The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Olanzapine

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • McLean Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Second Generation Antipsychotic Drug; Olanzapine; a single 2.5 mg dose PO daily followed by 5 mg dose PO daily for 14 days	Drug: Olanzapine; 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 Names: Zyprexa Zydis 5 mg tb

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Score	Change in Montgomery-Asberg Depression Rating Scale (MADRS) score, a 0-60 point scale rating depressive symptoms. Higher scores indicate more severe clinical symptoms.	baseline and after 15 days medication period
Change in Beck Depression Inventory (BDI) Score	Change in Beck Depression Inventory (BDI) score, a self-report questionnaire measuring depressive symptoms on a scale of 0-63. Scores ranging 0-9 generally indicate minimal depressive symptoms, while scores 10-18 indicate mild, 19-29 indicates moderate, and 30-63 indicates severe depressive symptoms, respectively.	baseline and after 15 days medication period
Change in Young Mania Rating Scale (YMRS) Score	Change in Young Mania Rating Scale (YMRS) score, an interview-based, 11-item scale that measures the severity of core features of clinical mania. 7 items are scored on a 0-4 point scale, while the remaining 4 are scored on a 0-8 point scale, for a total possible range of 0-64. Higher scores indicate more severe manic symptoms.	baseline and after 15 days medication period
Change in Beck Anxiety Inventory (BAI) Score	Change in Beck Anxiety Inventory (BAI) score, a self-report measure of anxiety symptoms. Scores range from 0-63, with higher scores indicating more severe anxiety.	baseline and after 15 days medication period
Change in The Columbia Suicide Severity Rating Scale Score	Change in The Columbia Suicide Severity Rating Scale score, a self-report scale measuring suicidality. Only the total score, not subscale of suicidal ideation intensity, will be measured. Total scores can range from 0-10, with higher scores indicating increased suicidality.	baseline and 2, 5, 10, 15 days during medication period
Change in Pittsburgh Sleep Quality Index Score	Change in Pittsburgh Sleep Quality Index score, a measurement of sleep quality. The index measures 7 sleep components on a 0-3 scale; each of the 7 raw scores is summed to get a global score. The global score ranges from 0-21, with higher scores indicating poor sleep quality. Scores >5 are typically considered poor sleep quality.	baseline and after 15 days medication period
Change in LUNSERS (Liverpool University Neuroleptic Side Effect Rating Scale) Score	Change in LUNSERS (Liverpool University Neuroleptic Side Effect Rating Scale) score, a self-report measure of antipsychotic side effects. The scale has 51 questions, 41 of which are about side-effects and 10 "red herrings" for validation purposes. The total neuroleptic side effect score is derived from the sum of the 41 side-effect questions, with a potential range of 0-164. Higher scores indicate more severe neuroleptic side effects.	baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
Change in Body Weight	Change in participant body weight in kg, as measured using a standing scale.	baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
Change in Hip Circumference	Change in the hip circumference measurement, taken as an average of 3 measures by tape measure	baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
Change in Waist Circumference	Change in waist circumference measurements, taken as an average of 3 measures by tape measure.	baseline and 2, 5, 10 and 15 days (or final assessment) during medication period
Change in Blood Glucose Levels	Change in fasting serum glucose levels.	baseline and after 15 days during medication period
Change in Fasting Total Cholesterol Level	Change in fasting total cholesterol level	baseline and after 15 days medication period
Change in Hemoglobin A1c Level	Change in fasting, Hemoglobin A1c level	baseline and after 15 days medication period
Change in Serum Insulin Levels	Change in insulin fasting serum levels	baseline and after 15 days medication period
Change in Prolactin Levels	Change prolactin serum levels	baseline and after 15 days medication period
Change in Total Caloric Intake	Change in total caloric intake as assessed by the ASA24 Dietary Recall and Food Frequency Questionnaire - Revised. The ASA24 is a self-administered 24-hour dietary recall assessment.	baseline and after 15 days medication period
Change in The Wisconsin Schizotypy Scales - Short Form Scores	Change in Wisconsin Schizotypy Scales (WSS) Short Form score, a self-report questionnaire assessing schizotypy in clinical and non-clinical samples. The measure has four scales, each with 15 True/False questions. There are 13 red-herring questions, that, if answered "True" invalidate the test. Each "false" response is scored 0, and each "true" response is scored 1. Scores for each scale range from 0 - 15, with higher scores indicating greater schizotypy. The WSS positive schizotypy score consists of the summed score of the perceptual aberration and magical ideation scales and scores range from 0-30, with higher scores indicating greater positive schizotypy. The WSS negative schizotypy score sums scores from the physical anhedonia and social anhedonia scales and ranges from 0-30, with higher scores indicating greater negative schizotypy.	baseline and after 15 days medication period
Change in the Early Psychosis Social Scale Survey Score	Change in the Early Psychosis Social Scale score item of missed absences from school or work. Scores range from 1-5, with higher scores indicating more absences from school or work.	baseline and after 15 days medication period
Change in the Prodromal Questionnaire, Brief Version Total Score	Change in the Prodromal Questionnaire, Brief Version score, a 21 item self-report questionnaire designed to help identify those at ultra-high risk for developing psychotic symptoms. The total score is derived as the sum of all 21 items, with a possible range of 0-21. Higher scores indicate greater psychopathology.	baseline and after 15 days medication period
Change in the Symptoms Checklist - 90 - Revised Global Severity Score	Changes in the Symptoms Checklist - 90 - Revised scale, which measures 9 domains of psychological dysfunction, summing to create an overall psychological distress (Global Severity Score). The scores of each of the 9 domains - somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism - combine for a total of 90 items, each measured on a 5-point scale. The sums of all 90 item scores, ranging 0-360, creates the Global Severity score. Higher scores indicate greater psychopathology.	baseline and after 15 days medication period
Change in the State-Trait Anxiety Inventory for Adults Scores	Change in the State-Trait Anxiety Inventory for Adults, which measures both state and trait anxiety using 2 subscales for a total of 40 items. Each subscale has a range of 20-80, with higher scores indicating greater state or trait anxiety, respectively.	baseline and after 15 days medication period
Change in the World Health Organization Quality of Life Questionnaire Score	Change in the World Health Organization Quality of Life questionnaire score, a 26-item assessment of overall quality of life. The questionnaire encompasses 4 domains: physical health, psychological health, social relationships, and environment. There are two additional questions, which assess the participant's perceptions of their own quality of life and physical health. Higher scores indicate better quality of life. Scores are summed within each domain. Total score is obtained by transforming for a total range of 0-100 within each domain.	baseline and after 15 days medication period

