Clinical trial NCT02536846: The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals
Official title: The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: Healthy volunteers
antipsychotic drugs
brain metabolism
Lead sponsor: Mclean Hospital
Sponsor class: OTHER
First posted: 2015-09-01
Enrollment: 35
Sex: ALL
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Brain Nicotinamide Adenine Dinucleotide Metabolites NAD+/NADH
timeFrame: Baseline and after 15 days medication period
measure: Change in Brain Phosphocreatine (PCr)
timeFrame: Baseline and after 15 days medication period
measure: Change in Brain Creatine Kinase (CK) Forward Reaction Rate
timeFrame: Baseline and after 15 days medication period
measure: Change in Brain Parenchymal pH
timeFrame: baseline and after 15 days medication period
Secondary outcomes:
measure: Change in Volumes of the Frontal, Parietal and Temporal Lobe Regions
timeFrame: baseline and after 15 day medication period
measure: Change in Surface Area of the Frontal, Parietal and Temporal Regions
timeFrame: baseline and after 15 days medication period
measure: Change in fMRI Resting State Functional Connectivity
timeFrame: baseline and after 15 days medication period
measure: Change in GABA Concentration
timeFrame: baseline and after 15 days medication period
measure: Change in Fractional Anisotropy (FA) Measured by Diffusion Tensor Imaging (DTI)
timeFrame: baseline and after 15 days medication period
measure: Change in Glutamate Metabolite Concentration
timeFrame: baseline and after 15 days medication period
measure: Change in MATRICS Cognitive Consensus Battery (MCCB) Total Composite Score
timeFrame: baseline and after 15 days medication period
Other outcomes:
measure: Change in Montgomery-Asberg Depression Rating Scale (MADRS) Score
timeFrame: baseline and after 15 days medication period
measure: Change in Beck Depression Inventory (BDI) Score
timeFrame: baseline and after 15 days medication period
measure: Change in Young Mania Rating Scale (YMRS) Score
timeFrame: baseline and after 15 days medication period
measure: Change in Beck Anxiety Inventory (BAI) Score
timeFrame: baseline and after 15 days medication period
measure: Change in The Columbia Suicide Severity Rating Scale Score
timeFrame: baseline and 2, 5, 10, 15 days during medication period
measure: Change in Pittsburgh Sleep Quality Index Score
timeFrame: baseline and after 15 days medication period
measure: Change in LUNSERS (Liverpool University Neuroleptic Side Effect Rating Scale) Score
timeFrame: baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
measure: Change in Body Weight
timeFrame: baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
measure: Change in Hip Circumference
timeFrame: baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
measure: Change in Waist Circumference
timeFrame: baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
measure: Change in Blood Glucose Levels
timeFrame: baseline and after 15 days during medication period
measure: Change in Fasting Total Cholesterol Level
timeFrame: baseline and after 15 days medication period
measure: Change in Hemoglobin A1c Level
timeFrame: baseline and after 15 days medication period
measure: Change in Serum Insulin Levels
timeFrame: baseline and after 15 days medication period
measure: Change in Prolactin Levels
timeFrame: baseline and after 15 days medication period
measure: Change in Total Caloric Intake
timeFrame: baseline and after 15 days medication period
measure: Change in The Wisconsin Schizotypy Scales - Short Form Scores
timeFrame: baseline and after 15 days medication period
measure: Change in the Early Psychosis Social Scale Survey Score
timeFrame: baseline and after 15 days medication period
measure: Change in the Prodromal Questionnaire, Brief Version Total Score
timeFrame: baseline and after 15 days medication period
measure: Change in the Symptoms Checklist - 90 - Revised Global Severity Score
timeFrame: baseline and after 15 days medication period
measure: Change in the State-Trait Anxiety Inventory for Adults Scores
timeFrame: baseline and after 15 days medication period
measure: Change in the World Health Organization Quality of Life Questionnaire Score
timeFrame: baseline and after 15 days medication period
Locations:
city: Belmont
country: United States
facility: McLean Hospital
state: Massachusetts
Study officials:
affiliation: Mclean Hospital
name: Dost Ongur, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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