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The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

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ClinicalTrials.gov Identifier: NCT02536846
Recruitment Status : Recruiting
First Posted : September 1, 2015
Last Update Posted : April 25, 2019
Sponsor:
Information provided by (Responsible Party):
Dost Ongur, Mclean Hospital

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

Condition or disease Intervention/treatment Phase
Healthy Drug: Olanzapine Phase 4

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 30 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals
Actual Study Start Date : November 17, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


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 Name: Zyprexa Zydis 5 mg tb




Primary Outcome Measures :
  1. Changes in levels of chemicals and kinetics of enzymes associated with cellular energy metabolism [ Time Frame: baseline and after 15 days medication period ]
    Changes in the levels of chemicals associated with cellular energy metabolism; kinetics of enzymes involved in cellular energy metabolisms in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Phosphorus magnetic resonance spectroscopy techniques will be used for this evaluation.


Secondary Outcome Measures :
  1. Changes in the gray and white matter volumes (cubic millimeters -mm3-) of medial prefrontal cortex and parietal cortex [ Time Frame: baseline and after 15 days medication period ]
    Changes in the gray and white matter volumes (cubic millimeters -mm3-) of medial prefrontal cortex and parietal cortex in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Structural magnetic resonance imaging techniques and Free Surfer program will be used for analysis and visualization of volumetric brain imaging data.

  2. Structural changes (assessment of expansions and constractions of the brain structures by vectorial analysis) of the gray and white matter in medial prefrontal cortex and parietal cortex [ Time Frame: baseline and after 15 days medication period ]
    Structural changes (assessment of expansions and constractions of the brain structures by vectorial analysis) of the gray and white matter in medial prefrontal cortex and parietal cortex in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Structural magnetic resonance imaging techniques and Free Surfer program will be used for analysis and visualization of structural brain imaging data.

  3. Changes in resting state functional brain activity (changes in low frequency BOLD -blood-oxygen-level-dependend- signals) in medial prefrontal cortex and parietal cortex [ Time Frame: baseline and after 15 days medication period ]
    Changes in resting state functional brain activity (changes in low frequency BOLD -blood-oxygen-level-dependend- signal) in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Resting state functional brain activity will be measured by using functional magnetic resonance imaging techniques.

  4. Changes in levels of brain chemicals (millimoles) including glutamate and GABA in medial prefrontal cortex and parietal cortex [ Time Frame: baseline and after 15 days medication period ]
    Changes in levels of brain chemicals (millimoles) including glutamate and GABA in medial prefrontal cortex and parietal cortex in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Levels of these chemicals will be measured by using proton magnetic resonance spectroscopy techniques.

  5. Changes in parameters (changes in FA -fractional anisotropy- which is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process) on white matter integrity from medial prefrontal cortex and parietal cortex [ Time Frame: baseline and after 15 days medication period ]
    Changes in parameters (changes in FA -fractional anisotropy- which is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process) on white matter integrity from medial prefrontal cortex and parietal cortex in brains of healthy people after use of antipsychotic drug olanzapine for 15 days. Diffusion tensor imaging techniques will be used for this evaluation.


Other Outcome Measures:
  1. Change in Montgomery-Asberg Depression Rating Scale (MADRS) score [ Time Frame: baseline and after 15 days medication period ]
    Change in Montgomery-Asberg Depression Rating Scale (MADRS) score, a 0-60 point scale rating depressive symptoms. Higher scores indicate more severe clinical symptoms. There are no subscales.

  2. Change in Beck Depression Inventory (BDI) score [ Time Frame: baseline and after 15 days medication period ]
    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.

  3. Change in Young Mania Rating Scale (YMRS) score [ Time Frame: baseline and after 15 days medication period ]
    Change in Young Mania Rating Scale (YMRS) score, an interview-based, 11-item scale that measures the severity of core features of clinical mania.8 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.

  4. Change in Beck Anxiety Inventory (BAI) score [ Time Frame: baseline and after 15 days medication period ]
    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.

