The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

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.