Medication, Weight Gain and GI Hormones

NCT ID: NCT00384332

Last Updated: 2017-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2010-03-31

Brief Summary

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.

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.

Conditions

Bipolar Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1

Orally disintegrating olanzapine

Group Type: EXPERIMENTAL

orally-disintegrating olanzapine

Intervention Type: DRUG

5 to 20 mg (daily) orally disintegrating olanzapine for approx.8 weeks.

Arm 2

regular olanzapine

Group Type: EXPERIMENTAL

regular olanzapine

Intervention Type: DRUG

5-20 mg. olanzapine daily for approximately 8 weeks.

Interventions

orally-disintegrating olanzapine

5 to 20 mg (daily) orally disintegrating olanzapine for approx.8 weeks.

Intervention Type: DRUG

regular olanzapine

5-20 mg. olanzapine daily for approximately 8 weeks.

Intervention Type: DRUG

Other Intervention Names

Zydis; Zyprexa

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Richard C. Shelton

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard C. Shelton, M.D.

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003 Nov;60(11):1079-88. doi: 10.1001/archpsyc.60.11.1079.

Reference Type: BACKGROUND

PMID: 14609883 (View on PubMed)

Shelton RC. Treating bipolar depression. J Fam Pract. 2003 Mar;Suppl:S14-7. No abstract available.

Reference Type: BACKGROUND

PMID: 12676079 (View on PubMed)

Farwell WR, Stump TE, Wang J, Tafesse E, L'Italien G, Tierney WM. Weight gain and new onset diabetes associated with olanzapine and risperidone. J Gen Intern Med. 2004 Dec;19(12):1200-5. doi: 10.1111/j.1525-1497.2004.40126.x.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 15765795 (View on PubMed)

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Gill SS. Stable monotherapy with clozapine or olanzapine increases the incidence of diabetes mellitus in people with schizophrenia. Evid Based Ment Health. 2005 Feb;8(1):24. doi: 10.1136/ebmh.8.1.24. No abstract available.

Reference Type: BACKGROUND

PMID: 15671515 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 12650740 (View on PubMed)

Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature. 1995 Apr 6;374(6522):542-6. doi: 10.1038/374542a0.

Reference Type: BACKGROUND

PMID: 7700379 (View on PubMed)

Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003 Mar;28(3):519-26. doi: 10.1038/sj.npp.1300027.

Reference Type: BACKGROUND

PMID: 12629531 (View on PubMed)

Bobo WV, Epstein RA Jr, Shelton RC. 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. Ann Clin Psychiatry. 2011 Aug;23(3):193-201.

Reference Type: DERIVED

PMID: 21808751 (View on PubMed)

Other Identifiers

051235

Identifier Type: -

Identifier Source: org_study_id