  5. Change in The Columbia Suicide Severity Rating Scale score [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    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.

  6. Change in Pittsburgh Sleep Quality Index score [ Time Frame: baseline and after 15 days medication period ]
    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.

  7. Change in LUNSERS (Liverpool University Neuroleptic Side Effect Rating Scale) score [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    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.

  8. Changes in weight measures [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    Change in participant body mass, as measured using a standing scale.

  9. Changes in hip circumference measures [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    Change in the circumference of participants' hips, taken as an average of 3 measures by tape measure

  10. Changes in waist circumference measures [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    Change in the circumference of participants' waist, taken as an average of 3 measures by tape measure

  11. Changes in blood glucose levels [ Time Frame: baseline and 2, 5, 10 and 15 days during medication period ]
    Change in results of fasting, serum metabolic panel blood test

  12. Changes in lipid parameters [ Time Frame: baseline and after 15 days medication period ]
    Change in results of fasting, whole blood lipid panel test

  13. Changes in HbA1c levels [ Time Frame: baseline and after 15 days medication period ]
    Change in results of fasting, Hemoglobin A1c whole blood test

  14. Changes in insulin levels [ Time Frame: baseline and after 15 days medication period ]
    Change in results of insulin fasting serum blood test

  15. Changes in prolactin levels [ Time Frame: baseline and after 15 days medication period ]
    Change in results of prolactin serum blood test

  16. Changes in dietary intake [ Time Frame: baseline and after 15 days medication period ]
    Changes in health parameters assessed by the ASA24 Dietary Recall and Food Frequency Questionnaire - Revised

  17. Changes in The Wisconsin Schizotypy Scales - Short Form scores [ Time Frame: baseline and after 15 days medication period ]
    Changes in The Wisconsin Schizotypy Scales - Short Form scores

  18. Changes in the Early Psychosis Social Scale Survey score [ Time Frame: baseline and after 15 days medication period ]
    Changes in the Early Psychosis Social Scale Survey score

  19. Changes in the Prodromal Questionnaire, Brief Version Total score [ Time Frame: baseline and after 15 days medication period ]
    Changes 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.

  20. Changes in the Symptoms Checklist - 90 - Revised Global Severity Score [ Time Frame: baseline and after 15 days medication period ]
    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.

  21. Changes in the State-Trait Anxiety Inventory for Adults scores [ Time Frame: baseline and after 15 days medication period ]
    Changes 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 4-80, with higher scores indicating greater state or trait anxiety, respectively.

  22. Changes in the World Health Organization Quality of Life questionnaire score [ Time Frame: baseline and after 15 days medication period ]
    Changes 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 and transformed for a total range of 0-100.



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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02536846


Contacts
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Contact: Margaret Gardner 617-855-2489 mgardner@mclean.harvard.edu
Contact: Dost E Ongur, MD, PhD 617-855-3922 dongur@partners.org

Locations
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United States, Massachusetts
McLean Hospital Recruiting
Belmont, Massachusetts, United States, 02478
Sub-Investigator: Virginie-Anne Chouinard, MD         
Principal Investigator: Dost Ongur, MD, PhD         
Sponsors and Collaborators
Mclean Hospital
Investigators
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Principal Investigator: Dost Ongur, MD, PhD Mclean Hospital

Additional Information:
Publications:

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Responsible Party: Dost Ongur, Chief of Psychotic Disorders Division at McLean Hospital and Associate Professor in Psychiatry at Harvard Medical School, Mclean Hospital
ClinicalTrials.gov Identifier: NCT02536846     History of Changes
Other Study ID Numbers: 2015P001140
041512 ( Other Grant/Funding Number: McLean Hospital )
First Posted: September 1, 2015    Key Record Dates
Last Update Posted: April 25, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dost Ongur, Mclean Hospital:
Healthy volunteers
antipsychotic drugs
brain metabolism
Additional relevant MeSH terms:
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Olanzapine
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents