Medication, Weight Gain and GI Hormones
Condition: Bipolar Depression
MeSH terms: Depression; Bipolar Disorder
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): orally-disintegrating olanzapine; regular olanzapine
Intervention type(s): Drug; Drug
Intervention description(s): 5 to 20 mg (daily) orally disintegrating olanzapine for approx.8 weeks.; 5-20 mg. olanzapine daily for approximately 8 weeks.
Other intervention name(s): Zydis; Zyprexa
Intervention MeSH terms: Olanzapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Bipolar Depression; Weight gain bipolar medicine; side effects olanzapine; gastrointestinal hormones bipolar medicine