in appetite and changes in weight (Case et al., 2010). Studies in rodents have generally shown some weight change or changes in feeding patterns in rodents subjected to chromic olanzapine administration, and some of these food consumption changes have been interpreted as indications of increases in appetite or changes in central regulation of the experience of satiation after feeding (Coccurello et al., 2008). Studies on the effects of antipsychotics, mostly second generation antipsychotics, on serum ghrelin in schizophrenic or psychotic patients have shown variable effects, with some studies showing increased ghrelin levels and others decreased levels or no change (Sentissi et al., 2008). The shorter term studies have generally shown decreased ghrelin levels while some longer term studies have shown increased ghrelin levels, but there are studies showing exceptions to both these trends. However, most of these studies only drew fasting ghrelin levels, and none used a provocative meal test. There are several other potential weaknesses of this study. First, we have no objective measures of food consumption in our study patients, and only subjective responses of perceived appetite. Some studies have shown that administration of olanzapine to animals leads to increases in food consumption or changes in eating patterns (Coccurello et al., 2008; Evers et al., 2010). One study in healthy men given oral olanzapine produced increased weight and increased food intake (Roerig et al., 2005), and one study in adolescent patients treated with olanzapine showed both increased caloric intake and increase in weight (Gothelf et al., 2002). Whether objective measurement of food consumption in chronic schizophrenic patients treated with these medications would show similar changes remains to be determined. Furthermore, administration of the same appetite scales, even on a oncea-month basis, may have produced decreased affective salience of the questions, and a regression of responses toward a mean lower level on repeated testing. Use of alternate forms of the appetite scales would help address this question. Although our eating behavior scales developed by Lilly researchers have been used in several studies of antipsychotic-induced weight gain and medications to treat them, they may not be as valid or standardized as some other appetite scales, such as the Three-Factor Eating Questionnaire or the Eating Behavior Inventory, which have more psychometric studies attesting to their validity and stability (Stauffer et al., 2009). Furthermore, in this study we measured total ghrelin rather than active (octanoylated) ghrelin and this part of the study had a smaller sample size. Active ghrelin may be more physiologically relevant for this hormone’s biological action and there are slightly more positive results in the literature in those studies measuring the effects of antipsychotics on active ghrelin; however, there is considerable heterogeneity of these
results, and some of the difference may depend on the radioimmunoassay kitused rather than the measurement of active ghrelin (Sentissi et al., 2008). In summary, the current study in chronically treated schizophrenic patients did not show that either olanzapine or risperidone produced a consistent increase in appetite, or a change in ghrelin response to a fatty meal. This suggests that changes in appetite and ghrelin may not be explanatory factors strongly related to any small additional weight gains in patients treated for many years with second generation antipsychotics who may have largely plateaued on the weight-gain effects of these medications. However, other studies we have cited suggest that there may be a stronger effect of second generation antipsychotics, such as olanzapine, on appetite, and a stronger relationship between changes in appetite and weight gain, in younger or neuroleptic naı¨ve patients treated with these medications.
5. Role of contributors Dr. Smith designed the study and wrote the protocol, analyzed the data, and wrote the draft of the paper and the final version submitted incorporating comments of coauthors. Dr. Davis reviewed the study design, addressed questions of additional biochemical determinations, assisted in statistical analysis, and reviewed and modified the draft of the manuscript. Dr. Dwivedi and Ms. Rachakonda helped perform statistical analyses and helped rewrite parts of the paper. All authors contributed to and have approved the final manuscript.
Conflict of interest Dr. Smith has received independent investigator grants and travel support from Eli Lilly. Dr. Smith is receiving drug supplies for a research study involving varenicline from Pfizer. Dr. Smith has received grants from the Stanley Foundation to study treatment of metabolic abnormalities in schizophrenia and received active and placebo drug supply for that study from Takeda Pharmaceuticals. The other authors report no additional financial or other relationships relevant to the subject of this article.
Acknowledgments This study was supported by an Independent Investigator Award to Dr. Smith from Eli Lilly Pharmaceuticals. Dr. Smith designed the study, and all study procedures, statistical analyses, and manuscript preparation were carried out independently by Dr. Smith and his coauthors. We wish to thank James Cornwell, Erin Kelly, Thomas F. Viviano, and Sumathi Vaidhyanathaswamy MD, for help with patient recruitment, protocol procedures and data processing.
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2012.03.011.
References Alvarez-Jimenez, M., Gonalez-Blanch, C., Crespo-Facorro, B., Hetrick, S., Rodriquez-Sanchez, M., Perez-Iglesias, R., Viaquez-Barquero, J., 2008. Antipsychotic-induced weight gain in chronic and first-episode psychotic disorders. CNS Drugs 22, 547–562.
