August 2011  << Back  

  Can't open the PDF? Click here for help.



Effects of orally disintegrating vs regular olanzapine tablets on body weight, eating behavior, glycemic and lipid indices, and gastrointestinal hormones: A randomized, open comparison in outpatients with bipolar depression

William V. Bobo, MD

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

Richard  A. Epstein, Jr, PhD

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

Richard C. Shelton, MD

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

BACKGROUND: This randomized, open-label trial aimed to compare the metabolic effects of olanzapine orally disintegrating tablets (ODT) and solid oral tablets (SOT) in bipolar depressed and mixed outpatients.

METHODS: Participants were openly randomized to receive olanzapine ODT (n = 13) or SOT (n = 10), 10 to 20 mg, once daily. Weight, body mass index (BMI), Food Craving Inventory (FCI), and Three-Factor Eating Questionnaire (3-FEQ) scores were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Fasting glucose and lipid levels were assessed at baseline and at week 8. Insulin and leptin concentrations were measured just prior to olanzapine baseline dosing, 1 and 2 hours following administration of baseline dose, and at weeks 4 and 8.

RESULTS: Patients showed significant increases in weight, BMI, and leptin area under the concentration-time curve (AUC), but not in FCI or 3-FEQ scores, over 8 weeks of treatment with olanzapine ODT and SOT. However, no significant differences between olanzapine formulations (ODT vs SOT) were observed in any of the measures assessed, except for a significantly lower triglyceride concentration in the ODT group at week 8.

CONCLUSIONS: There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations during short-term treatment of bipolar depressed patients. Potential differences related to effects on triglyceride concentration warrant further confirmation.

KEYWORDS: bipolar disorder, body mass index, olanzapine, orally disintegrating, eating behavior, food craving, gastrointestinal hormones



Olanzapine, an atypical antipsychotic medication, has been shown to be effective for treating all phases of bipolar disorder both as monotherapy and as a therapeutic adjunct.1-3 This agent is approved in the United States for the treatment of acute mania and acute bipolar depression (in combination with the antidepressant fluoxetine), as well as for bipolar maintenance therapy. The long-term use of olanzapine has been limited by the risk of clinically significant weight gain and other adverse metabolic side effects associated with its use. Among the atypical antipsychotic agents, olanzapine and clozapine have been consistently associated with greatest risk of treatment-emergent weight gain, central adiposity, dyslipidemia, hyperglycemia, and new-onset diabetes mellitus compared with other antipsychotics.4-6 The mechanisms underlying olanzapine-associated metabolic risk have not been established. However, olanzapine exposure has been associated with insulin resistance,7-9 independent of its effects on body weight.10

Olanzapine is available as a solid oral tablet (SOT) and an orally disintegrating tablet (ODT). While weight gain has been shown to occur with both forms of olanzapine,11-16 several reports have suggested treatment with olanzapine ODT may be associated with less risk of weight gain and related metabolic adverse effects compared with olanzapine SOT. In a 16-week open, non-randomized study of olanzapine involving SOT-treated adolescents and young adults with recently diagnosed schizophrenia,15 those who switched to ODT experienced a mean weight loss of 6.6 kg, while those who continued on SOT experienced a mean weight increase of 3.7 kg. Similar results were reported in a study in which obese olanzapine SOT-treated patients with schizophrenia were switched to ODT for 12 months.13 Weight loss was observed in 82% of these patients. Olanzapine SOT was associated with significantly greater weight gain (6.3 vs 3.3 kg, P = .009) and higher rates of clinically significant weight gain (≥7% above baseline weight; 84.2% vs 41.6%, P = .014) compared with ODT (3.3 kg, P = .009) in a 6-week open comparison in antipsychotic-naïve patients with schizophrenia.12 In another nonrandomized, open comparison study involving patients with a mixture of mood and anxiety disorders, olanzapine SOT was associated with significantly greater increases in weight (8.9 vs 3.0 kg, P < .001) and body mass index (BMI) (1.9 vs 1.1 kg/m2, P = .001) than olanzapine ODT.14

Results of 2 more recent studies comparing the metabolic effects of olanzapine SOT and ODT have challenged these findings. In a 16-week, randomized, double-blind study of 65 SOT- and 84 ODT-treated patients with primary psychotic illnesses or bipolar disorder, there were no significant differences between the 2 formulations with regard to mean change in weight or BMI.17 Olanzapine SOT and ODT also showed similar effects on gut hormone concentration in a randomized 8-day crossover study of 10 healthy male subjects.18

There remain several unresolved questions about olanzapine in general, and possible differences between the SOT and ODT formulations, in particular, with regard to metabolic effects. The current study was intended to evaluate the comparative effects of SOT and ODT olanzapine on psychopathology, weight, eating behavior, and gastrointestinal hormone levels in a single randomized study of patients with bipolar disorder, depressed phase. The effects of SOT and ODT on psychopathology have been reported elsewhere.19 This article focuses on results of the SOT-ODT comparison on anthropometric and metabolic outcomes and eating behaviors in all 23 randomized patients.


