The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

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

Detailed Description
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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.

Official Title
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The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

Conditions
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Healthy

Intervention / Treatment
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* Drug: Olanzapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 21-50 years old Male or female Without psychiatric diagnosis according to a structured psychiatric interview (SCID) Without history of a psychotic disorder among parents, siblings, or children Exclusion Criteria: Significant medical or neurological illness Diagnosis diabetes mellitus, uncontrolled hypertension, severe hypotension, coronary artery disease, metabolic syndrome, glaucoma, liver impairment, decreased renal function, respiratory disorders, peptic ulcer disease (absolute and relative contraindications to use of antipsychotic drugs) Body mass index (BMI) over 30 Taking any other medications, including over the counter supplements with the exception of oral contraceptives for women Pregnancy. Females of child-bearing age must be using an effective contraceptive method History of smoking, substance abuse or dependence Contraindication to MR scan (claustrophobia, cardiac pacemakers, metal clips and stents on blood vessels, artificial heart valves, artificial arms, hands, legs, etc., brain stimulator devices, implanted drug pumps, ear implants, eye implants or known metal fragments in eyes, exposure to shrapnel or metal filings, other metallic surgical hardware in vital areas, certain tattoos with metallic ink, certain transdermal patches, metal-containing IUDs) Medical condition that would prevent blood draws

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Second Generation Antipsychotic Drug<br>Olanzapine; a single 2.5 mg dose PO daily followed by 5 mg dose PO daily for 14 days | Drug: Olanzapine<br>* 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).<br>* Other names: Zyprexa Zydis 5 mg tb;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Nicotinamide Adenine Dinucleotide Metabolites NAD+/NADH | Change in brain nicotinamide adenine dinucleotide NAD+/NADH metabolite ratio as measured by in vivo 31P magnetic resonance spectroscopy | Baseline and after 15 days medication period | 
| Change in Brain Phosphocreatine (PCr) | Change in Phosphocreatine (PCr) metabolite concentration as measured by in vivo 31P magnetic resonance spectroscopy | Baseline and after 15 days medication period | 
| Change in Brain Creatine Kinase (CK) Forward Reaction Rate | Change in forward reaction rate constant (kf) of the creatine kinase (CK) as measured by in vivo 31P magnetic resonance spectroscopy magnetization transfer | Baseline and after 15 days medication period | 
| Change in Brain Parenchymal pH | Change in brain parenchymal pH as measured by in vivo 31P magnetic resonance spectroscopy | baseline and after 15 days medication period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Volumes of the Frontal, Parietal and Temporal Lobe Regions | Change in the gray matter volumes (cubic millimeters) of the frontal, parietal and temporal lobes as defined by Freesurfer's Desikan-Killiany Brain Atlas. Data was acquired using structural magnetic resonance imaging (MRI) at 3T. | baseline and after 15 day medication period | 
| Change in Surface Area of the Frontal, Parietal and Temporal Regions | Change in the cortical surface area (millimeters squared) of the frontal, parietal and temporal lobes as defined by Freesurfer's Desikan-Killiany Brain Atlas. Data was acquired using structural magnetic resonance imaging (MRI) at 3T. | baseline and after 15 days medication period | 
| Change in fMRI Resting State Functional Connectivity | Change in resting state functional connectivity to the medial prefrontal cortex and superior parietal lobules following olanzapine administration period. Whole-brain, seed-to-voxel analyses were conducted utilizing anatomically-defined seed regions and age-corrected within-subjects f-tests were run to determine the presence and size (in voxels) of clusters where connectivity changed significantly following olanzapine administration. Results are reported in units of voxels for each cluster meeting a threshold of voxel-level uncorrected p<.001 and cluster-level p-FDR<.05. A result of zero indicates that no clusters were identified within subjects as changed in connectivity relative to the seed regions. | baseline and after 15 days medication period | 
| Change in GABA Concentration | Change in GABA concentration measured by proton magnetic resonance spectroscopy. | baseline and after 15 days medication period | 
| Change in Fractional Anisotropy (FA) Measured by Diffusion Tensor Imaging (DTI) | Change in fractional anisotropy (FA), a scalar measure of diffusivity, of water in the brain assessed by DTI at 3T. FA values range from 0 (isotropic, meaning diffusion is equally restricted in 3D space) to 1 (anisotrophic, meaning that diffusion is completely restricted to a single direction). | baseline and after 15 days medication period | 
| Change in Glutamate Metabolite Concentration | Change in glutamate metabolite concentration measured by proton magnetic resonance spectroscopy. | baseline and after 15 days medication period | 
| Change in MATRICS Cognitive Consensus Battery (MCCB) Total Composite Score | Change in the MATRICS Cognitive Consensus Battery (MCCB), that includes 10 tasks that measure processing speed (Brief Assessment of Cognition in Schizophrenia - Symbol Coding, Animal Fluency, Trails A), attention (Continuous Performance Test), working memory (WMS-III Spatial Span, Letter-Number Span), verbal learning (Hopkins Verbal Learning Test - Revised), visual learning (Brief Visuospatial Memory Test - Revised), problem solving (Neuropsychological Assessment Battery Mazes) and social cognition (Mayer-Salovey-Caruso Emotional Intelligence Test). Scores from each subtest are normed and their T-scores are summed to yield a MCCB composite score, then the total composite T-score is standardized to normative data among a healthy population. The composite T-score has a mean of 50 and a standard deviation of 10. Higher total composite scores indicate better cognitive outcomes. | baseline and after 15 days medication period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, antipsychotic drugs, brain metabolism