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HealthyPhase 4NCT02536846

The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

A Phase 4 study testing Olanzapine in people with Healthy, run by Dost Ongur at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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

Who is it for?
Ages 21 to 50 yearsHealthy volunteers can take part
Conditions the study is for
Healthy
What is being tested?
Olanzapine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
1 siteUnited States
Study dates
17 Nov 2017to 8 Nov 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 50 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • McLean Hospital

    Belmont, Massachusetts, 02478

Other trials in United States

About this study

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

Read the 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.

Conditions
Healthy
Being tested
Olanzapine
Keywords
Healthy volunteers, antipsychotic drugs, brain metabolism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OlanzapineDrug

    Also called Zyprexa Zydis 5 mg tb

    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).

Study groups in NCT02536846
Study groupRoleWhat they receive
Second Generation Antipsychotic DrugExperimentalOlanzapine; a single 2.5 mg dose PO daily followed by 5 mg dose PO daily for 14 days
Receives: Drug: Olanzapine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Baseline and after 15 days medication period

  2. Change in Brain Phosphocreatine (PCr)

    Change in Phosphocreatine (PCr) metabolite concentration as measured by in vivo 31P magnetic resonance spectroscopy

    Measured: Baseline and after 15 days medication period

  3. 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

    Measured: Baseline and after 15 days medication period

  4. Change in Brain Parenchymal pH

    Change in brain parenchymal pH as measured by in vivo 31P magnetic resonance spectroscopy

    Measured: baseline and after 15 days medication period

Secondary outcomes (7)

  1. 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.

    Measured: baseline and after 15 day medication period

  2. 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.

    Measured: baseline and after 15 days medication period

  3. 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.

    Measured: baseline and after 15 days medication period

  4. Change in GABA Concentration

    Change in GABA concentration measured by proton magnetic resonance spectroscopy.

    Measured: baseline and after 15 days medication period

  5. 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).

    Measured: baseline and after 15 days medication period

  6. Change in Glutamate Metabolite Concentration

    Change in glutamate metabolite concentration measured by proton magnetic resonance spectroscopy.

    Measured: baseline and after 15 days medication period

  7. 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.

    Measured: baseline and after 15 days medication period

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Sep 2015 (estimated)
  2. Study start17 Nov 2017
  3. Primary completion8 Nov 2019
  4. Study completion8 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02536846
Sponsor's protocol ID
2015P001140
Other IDs
041512
Status last verified
Sep 2022
First submitted
20 Aug 2015
Last updated
3 Oct 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

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.

    PubMed 11027917

  • 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.

    PubMed 20971158

  • 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.

    PubMed 15756305

  • 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.

    PubMed 17063154

  • 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.

    PubMed 17945195

  • 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.

    PubMed 17671875

  • 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.

    PubMed 19689326

  • 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.

    PubMed 24493852

  • 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.

    PubMed 19131173

  • 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.

    PubMed 19906788

  • 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.

    PubMed 17712347

  • 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.

    PubMed 20441717

  • 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.

    PubMed 20134408

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Olanzapine in people with Healthy, run by Dost Ongur at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Brain Nicotinamide Adenine Dinucleotide Metabolites NAD+/NADH (time frame: Baseline and after 15 days medication period). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02536846, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2022.

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