Study design and treatment

This was an 8-week, randomized, open-label, flexible-dose (5 to 20 mg/d) comparison of olanzapine ODT and SOT in outpatients with bipolar disorder types I, II, or not otherwise specified (NOS), depressed phase. The primary objective of this study was to compare the effects of olanzapine SOT vs ODT on body weight and BMI. Secondary objectives were to compare the 2 dosing forms on validated measures of eating behavior and food craving, routine metabolic indices, and insulin and leptin levels.

A total of 23 eligible patients were recruited between November 27, 2007 and December 31, 2008. Patients who were taking psychotropic medications prior to study entry were tapered off of these medications over the 7 to 10 days prior to their baseline visit. After the screening and washout period, eligible patients were randomized using the Marsenne Twister subroutine in SPSS (Version 17.0, SPSS Inc., Chicago, IL) to either olanzapine SOT or ODT. Both formulations were initiated at a dose of 5 mg/d. The daily dose was increased as tolerated to 10 mg/d after 1 week, and was adjusted thereafter between 10 to 20 mg/d on clinical grounds. All doses were dispensed as single 5-, 10-, 15- or 20-mg tablets. Other psychotropic medications, including mood stabilizers, were prohibited during the study, with the exception of non-benzodiazepine sleep-promoting agents (chloral hydrate, eszopiclone, zaleplon, and zolpidem). No specific instructions or restrictions with regard to diet were given. Study visits occurred at baseline and at 1, 2, 4, 6, and 8 weeks. All study visits occurred at the Vanderbilt Mood and Anxiety Disorders specialty clinic. All study subjects provided written informed consent before participating. Study procedures were approved by the Institutional Review Board of Vanderbilt University Medical Center.

Patient inclusion and exclusion criteria

Eligible subjects (age 18 to 60) had a principal diagnosis of bipolar I disorder, bipolar II disorder, or bipolar disorder NOS, with a Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥15 at screening, were physically healthy with a BMI of 21 to 32 kg/m2, and were capable of providing valid written informed consent. All bipolar disorder diagnoses were validated via clinical interview performed by one of the authors (W.V.B., R.C.S.), followed by use of the Structured Clinical Interview for DSM Disorders (SCID) for Axes I and II disorders.

Exclusion criteria included current or prior history of diabetes mellitus (any subtype), BMI <21 or >32 kg/m2, fasting blood glucose >124 mg/dL or random blood glucose >200 mg/dL at screening, abnormal fasting lab values (total cholesterol >240 mg/dL, high-density lipoprotein [HDL] <50 mg/dL [regardless of sex], low-density lipoprotein [LDL] >160 mg/dL, or triglycerides >199 mg/dL), history of a non-affective psychotic disorder, alcohol or other substance use disorder in the 6 months prior to screening, current or past history of taste or olfactory dysfunction, or pregnancy. Patients treated with olanzapine within the last 3 months and those with a history of poor olanzapine tolerability, afebrile seizures, or impaired olfaction or taste sensation were excluded as well.

Data collection and study endpoints

The primary study endpoints were body weight (kg) and BMI (kg/m2). These anthropometric measurements were taken at baseline and at weeks 1, 2, 4, 6, and 8. Patients were weighed in the fasting state, without shoes, pockets emptied, in light clothing.

Secondary endpoints included validated measures of eating behavior and food craving, fasting blood glucose, fasting lipids, and insulin and leptin levels. To assess craving for specific food types (sweets, high fats, carbohydrates/starches, and fast-food fats), the Food Craving Inventory (FCI) was used.20 The average scores from each of these specific food types were used to generate a general craving score.21,22 Problematic eating behaviors were assessed using the Three-Factor Eating Questionnaire (3-FEQ).23 This instrument was designed to measure 3 pathological eating behavior dimensions: cognitive restraint, disinhibition, and hunger. These assessments were performed at baseline and at all follow-up study visits.