Collaborators and Investigators

• Sponsor: Dost Ongur
• Investigators: Principal Investigator: Dost Ongur, MD, PhD, McLean Hospital

Publications and helpful links

General Publications

• Martinez ZA, Oostwegel J, Geyer MA, Ellison GD, Swerdlow NR. "Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits. Neuropsychopharmacology. 2000 Nov;23(5):517-27. doi: 10.1016/S0893-133X(00)00147-0.
• Agostinho FR, Reus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Benedet J, Rochi N, Scaini G, Streck EL, Quevedo J. Treatment with olanzapine, fluoxetine and olanzapine/fluoxetine alters citrate synthase activity in rat brain. Neurosci Lett. 2011 Jan 10;487(3):278-81. doi: 10.1016/j.neulet.2010.10.037. Epub 2010 Oct 28.
• Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005 Sep;30(9):1649-61. doi: 10.1038/sj.npp.1300710.
• Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology. 2007 Jun;32(6):1216-23. doi: 10.1038/sj.npp.1301233. Epub 2006 Oct 25.
• Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry. 2008 Apr 15;63(8):759-65. doi: 10.1016/j.biopsych.2007.08.018. Epub 2007 Oct 22.
• Vita A, De Peri L. The effects of antipsychotic treatment on cerebral structure and function in schizophrenia. Int Rev Psychiatry. 2007 Aug;19(4):429-36. doi: 10.1080/09540260701486332.
• Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue EW, McGuire PK, Riecher-Rossler A, Borgwardt SJ. The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia?--a systematic review. Curr Pharm Des. 2009;15(22):2535-49. doi: 10.2174/138161209788957456.
• Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull. 2014 Mar;40(2):314-26. doi: 10.1093/schbul/sbu001. Epub 2014 Feb 3.
• Vidarsdottir S, Roelfsema F, Frolich M, Pijl H. Olanzapine shifts the temporal relationship between the daily acrophase of serum prolactin and cortisol concentrations rhythm in healthy men. Psychoneuroendocrinology. 2009 Jun;34(5):705-12. doi: 10.1016/j.psyneuen.2008.11.008. Epub 2009 Jan 7.
• Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab. 2010 Jan;95(1):118-25. doi: 10.1210/jc.2008-1815. Epub 2009 Nov 11.
• Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Muller M, Kasper S. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology. 2008 Jun;33(7):1633-41. doi: 10.1038/sj.npp.1301541. Epub 2007 Aug 22.
• Vidarsdottir S, Vlug P, Roelfsema F, Frolich M, Pijl H. Orally disintegrating and oral standard olanzapine tablets similarly elevate the homeostasis model assessment of insulin resistance index and plasma triglyceride levels in 12 healthy men: a randomized crossover study. J Clin Psychiatry. 2010 Sep;71(9):1205-11. doi: 10.4088/JCP.08m04654yel. Epub 2010 Apr 20.
• Fountaine RJ, Taylor AE, Mancuso JP, Greenway FL, Byerley LO, Smith SR, Most MM, Fryburg DA. Increased food intake and energy expenditure following administration of olanzapine to healthy men. Obesity (Silver Spring). 2010 Aug;18(8):1646-51. doi: 10.1038/oby.2010.6. Epub 2010 Feb 4.

Helpful Links

• APA (American Psychiatric Association) Practice Guideline for the Treatment of Patients With Schizophrenia

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2017
• Primary Completion (Actual): November 8, 2019
• Study Completion (Actual): November 8, 2019

Study Registration Dates

• First Submitted: August 20, 2015
• First Submitted That Met QC Criteria: August 27, 2015
• First Posted (Estimate): September 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 3, 2022
• Last Update Submitted That Met QC Criteria: September 22, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Healthy volunteers; antipsychotic drugs; brain metabolism
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Olanzapine
• Other Study ID Numbers: 2015P001140; 041512 (Other Grant/Funding Number: McLean Hospital)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No