Official Title: “Orally-Disintegrating vs. Regular Olanzapine Tablets: Effects on Weight and GI Hormones”

This is an 8 week study that compares two medications. One medication is olanzapine (5-20 mg daily) whereas the other medication is an orally disintegrating medication. Both medications are used to treat depressed bipolar patients. The main focus of this study is the comparison of these two medications on gastro-intestinal hormones and weight gain.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: March 2010

Olanzapine is undeniably one of the most effective treatments available for all phases of bipolar disorder. After FDA approval for bipolar mania, the drug became one of the most widely prescribed of treatments for this difficult-to-treat disorder. However, concerns about weight gain and the associated metabolic syndrome/type II diabetes have impacted the use of olanzapine.

In fact, weight gain is quite common with olanzapine. For example, in one large scale 8-week placebo-controlled trial of olanzapine in bipolar depression, the olanzapine-treated patients gained an average of 2.59 kg., while placebo patients lost an average of 0.47 kg. Further, weight gain can continue over an extended period of time, mounting to an average of about 6 kg. over one year. It should be noted, however, that in prior studies, no efforts have been made to limit weight gain. More recent data suggest that interventions such as dietary counseling are effective in either preventing or reversing weight gain.

Olanzapine is a potent antagonist of serotonin (5-HT) 2A, 5-HT2C, and histamine (H) 1 receptors. Significant and potentially additive weight gain is associated with blockade of 5-HT2C and H1 receptors. In addition, serotonin and its receptors are significantly involved in the regulation of gastrointestinal (GI) - related hormone secretion. Animal studies suggest significant involvement of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors in the regulation of appetite, satiety, and GI-related hormones. However, the interplay of selective activation or inhibition of these receptor subtypes is complex, and difficult to distinguish from effects on activity and anxiety. Suffice it to say that activation or blockade of these receptors have differential effects on appetite, satiety, metabolic activity, as well as leptin, secretin, insulin, glucagon, ghrelin, neuropeptide Y, and cholecystokinin.

Weight gain and the corresponding metabolic syndrome represent a "deal killer" with regard to the treatment of most patients. However, one recent small study may be highly relevant to this discussion. De Haan et al.28 investigated the relative effects of standard olanzapine tablets to the orally-disintegrating form (ZydisTM) in adolescents and young adults who had gained weight with olanzapine. The group randomly assigned 18 patients to continuation olanzapine tablets or ZydisTM for a 16-week period. The ZydisTM-treated patients lost an average of 6.6 kg. while the continuation regular olanzapine group gained 3.7 kg. Although small, this study suggests a potential solution to the weight-gain problem associated with olanzapine.

Most of the pharmacological effects on weight and hormones are thought to be mediated centrally. However, De Haan et al. (de Haan L, et al. Psychopharmacology (Berl).

2004;175:389-390) proposed that at least some of the difference could be attributable to local effects in the GI tract. In particular, the site of absorption was suggested as a possible explanation, with the orally disintegrating form (ZydisTM) yielding less exposure of the pylorus to olanzapine than the standard ZyprexaTM tablets. 5-HT2 receptors may play a role in satiety and appetite via contraction of the duodenum. As well, 5-HT2 and 5-HT3 receptors have been shown to mediate the release of secretin and pancreatic secretion of fluid and bicarbonate secondary to acidification of the duodenum (i.e., gastric emptying).

This effect may be mediated via peripheral activation of 5-HT2A receptors.

In this project we will treat 20 patients with bipolar disorder with olanzapine (a widely-used and FDA approved treatment for this condition); patients will be randomly assigned (1:1) to either standard Zyprexa tablets or orally disintegrating Zydis. We will measure symptom improvement and weight gain over the course of the study. Patients will be given dietary counseling prior to initiating either medication. In addition, we will contrast the effects of the treatments on GI-related hormones.

Intervention(s) in this Clinical Trial

• Drug: orally-disintegrating olanzapine
  • 5 to 20 mg (daily) orally disintegrating olanzapine for approx.8 weeks.
• Drug: regular olanzapine
  • 5-20 mg. olanzapine daily for approximately 8 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm 1
  • Orally disintegrating olanzapine
• Experimental: Arm 2
  • regular olanzapine

Primary Measures

• Weight in Kg.
  • Time Frame: 10 weeks
    Safety Issue?: Yes

Secondary Measures

• MADRS,depression/mania self-report scales, GI hormones - units, waist circum., blood tests, CGI scales, smell/taste tests, food inventories, vitals.
  • Time Frame: 10 weeks
    Safety Issue?: Yes

Inclusion Criteria:

• A principal diagnosis of bipolar 1 or II disorder
• Ages 18-60
• Physically healthy
• Outpatient status
• Montgomery-Asberg Rating Scale (MADRS) Score greater than or equal to 15
• BMI 23-30
• Able and willing to give written informed consent

Exclusion Criteria:

• Prior history of diabetes (types I or II)
• BMI>30
• Non-fasting blood glucose >124
• Fasting blood glucose >125 or random blood glucose >200
• Presence of dyslipidemia (baseline total cholesterol >240, HDL<50, LDL>160, triglycerides >199)
• Current or past history of a non-affective psychotic disorder
• Alcohol or other substance abuse or dependence in the 6 months prior to the evaluation (except for caffeine)
• Current use of any nicotine products
• Schizoid, schizotypal, or borderline personality disorder
• Treatment with olanzapine in the prior 3 months or any history of non- response to or intolerance of olanzapine or the olanzapine-fluoxetine combination (SymbiaxTM)
• Suicide potential that, in the opinion of the investigator, precludes outpatient treatment or participation in a trial
• Participation of subjects in another drug trial within 30 days of evaluation
• The presence of any current medical condition judged by the investigator to potentially interfere with the study procedures or measures
• The likelihood of requiring hospitalization over the period of the study
• The presence of any clinically-significant laboratory abnormality as judged by the investigator
• Pregnancy or lactation
• History of seizure disorder, excluding febrile seizures of childhood
• Any disorder of taste or smell, including severe nasal allergies
• Any other condition which, in the investigator's judgment might increase the risk to the subject or decrease the chance of obtaining satisfactory data to achieve the objectives of the study
• Being unable to comprehend or follow the study procedures.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 60 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Richard C. Shelton, M.D. Principal Investigator Vanderbilt University  

Overall Contact: Stephanie Addington, M.A. 615-343-1973 stephanie.addington@vanderbilt.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00384332

Study ID Number: 051235

ClinicalTrials.gov Identifier: NCT00384332

Health Authority: United States: Institutional Review Board

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