Fasting blood glucose and lipids (total cholesterol, HDL, LDL, triglycerides) were measured at baseline and at 8 weeks, while gastrointestinal hormone levels (insulin and leptin) were measured at baseline, week 4, and week 8. Blood sampling for analysis of insulin and leptin levels occurred under fasting conditions at 3 time intervals during each visit: 1) time zero (t0), just before the subject’s scheduled daily study drug dose, 2) 1 hour after time zero (t1), and 3) 2 hours after time zero (t2). Blood samples were immediately centrifuged and the serum samples were stored at -80°C until thawing for analysis. Serum concentrations of insulin and leptin were measured in duplicate by radioimmunoassay. All assays were performed with a Millipore (Millipore Inc., Billerica, MA, USA) RIA kit or a modification thereof as validated by the Hormone Assay & Analytical Services Core, Vanderbilt Diabetes Center. The limits of sensitivity for insulin and leptin were 2 μU/mL and 0.5 ng/mL, respectively. Intra- and inter-assay coefficients of variance were <8.5% for both insulin and leptin, with no cross-reactivity. Insulin and leptin concentration was reported as the area under the plasma concentration-time curve (AUC [t0, t1, t2]), as calculated with the trapezoidal rule, at each time interval.

We established intact olfaction and gustatory functioning at the screening visit using the University of Pennsylvania Smell Identification Test,24 a standardized test consisting of 4 booklets containing 10 odorants each. One advantage of this test is it provides an olfactory diagnosis (normosmia, anosmia, and varying levels of microsmia) based on comparing the subjects’ scores with normative data.25 To establish intact gustatory sensation, subjects sampled a series of sucrose solutions at 5 concentrations (.05, .10, .21, .42, and .83 M). Each solution was sampled twice, in random order. After sampling each solution, subjects were asked to rate the subjective intensity of sweetness on an analog scale, with 0 mm representing “not sweet at all.”26,27 Intact gustatory functioning was defined as demonstrating a strong correlation (r ≥ 0.75) between sucrose test solution concentration and subjective analog sweetness ratings.

Statistical analyses

The primary data analysis was a mixed model repeated measures analysis, with time (study visit) as the within-subjects factor and study drug (SOT, ODT) as the between-subjects factor. Data were adjusted for baseline values using the PROC MIXED procedure in SAS (SAS Institute, Inc., 1994). This procedure was used to examine drug, time, and drug × time interactions for all continuous dependent variables, including the AUC for insulin and leptin. Last observation carried forward was used to handle missing values. Descriptive statistics and χ2 analysis were used to report baseline characteristics of the study sample. Spearman correlation was used to examine the relationship between weight/BMI, measures of food craving and eating behavior, and gut hormone levels.


Subject demography, disposition, and treatment

A total of 39 patients were screened, 12 of whom did not meet study inclusion criteria, and 4 of whom declined to participate. Thus, a total of 23 subjects were enrolled, 13 of whom were randomly assigned to olanzapine ODT and 10 of whom were assigned to olanzapine SOT. The majority of patients were not taking any psychotropic medications at screening (10 patients in the ODT group, 7 in the SOT group); 2 patients were taking quetiapine (1 in each group), while 4 were taking a selective serotonin reuptake inhibitor or venlafaxine (2 in each group). Only 1 enrolled patient (randomized to SOT) had a history of olanzapine SOT treatment, which had been discontinued 6 months prior to study entry. Intact gustatory and olfactory functioning was confirmed in all randomized patients.

There were no significant differences between the ODT and SOT groups with respect to age, sex, or race (TABLE 1). Bipolar I depression was the most common diagnosis (n = 11 [47.8%]), followed by bipolar II depression (n = 7 [30.4%]). Remaining patients had SCID-confirmed diagnoses of bipolar I mixed episodes (n = 3 [13.1%]) or bipolar disorder, NOS (n = 2 [8.7%]). All patients were moderately to severely depressed, with baseline mean ± SD MADRS scores of 30.4 ± 10.6. There were no significant differences in baseline MADRS scores between patients assigned to olanzapine ODT vs SOT.

