The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary aim of this study is to investigate antipsychotic drug effects on healthy brain
      metabolism.
    

Detailed description: 
      Schizophrenia is a complex psychiatric disorder characterized by alterations in brain
      structure. It is not clear yet whether some of these alterations are primarily related to
      pathophysiology of illness per se or consequence of brain exposure to the effects of
      psychotropic drugs. In recent years accumulating evidence suggests that exposure to the
      effects of psychotropic drugs may contribute to the structural and other changes in brain.
      Therefore, use of antipsychotic medications as treatment for schizophrenia represents a
      potential confounding factor in many of the studies. Most neuroimaging studies of
      schizophrenia to date have not included the examination of non-medicated patients, making
      conclusions about medication effects on neuroimaging measures difficult. MRI studies of
      structural brain changes across time are limited by the fact that due to ethical reasons
      neither untreated subjects with schizophrenia nor control subjects exposed to antipsychotic
      medications can be used as comparison groups. There are some preclinical rat and primate
      models which revealed chronic antipsychotic-induced alterations in the brain. However few
      studies investigate the effects of chronic exposure to antipsychotic drugs on healthy human
      brain. Therefore in this study, investigators aimed to evaluate brain alterations induced by
      chronic drug exposure in healthy volunteers. To address this problem, we will conduct a
      single-site, single arm, open-label, interventional, multimodal neuroimaging study of healthy
      comparison subjects who are exposed to antipsychotic medication for 15 days. This study will
      include up to 40 healthy adult (21-50 years old) volunteers. Participants will be recruited
      via online advertisements and flyers as well as approaching healthy individuals who
      participated in previous studies. Investigators have three aims: 1. to study the levels of
      chemicals and kinetics of enzymes associated with cellular energy metabolism in brain before
      and after use of antipsychotic drug (using 1P MRS). 2. to collect data on the structure of
      the gray matter and white matter; resting state functional brain activity; levels of brain
      chemicals including glutamate and GABA; and white matter integrity before and after use of
      antipsychotic drug (using structural MRI, fMRI, dTI, 1H MRS). 3. to investigate side effects
      of antipsychotic drugs. It was planed to give healthy participants a single 2.5 mg dose of
      olanzapine followed by a 5 mg dose for 14 days. Olanzapine, a second generation antipsychotic
      agent, was selected to administer because this medication has strong effects on energy
      metabolism in general. The recommended daily dose range for olanzapine is indicated as 10-30
      mg/d in the last "APA (American Psychiatric Association) Practice Guideline for the Treatment
      of Patients With Schizophrenia". A recent study suggests that minimum effective dose for
      olanzapine in schizophrenia is 7.5 mg/d (the upper range of 5 mg ± 2.5 mg/d) and higher
      olanzapine doses (10, 10 ± 2.5, 15, and 15 ± 2.5 mg/d) are more efficacious than placebo.
      Therefore it was determined to give healthy subjects only 5 mg/d olanzapine, the lower limit
      of the optimal dose range (5 mg ± 2.5 mg/d), to mimic the therapeutic effect but also protect
      the participants from adverse effects of treatment. As the goal is to examine the effects of
      chronic drug use, the duration of medication was determined to be 15 days, the longest but
      historically safe olanzapine usage period in healthy individuals up to now. There is no
      published literature on the effects of olanzapine on brain measures. Therefore, it is not
      possible to calculate a sample size that would detect a given between-group difference in
      this study. Investigators plan to recruit a sample that is large enough to establish the
      absence of a moderate or large effect. It was proposed that sample size of 30 subjects will
      be sufficient to detect a difference with effect sizes of 0.45 or greater as significant at
      the p<0.05 level with 80% power. Effect sizes of 0.5 are generally considered moderate and
      0.8 considered large. Therefore, a not-statistically significant finding with this sample
      size will suggest that any effects of olanzapine on brain metabolism are small at most.
      Investigators will collect interview and neuroimaging data at baseline and after the
      medication period. Deviations induced by the study drug on healthy brain will be examined
      using paired t-tests for before and after measurements. Investigation of parameters before
      and after the use of antipsychotic drug in healthy people will give a chance to determine
      brain alterations related to drug itself, independent from the pathophysiology of the
      illness.
    

Intervention name(s): Olanzapine
Intervention type(s): Drug
Intervention description(s): All subjects will take a single 2.5 mg dose of olanzapine (Zyprexa Zydis) followed by a 5 mg dose for 14 days. (2.5 mg/d for 1 day, 5 mg/d for 14 days).
Other intervention name(s): Zyprexa Zydis 5 mg tb
Intervention MeSH terms: Olanzapine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Healthy volunteers; antipsychotic drugs; brain metabolism