Medication, Weight Gain and GI Hormones

June 29, 2017 updated by: Richard C. Shelton, Vanderbilt University

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 Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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 and histamine 1 receptors. Significant and potentially additive weight gain is associated with blockade of serotonin 2C and Histamine 1 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 other serotonin 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. investigated the relative effects of standard olanzapine tablets to the orally-disintegrating form (Zydis) in adolescents and young adults who had gained weight with olanzapine. The group randomly assigned 18 patients to continuation olanzapine tablets or Zydis for a 16-week period. The Zydis-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 (Zydis) yielding less exposure of the pylorus to olanzapine than the standard Zyprexa tablets.

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Arm 1
Orally disintegrating olanzapine
Drug: orally-disintegrating olanzapine
5 to 20 mg (daily) orally disintegrating olanzapine for approx.8 weeks.
Other Names:
  • Zydis
EXPERIMENTAL: Arm 2
regular olanzapine
Drug: regular olanzapine
5-20 mg. olanzapine daily for approximately 8 weeks.
Other Names:
  • Zyprexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Weight in Kilograms at Baseline, Weeks 1, 4, 6, and 8
Time Frame: 10 weeks
Change in weight from baseline to endpoint in kilograms. Reported as weight in Kilograms at Baseline, Weeks 1, 4, 6, and 8
10 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline Montgomery Asberg Depression Rating Scale
Time Frame: 10 weeks
Montgomery Asberg Depression Rating Scale (MADRS) total score. Construct: Depression severity. Scores below represent mean change scores, endpoint minus baseline. Minimum total score: 0 (no depression). Maximum total score: 60 (severe depression). Lower (more negative) scores indicate a better outcome. There are no subscales.
10 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Collaborators

Eli Lilly and Company

Investigators

  • Principal Investigator: Richard C. Shelton, M.D., Vanderbilt University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (ACTUAL)

March 1, 2010

Study Completion (ACTUAL)

March 1, 2010

Study Registration Dates

First Submitted

October 4, 2006

First Submitted That Met QC Criteria

October 5, 2006

First Posted (ESTIMATE)

October 6, 2006

Study Record Updates

Last Update Posted (ACTUAL)

July 31, 2017

Last Update Submitted That Met QC Criteria

June 29, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 051235

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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