The mean doses of olanzapine at study endpoint were 13.3 mg/d in the ODT group and 16.5 mg/d in the SOT group (P = not significant [NS]). Only 1 patient required treatment with zolpidem (5 mg at bedtime, for 3 days). No other concurrent psychotropic drugs, including mood stabilizers, were initiated during the study. Nineteen patients (82.6%) completed the 8-week study. Dropouts occurred at weeks 2 (n = 1), 4 (n = 1), and 6 (n = 2). All dropouts were a result of loss to follow-up. There were no significant differences in age, sex, baseline MADRS score, or olanzapine dosage between study completers and non-completers (data not shown). All individuals who dropped out of the study had been randomized to the ODT formulation.


Clinical and demographic characteristics of study sample

N 13 10
Age, y, mean ± SD 36.4 ± 8.5 39.7 ± 9.9
Sex, n (%)
  Male 6 (46.2%) 4 (40%)
  Female 7 (53.8%) 6 (60%)
Race, n (%)
  White 9 (69.2%) 6 (60%)
  African American 4 (30.8%) 4 (40%)
  Other 0 0
Diagnosis, n (%)
  Bipolar I, depressed 7 (53.8%) 4 (40%)
  Bipolar II, depressed 4 (30.8%) 3 (30%)
  Bipolar I, mixed 1 (7.7%) 2 (20%)
  Bipolar disorder, NOS 1 (7.7%) 1 (10%)
NOS: not otherwise specified; ODT: olanzapine orally disintegrating tablet; SD: standard deviation; SOT: olanzapine solid oral tablet.
Effects on weight and body mass index

The effects of study drugs on body weight and BMI are shown in TABLE 2. There were significant effects of time for both weight (F[5,94] = 11.0, P < .0001) and BMI (F[5,94] = 11.7, P < .0001], indicating the group as a whole (N = 23 patients) experienced significant increases in both of these measures over the 8-week study period. Significant increases in both parameters were observed in both groups beginning at week 2, and remained so throughout the remainder of the study period. However, there was no significant drug (ODT, SOT) or drug × time interaction effect, which indicated weight and BMI increases did not differ significantly between the study drugs. There were also no significant between-groups differences in these measures at any follow-up time point. These results were unchanged when the analyses were repeated only in study completers.


Study drug effects on weight and body mass index

Time All patients N = 23 LS Mean (SE) ODT n = 13 LS Mean (SE) SOT n = 10 LS Mean (SE) Difference in P valuea Drugb Timeb Drug × Time
Weight, kg
Baseline 76.0 (0.5) 76.0 (0.6) 76.1 (0.7) NS F (1,20) = .4, P = NS F (5,94) = 11.0, P < .0001 F (5,94) = .2, P = NS
Week 1 77.5 (0.5)d 77.4 (0.6) 77.6 (0.7)c NS      
Week 2 78.1 (0.5)e 77.8 (0.6)d 78.3 (0.7)d NS      
Week 4 78.6 (0.5)f 78.6 (0.6)e 78.7 (0.7)e NS      
Week 6 79.2 (0.5)f 78.9 (0.7)e 79.4 (0.7)f NS      
Week 8 79.6 (0.5)f 79.1 (0.7)f 80.1 (0.7)f NS      
BMI, kg/m2
Baseline 26.8 (0.1) 26.8 (0.2) 26.8 (0.2) NS F (1,20) = .1, P = NS F (5,94) = 11.7, P < .0001 F (5,94) = .2, P = NS
Week 1 27.3 (0.1)d 27.3 (0.2)c 27.3 (0.2) NS      
Week 2 27.5 (0.1)e 27.4 (0.2)d 27.6 (0.2)d NS      
Week 4 27.7 (0.1)f 27.7 (0.2)e 27.8 (0.2)e NS      
Week 6 27.9 (0.2)f 27.8 (0.2)f 28.0 (0.2)f NS      
Week 8 28.0 (0.2)f 27.8 (0.2)f 28.2 (0.2)f NS      
All values are LS-means (SE) unless otherwise specified.
aP values in this column represent between-groups comparisons at each follow-up time point.
bMixed model for repeated measures analysis adjusted for baseline values of dependent variables, with drug (ODT, SOT) as between-subjects factor and time as within-subjects factor.
cP < .05.
dP ≤ .01.
eP ≤ .001.
fP ≤ .0001.
BMI: body mass index; LS: least squares; NS: not significant; ODT: olanzapine orally disintegrating tablets; SE: standard error; SOT: olanzapine solid oral tablet.
Effects on food craving and eating behavior

There were no significant drug, time, or drug × time interaction effects for FCI total, FCI subscales, or 3-FEQ subscales scores (data not shown). There were also no significant changes in these scores at any follow-up time point compared with baseline in the whole sample (N = 23) or in the individual treatment groups. In addition, no significant between-groups differences in these scores occurred at baseline or at any follow-up time point.

Effects on glycemic and lipid indices

The effects of study drugs on fasting glucose levels and lipid profile are shown in TABLE 3. There were significant study drug [F(1,19) = 7.4, P = .01) and drug × time interaction effects [F(1,16) = 6.6, P = .02] for triglycerides favoring olanzapine ODT. At week 8, there was a trend-level (P < .08) decrease in LS-mean triglyceride level relative to baseline in the ODT group, while the LS-mean triglyceride level was non-significantly increased from baseline in the SOT group. At week 8, the LS-mean triglyceride level was significantly lower in the ODT group compared with the SOT group (P = .003).

HDL cholesterol levels decreased significantly in the ODT group (P < .01) and decreased at the trend level in the SOT group (P < .08); however, there was no significant drug x time interaction. Total cholesterol levels were non-significantly decreased from baseline in the ODT group, and were non-significantly increased in the SOT group, at week 8. The drug × time interaction effect for total cholesterol nearly reached statistical significance (F[1,16] = 4.0, P = .06). No significant drug, time, or drug × time interaction effects were observed for fasting blood glucose or LDL cholesterol.


Study drug effects on fasting glucose and lipid levels

  Time ODT n = 13 LS Mean (SE) SOT n = 10 LS Mean (SE) Difference in P valuea Drugb Timeb Drug × Time
Glucose, mg/dL Baseline 96.6 (5.9) 93.5 (6.5) NS F (1,19) = .03 F (1,15) = 3.0 F (1,15) = .1
  Week 8 107.1 (7.8) 108.2 (6.5) NS P = NS P = NS P = NS
Cholesterol, mg/dL Baseline 190.9 (6.9) 188.5 (7.6) NS F (1,19) = 2.4 F (1,16) = .5 F (1,16) = 4.0
  Week 8 180.9 (8.6) 208.7 (7.6) c .03 P = NS P = NS P = .06
HDL, mg/dL Baseline 55.3 (1.3) 55.3 (1.4) NS F (1,19) = .6 F (1,16) = 12.7 F (1,16) = .6
  Week 8 49.0 (1.6) d 51.2 (1.4) c NS P = NS P = .003 P = NS
LDL, mg/dL Baseline 113.6 (5.9) 113.7 (6.5) NS F (1,19) = 2.0 F (1,15) = 2.9 F (1,15) = 2.2
  Week 8 115.2 (7.2) 134.6 (6.8) e .07 P = NS P = NS P = NS
Triglycerides, mg/dL Baseline 110.0 (8.4) 111.2 (9.2) NS F (1,19) = 7.4 F (1,16) = .2 F (1,16) = 6.6
  Week 8 81.7 (10.4) c 131.2 (9.2) .003 P = .01 P = NS P = .02
All values are LS-means (SE) unless otherwise specified.
aP values in this column represent between-groups comparisons at each follow-up time point.
bMixed model for repeated measures analysis adjusted for baseline values of dependent variables, with drug (ODT, SOT) as between-subjects factor and time as within-subjects factor.
c.05 ≤ P ≤ .08 (trend) for within group comparisons at each follow-up time point against the baseline values.
dP ≤ .01.
eP < .05.
HDL: high-density lipoprotein; LDL: low-density lipoprotein; LS: least squares; NS: not significant; ODT: olanzapine orally disintegrating tablets; SE: standard error; SOT: olanzapine solid oral tablet.
Effects on insulin and leptin concentration

There was a significant time interaction effect for leptin (F[2.19] = 4.1, P = .03) AUC, indicating the LS-mean leptin values increased in both groups over time; however, no significant drug or drug × time interaction effects were observed (TABLE 4). In the entire sample, baseline to endpoint change in leptin AUC correlated positively with change in body weight (rs = 0.60, P = .02) and BMI (rs = 0.60, P = .02). When BMI was added to the mixed model, the time effect for leptin AUC was no longer statistically significant. There were no significant drug, time, or drug × time interaction effects for insulin AUC. Insulin AUC values did not change significantly from baseline in either group. No significant between-groups differences were observed for either insulin or leptin AUC at any follow-up time point.