R.C. Smith et al. / Psychiatry Research 199 (2012) 159–163
Blouin, M., Tremblay, A., Jalbert, M.-E., Venables, H., Bouchard, R.-H., Roy, M.-A., Almras, N., 2008. Adiposity and eating behaviors in patients under second generation antipsychotics. Obesity 16, 1780–1787. Brixner, D., Said, O., Corey-Lisie, A., L’Italien, G., Stockdate, W., Wagner, T., Oderdiam, G., 2006. Naturalistic impact of second-generation antipsychotics on weight gain. Annals of Pharmacotherapy 40, 626–632. Case, M., Trejer, T., Karangianis, J., Poole, V., 2010. The potential role of appetite in predicting weight changes during treatment with olanzapine. BMC Psychiatry, 10. http://www/biomedcentral.com/1471-244X/10/72. Cavazzoni, P., Tanaka, Y., Roychowdhury, S., Breier, A., Allison, D., 2003. Nizatidine for prevention of weight gain with olanzapine: a double-blind placebocontrolled trial. European Neuropsychopharmacology 13, 81–85. Coccurello, R., D’Amato, F.R., Moles, A., 2008. Chronic administration of olanzapine affects behavioral satiety sequence and feeding behavior in female mice. Eating and Weight Disorders 13, e55–e60. Cummings, D., Purnell, J., Frayo, R.K.S., Wisse, B., Weile, D., 2001. A preprandial rise in plasma ghrelin levels suggest a role in meal initiation in humans. Diabetes 50, 1714–1719. Deberdt, W., Winokur, A., Cavazzoni, P., Trzaskoma, Q., Carlson, C., Bymaster, F., Wiener, K., Floris, M., Breier, A., 2005. Amantadine for weight gain associated with olanzapine treatment. European Neuropsychopharmacology 15, 13–21. Elman, I., Borsook, D., Lukas, S., 2006. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 31, 2091–2120. Evers, S., Calcagnoli, F., Van Dijk, C., Scheurink, A., 2010. Olanzapine causes hypothermia, inactivity, a deranged feeding pattern and weight gain in female Wistar rats. Pharmacology Biochemistry and Behavior 97 (1), 163–169. Gothelf, D., Falk, B., Singer, P., Kairi, M., Phillip, M., Zigel, L., Poraz, I., Frishman, S., Constantini, N., Zalsman, G., Weizman, A., Apter, A., 2002. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. The American Journal of Psychiatry 159, 1055–1057. Henderson, D., Sharma, B., Fan, X., Copeland, P., Borba, C., Freudenreich, O., Cather, C., Evins, A.E., Goff, D., 2010. Dietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone. Annals of Clinical Psychiatry 22, 33–42. Hosoda, H., Kojima, M., Kangawa, K., 2002. Ghrelin and the regulation of food intake and energy balance. Molecular Interventions 2, 494–503. Kim, S., Huang, A., Snowman, A., Tuescher, C., Snyder, S., 2007. Antipsychotic druginduced weight gain mediated by histamine H1 receptor-lined activation of hypothalamic AMP-kinase. Proceedings of the National Academy of Sciences of the United States of America 104, 3456–3459.
163
Reynolds, G., Kirk, S., 2010. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacology & Therapeutics 125, 169–179. Roerig, J., Mitchell, J., de Zwaan, M., Crosby, R., Gosnell, B., Steffen, K., Wonderlich, S., 2005. A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors. Journal of Clinical Psychopharmacology 25, 413–418. Rosicka, M., Krsek, M., Jarkovsk, Z., Marek, J., Schreiber, V., 2002. Ghrelin—a new endogenous growth hormone secretagogue. Physiological Research 51, 435–441. Sentissi, O., Epelbaum, J., Oli, J.-P., Poirier, M.-F., 2008. Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a review. Schizophrenia Bulletin 34, 1189–1199. Sentissi, O., Viala, A., Bourdel, M., Kaminski, F., Bellisle, F., Oli, J., Poirier, M., 2009. Impact of antipsychotic treatments on the motivation to eat: preliminary results in 153 schizophrenic patients. International Clinical Psychopharmacology 24, 257–264. Smith, R., Lindenmayer, J.-P., Hu, Q., Kelly, E., Viviano, T., Cornwell, J., Vaidhyanathaswamy, S., Marcovina, S., Davis, J., 2010. Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with longterm antipsychotic treatment: a randomized five month study. Schizophrenia Research 120, 204–209. Smith, R., Lindenmayer, J., Davis, J., Kelly, E., Viviano, T., Cornwell, J., Hu, Q., Khan, A., Vaidhyanathaswamy, S., 2009. Effects of olanzapine and risperidone on glucose metabolism and insulin sensitivity in chronic schizophrenic patients with longterm antipsychotic treatment: a randomized five month study. Journal of Clinical Psychiatry 70, 1501–1513. Stauffer, V.L., Lipovich, I., Hoffman, V.P., Heinloth, A., McGregor, H.S., Kinon, B.J., 2009. Predictors and correlates for weight changes in patients treated with olanzapine and weight mitigating agents: a post-hoc analysis. BMC Psychiatry 9. Strassnig, M., Brar, J., Ganguli, R., 2003. Nutritional assessment of patients with schizophrenia: a preliminary study. Schizophrenia Bulletin 29, 393–397. Strassnig, M., Singh Brar, J., Ganguli, R., 2005. Dietary fatty acid and antioxidant intake in community-dwelling patients suffering from schizophrenia. Schizophrenia Research 76, 343–351. Treuer, T., Hoffmann, V., Chen, A., Irimia, V., Ocampo, M., Wang, G., Singh, P., Holt, S., 2009. Factors associated with weight gain during olanzapine treatment in patients with schizophrenia or bipolar disorder: results from a six-month prospective, multinational, observational study. The World Journal of Biological Psychiatry 10, 729–740. Wren, A., Seal, L., Cohen, M., Brynes, A., Frost, G., Murphy, K., Dhillo, W., Ghatei, M., Bloom, S., 2001. Ghrelin enhances appetite and increases food intake in humans. Journal of Clinical Endocrinology and Metabolism 86, 5992–5995.