Study drug effects on insulin and leptin (AUC)a

  Time ODT n = 13 LS mean (SE) SOT n = 10 LS mean (SE) Drugb Timeb Drug × Time
Insulin level Baseline 27.7 (10.1) 21.3 (11.4) F (1,13) = .02 F (2,15) = .4 F (2,15) = .1
  Week 4 34.0 (12.3) 37.1 (12.1) P = NS P = NS P = NS
  Week 8 22.3 (15.9) 27.1 (12.5)      
Leptin level Baseline 13.9 (1.6) 13.9 (1.9) F (1,14) = .1 F (2,19) = 4.1 F (2,19) = .3
  Week 4 18.2 (1.9)c 17.3 (2.1) P = NS P = .03 P = NS
  Week 8 17.7 (3.0) 20.2 (1.9)      
All values are LS-means (SE) AUC calculated with the trapezoidal rule.
aThere were no significant between groups differences (ODT vs SOT) for either outcome measure at any follow-up time point.
bMixed model for repeated measures analysis adjusted for baseline values of dependent variables, with drug (ODT, SOT) as between-subjects factor and time as within-subjects factor.
c.05 ≤ P ≤ .08 (trend), for within group comparisons at each follow-up time point against the baseline values.
AUC: area under the concentration-time curve; LS: least squares; ODT: olanzapine orally disintegrating tablets; NS: not significant; SE: standard error; SOT: olanzapine solid oral tablet


This is the first randomized comparison of olanzapine ODT and SOT in olanzapine-naïve patients with bipolar depression. This was also the first single study to examine differential effects of these 2 olanzapine formulations on body weight/BMI, eating behavior, and gastrointestinal hormone (insulin and leptin) concentration. None of these outcome measures differed significantly according to olanzapine formulation over 8 weeks of follow-up. Significant weight gain occurred in the entire sample absent changes in validated measures of food craving or eating behavior. Increases in leptin AUC for the whole olanzapine-treated patient sample appeared to be closely related to increases in body weight and BMI, consistent with prior reports.28-31

Initial reports suggesting differential effects of olanzapine ODT and SOT formulations on weight change, favoring ODT,12-15 were not supported by later studies utilizing randomized designs. Our results are consistent with these latter studies. In the recently published PLATYPUS study,17 149 patients with schizophrenia, schizoaffective disorder, or bipolar disorder who had experienced a ≥5 kg weight gain or ≥1 kg/m2 increase in BMI on olanzapine SOT prior to study entry were randomized to olanzapine ODT (n = 84) or continuation of SOT (n = 65). Thus, as mentioned by the authors, the PLATYPUS results generalize only to patients with pre-existing weight gain on oral olanzapine. No statistically significant difference in mean BMI change was observed after 16 weeks of follow-up. While more patients randomized to the ODT group experienced a ≥7% increase in weight from baseline than the SOT group (14.6% vs 11.1%), these differences were not statistically significant. There were also no differences by study drug related to cardiometabolic profile, including changes in fasting lipids and glucose measures.

Although the present study is much smaller than the PLATYPUS study, our results are in agreement. Unlike PLATYPUS, patients in our sample were not receiving olanzapine treatment at study entry. In our study of bipolar depressed subjects, olanzapine-treated patients experienced increases in weight and BMI; however, no significant differences by olanzapine formulation were observed over 8-week follow-up. Additionally, no significant drug by time interactions emerged for fasting lipid or glycemic indices, with the exception of fasting triglycerides. LS-mean triglyceride levels decreased in the ODT group at the level of statistical trend, while LS-mean triglycerides increased nonsignificantly in the SOT group. Thus, endpoint differences in LS-mean triglyceride values were statistically significantly lower for the ODT group. While olanzapine treatment has been associated with adverse changes from baseline values for all lipid fractions, triglycerides appear to be the most vulnerable. Elevations in triglyceride values during olanzapine treatment may reflect adverse effects of olanzapine on insulin sensitivity.32

We examined additional endpoints, including measures of food craving and eating behavior. Loss of control over appetite has been implicated as at least 1 important mechanism underlying the weight-promoting effects of some antipsychotic drugs, including olanzapine.33-35 Indeed, olanzapine was associated with relatively high rates of food craving (48.9%) and binge-eating behavior (16.7%) in a recent randomized, double-blind study of patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder.33 In another study, hunger and satiety ratings were determined in a cohort of 48 healthy volunteers randomized to olanzapine, risperidone, or placebo for 2 weeks using a standardized feeding protocol.34 Although the magnitude of weight gain with olanzapine was greater at study endpoint than that of risperidone (P = .015) and placebo (P = .0001), there were no differences between groups with respect to hunger and satiety ratings. Consistent with these findings, the current study documented a lack of significant variability in food craving or eating behavior ratings over time in the entire sample. In addition, no significant variability in food craving or eating behavior was observed over time in either group (ODT or SOT), and no significant drug-by-time interaction effects emerged.

We were also interested in investigating the effects of olanzapine ODT and SOT on AUC for insulin and leptin, both of which are gastrointestinal hormones believed to be involved in the long-term regulation of appetite and eating behavior.36-38 In our study, AUC for leptin increased significantly over time in the entire sample, in parallel with weight gain; however, there was no differential pattern of increase according to olanzapine formulation. There was a nonsignificant increase in AUC for insulin in the SOT group and a nonsignificant decrease in the ODT group, but no significant overall effect of time. There was also no significant correlation between BMI and AUC for either insulin or leptin.

Our results suggest there are no differences in AUC for insulin or leptin concentrations between ODT and SOT in bipolar depressed patients who receive short-term treatment with olanzapine. Only 1 other study investigated the comparative effects of olanzapine ODT and SOT on gastrointestinal hormone levels.18 This was a small, randomized, crossover study of 10 healthy male volunteers who received olanzapine ODT or SOT at a dose of 10 mg/d for 8 days per crossover phase. Pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin concentration were measured at breakfast and dinner. Anthropometric effects were also assessed. Olanzapine treatment did not significantly alter hormone concentrations, with the exception of cholecystokinin concentration at breakfast and ghrelin concentration at dinner (both comparisons, P < .05). Gastrointestinal peptide concentrations, BMI, waist-to-hip ratio, and body composition did not differ by olanzapine formulation.

Limitations of this study include a small sample size, which may have limited the statistical power for many of the comparisons between olanzapine formulations. Second, there was also a relatively short duration of follow-up. A longer period of follow-up may have allowed for greater weight gain and changes in eating behaviors and insulin and leptin AUC to develop, although these still may not have differed based on olanzapine formulation. Third, we investigated the effects of drug exposure on just a few elements of eating behavior and only 2 hormones. Thus, we cannot exclude the possibility of differential effects of olanzapine ODT and SOT on other aspects of eating behavior or appetite-regulating hormones. Finally, we did not estimate drug effects on insulin sensitivity. Instead, we measured hormone levels within a 2-hour window beginning just prior to a single daily dose of olanzapine; thus, we were unable to consider the effect of circadian variation in hormone secretion


There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations over 8 weeks of treatment in a sample of patients with bipolar disorder, depressed phase. Potential between group differences in triglyceride response in our study warrant further investigation.

ACKNOWLEDGEMENTS: This study was funded by an investigator-initiated research grant from Eli Lilly (NCT00384332) awarded to Richard C. Shelton, MD.

DISCLOSURES: Dr. Bobo has received grant/research support from Cephalon. In the past, Dr. Bobo has served on the speakers bureau for Janssen Pharmaceutica and Pfizer Inc. (>3 years). Dr. Epstein reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Shelton has received grant/research support from Abbott Laboratories, AstraZeneca, Eli Lilly and Company, Euthymics Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Medtronic Inc., PamLab, Pfizer Inc., Ridge DX, sanofi-aventis, and Wyeth-Ayerst Laboratories; has served as a paid consultant for Janssen Pharmaceutica, Pfizer Inc., and Sierra Neuropharmaceuticals; and has served on the speakers bureau for Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc., and Wyeth-Ayerst Laboratories.


  1. Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol. 2008;11:999–1029.
  2. Lieberman DZ, Goodwin FK. Use of olanzapine in the treatment of bipolar I disorder. Expert Rev Neurother. 2004;4:759–767.
  3. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003;160:1263–1271.
  4. Lambert BL, Cunningham FE, Miller DR, et al. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol. 2006;164:672–681.
  5. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19:1–93.
  6. Smith M, Hopkins D, Peveler RC, et al. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2008;192:406–411.
  7. Ebenbichler CF, Laimer M, Eder U, et al. Olanzapine induces insulin resistance: results from a prospective study. J Clin Psychiatry. 2003;64:1436–1439.
  8. Henderson DC, Copeland PM, Borba CP, et al. Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis. J Clin Psychiatry. 2006;67:789–797.
  9. Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 2000;61:742–749.
  10. Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry. 2002;59:337–345.
  11. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686–1696.
  12. Arranz B, San L, Duenas RM, et al. Lower weight gain with the orally disintegrating olanzapine than with standard tablets in first-episode never treated psychotic patients. Hum Psychopharmacol. 2007;22:11–15.
  13. Chawla B, Luxton-Andrew H. Long-term weight loss observed with olanzapine orally disintegrating tablets in overweight patients with chronic schizophrenia. A 1 year open-label prospective trial. Hum Psychopharmacol. 2008;23:211–216.
  14. Crocq MA, Guillon MS, Bailey PE, et al. Orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets. Eur Psychiatry. 2007;22:453–454.
  15. de Haan L, van Amelsvoort T, Rosien K, et al. Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets. Psychopharmacology (Berl). 2004;175:389–390.
  16. Karagianis J, Hoffmann VP, Arranz B, et al. Orally disintegrating olanzapine and potential differences in treatment-emergent weight gain. Hum Psychopharmacol. 2008;23:275–281.
  17. Karagianis J, Grossman L, Landry J, et al. A randomized controlled trial of the effect of sublingual orally disintegrating olanzapine versus oral olanzapine on body mass index: the PLATYPUS Study. Schizophr Res. 2009;113:41–48.
  18. Vidarsdottir S, Roelfsema F, Streefland T, et al. Short-term treatment with olanzapine does not modulate gut hormone secretion; olanzapine disintegrating vs standard tablets. Eur J Endocrinol. 2010;162:75–83.
  19. Bobo WV, Epstein RA, Shelton RC. Olanzapine monotherapy for acute depression in patients with bipolar I or II disorder: results of an 8-week open label trial. Hum Psychopharmacol. 2010;25:30–36.
  20. White MA, Whisenhunt BL, Williamson DA, et al. Development and validation of the food-craving inventory. Obes Res. 2002;10:107–114.
  21. Martin CK, O’Neil PM, Pawlow L. Changes in food cravings during low-calorie and very-low-calorie diets. Obesity (Silver Spring). 2006;14:115–121.
  22. Martin CK, Han H, Anton SD, et al. Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial. J Psychopharmacol. 2009;23:814–825.
  23. Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint disinhibition and hunger. J Psychosom Res. 1985;29:71–83.
  24. Doty RL, Newhouse MG, Azzalina JD. Internal consistency and short-term test-retest reliability of the University of Pennsylvania Smell Identification Test. Chem Senses. 1985;10:297–300.
  25. Doty RL. The Smell Identification Test Administration Manual. Haddon Heights NJ: Sensonics, Inc; 1995.
  26. Kampov-Polevoy A, Garbutt JC, Janowsky D. Evidence of preference for a high-concentration sucrose solution in alcoholic men. Am J Psychiatry. 1997; 154:269–270.
  27. Looy H, Callaghan S, Weingarten HP. Hedonic response of sucrose likers and dislikers to other gustatory stimuli. Physiol Behav. 1992;52:219–225.
  28. Eder U, Mangweth B, Ebenbichler C, et al. Association of olanzapine-induced weight gain with an increase in body fat. Am J Psychiatry. 2001; 158:1719–1722.
  29. Ebenbichler C, Laimer M, Kranebitter M, et al. The soluble leptin receptor in olanzapine-induced weight gain: results from a prospective study. Schizophr Res. 2005;75:143–146.
  30. Murashita M, Kusumi I, Inoue T, et al. Olanzapine increases plasma ghrelin level in patients with schizophrenia. Psychoneuroendocrinology. 2005;30:106–110.
  31. Hosojima H, Togo T, Odawara T, et al. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol. 2006;20:75–79.
  32. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005;96:399–404.
  33. Kluge M, Schuld A, Himmerich H, et al. Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study. J Clin Psychopharmacol. 2007;27:662–666.
  34. Roerig JL, Mitchell JE, de Zwaan M, et al. A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors. J Clin Psychopharmacol. 2005;25:413–418.
  35. Theisen FM, Linden A, Konig IR, et al. Spectrum of binge eating symptomatology in patients treated with clozapine and olanzapine. J Neural Transm. 2003;110:111–121.
  36. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science. 2005;307:1909–1914.
  37. Havel PJ. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med. 2001;226:963–977.
  38. Schwartz MW, Figlewicz DP, Baskin DG, et al. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992;13:387–414.

CORRESPONDENCE: William V. Bobo, MD Village at Vanderbilt, 1500 21st Ave. South, Suite 2200, Nashville, TN 37212 USA, E-MAIL: