The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals
Phase: PHASE4
Conditions: Healthy
Sponsor: Dost Ongur

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NCT02536846 
 
Protocol Title: The effects of antipsychotic drugs on brain metabolism in healthy individuals 
 
Protocol Version date: 4/5/21 
 
 
 
 

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PRINCIPAL INVESTIGATOR 
 
Dost Öngür, MD, PhD  
Phone: 617-855-3922 
Schizophrenia & Bipolar Disorder Program 
e-mail: dongur@partners.org 
 
PROTOCOL TITLE 
The effects of antipsychotic drugs on brain metabolism in healthy individuals.
BACKGROUND  
Schizophrenia is a complex psychiatric disorder characterized by alterations in brain structure. It 
remains unclear yet whether some of these alterations may be related to pathophysiology of illness 
per se, or are the consequence of brain exposure to the effects of psychotropic drugs. In recent years 
evidence suggests that exposure to the effects of psychotropic drugs may contribute to some structural 
and other changes in brain. In this study, we aim to evaluate the effects of short-term antipsychotic 
medication use in healthy subjects on neuroimaging markers. We will also examine effects of 
antipsychotic exposure on neurocognitive performance. 
 
The primary aim of this study is to investigate antipsychotic drug effects on brain energy metabolism 
in 30 healthy people by administering olanzapine over 15 days and using 31P MRS imaging at 4 Tesla. 
Secondary aims include studying the effects of olanzapine on other neuroimaging markers 
collected using MRI approaches and cognition.
 
We plan to study the levels of chemicals associated with cellular energy metabolism: kinetics of 
enzymes involved in cellular energy metabolisms in brains of healthy people before and after use of 
antipsychotic drug olanzapine for 15 days. In addition, we will also 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; white matter integrity; and neurocognition. We will collect whole brain data 
where possible and focus on the medial prefrontal cortex and parietal cortex as two regions of interest 
whenever whole-brain data collection is not possible due to technical limitations.  
 
RESEARCH DESIGN AND METHODS 
 
Enrollment: The study will enroll up to 30 healthy people with no history of psychiatric illness 
or family history of psychosis. 
 
There are no restrictions on subject recruitment based on sex, ethnic background or health status other 
than those mentioned below. Individuals who do not speak English will be excluded. 
 
Inclusion Criteria 
1. Age: 21-50 years old. 
2. Male or female. 
3. Without psychiatric diagnosis according to a structured psychiatric interview (SCID; First et al 
1994). 
4. Without history of a psychotic disorder among parents, siblings, or children. 

 
 
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Exclusion Criteria 
1. Significant medical or neurological illness. 
2. Unstable/active disease or potential contraindications. 
3. Body mass index (BMI) greater than or equal to 30. 
4. Taking any other medications, including over the counter supplements, with the exception of 
oral contraceptives for women. 
5. Pregnancy. Females of child-bearing age must be using an effective contraceptive method. 
6. History of smoking, substance abuse or dependence. 
7. Contraindication to MR scan, 
8. Medical condition that would prevent blood draws. 
 
This study will be comprised of three main parts. The subject is free to withdraw from the study at any 
time. Similarly, the investigators may decide to stop the study if the purposes of the study cannot be 
met. All participants will be asked not to use alcohol or any other substances and drugs during the study 
period. 
 
1. Baseline Assessments: The first part of the study will be carried out within 10 days of study 
entrance and consists of 3 separate visits which will take about 8 hours in total. This part of the 
study will consist of the following procedures: 
a. Consenting procedures (20 minutes) 
b. Clinical evaluation (120 minutes) 
c. Urine toxicology screen (5 minutes) and blood pregnancy test (5 minutes) 
d. MRI procedure: 
i. Common Anatomic Protocol (CAP) at 3T (MR Scan at 3T – 1) (45 minutes) 
ii. MRS protocol at 3T (MR Scan at 3T – 2) (30 minutes) 
iii. Phosphorous MRS/MT at 4T (MR Scan at 4T – 1) (90 minutes) 
iv. Diffusion Tensor Spectroscopy (DTS) at 4T (MR Scan at 4T – 2) (90 minutes) 
e. Fasting (12 hours) blood draw of 20 mL (10 minutes) 
f. Assessment of vital signs, weight, height, waist and hip circumference (5 minutes) 
g. ECG (10 minutes) 
h. Neuropsychiatric assessment (60-90 minutes) 
i. MATRICS Consensus 
i. 24-Hour food recall (Total Dietary Intake ASA24)  
 
 
2. Study Visits: The second part of the study in which participants will take daily antipsychotic 
medication will be carried out within 15 days. There will be 5 separate visits on 1st, 2nd, 5th, 10th, 
and 14th days of medication and each visit will take about thirty to sixty minutes. 
 
Participants will take daily olanzapine as the antipsychotic medication, Zyprexa Zydis. 
On the first day of medication each participant will take Zyprexa Zydis 2.5 mg/day PO. Dose 
will be increased in the second day and participants will be taking Zyprexa Zydis 5 mg/day, PO, 
for the following days. 
 

 
 
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The medication will always begin on weekdays except Friday. On the 1st and 2nd day of the 
medication, participants will be asked to take the medication at McLean Hospital. After they take 
the medication we will monitor them closely for 1 hour to observe any side effects.  
If the participants do not have any unacceptable side effects in the first two days, then they will 
be able to take the 13 remaining doses at home starting from the third day 
 
On the 2nd, 5th, and 10th days of medication we will administer LUNSERS (Liverpool University 
Neuroleptic Side Effect Rating Scale), ESRS (Extrapyramidal Symptom Rating Scale) and the 
Columbia Suicide Severity Rating Scale to assess potential side effects better. Weight and vital 
signs assessment, random blood glucose test will be done and ECG will be taken in these visits. 
On 5th, 10th, and 14th days all participants will have blood drawn for assessment of olanzapine 
plasma levels. Each visit will take about 30 minutes to an hour. 
 
Participants’ dietary intake will be assessed throughout the study using the 24-Hour Food Recall 
ASA24 at visits 3 and 8, and with the Food Craving Questionnaire-Trait-reduced (FCQ-T-r) at 
the 1st, 7th and 9th visits.  
 
We will still complete the study with participants who miss up to 3 days of medication 
administration and qualify those participants as having received the intended course of 
medication (while recording their degree of noncompliance). Participants who miss more than 3 
days of medication will be discontinued from the study.  
 
3.  Endpoint Assessments: All participants will undergo final investigations on the 15th and 16th 
days of the medication follow up period. The participants will take their last olanzapine dose on 
the evening of the 15th day. They will not be asked to take it on the 16th day as we plan to finish 
all final assessments during daytime and they take their medications in the evening. Participants 
will undergo 4T MR scan and neurocognitive testing on the 16th day. All other assessment and 
3T MR scans will be done on the 15th day. The third part of the study will consist of the 
following procedures: 
a. Clinical evaluation (60 minutes) 
b. Urine toxicology screen (5 minutes) and pregnancy test (5 minutes) 
c. MRI procedure: 
i. Common Anatomic Protocol (CAP) at 3T 
ii. MRS protocol to quantify Glu and GABA at 3T  
iii. Phosphorous MRS/MT at 4T  
iv. Diffusion Tensor Spectroscopy (DTS) at 4T  
d. Fasting (12 hours) blood draw of 20 mL (10 minutes) 
e. Assessment of vital signs, weight, height, waist, and hip circumference (5 minutes) 
f. ECG (10 minutes) 
g. Neuropsychological Assessment (60-90 minutes) 
i. MATRICS Consensus Cognitive Battery 
h. 24-Hour food recall (Total Dietary Intake ASA24) 
 
Medication: The half-life of olanzapine is 30 hours and one week would be sufficient to reach steady 
state. However, we decided to give medication longer than 1 week as we know that drug-induced 
adaptive changes take time to occur. Up until now, the longest duration of olanzapine use in healthy 

 
 
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volunteers has been 15 days. It is a randomized, PBO controlled, two- treatment (OLZ and PBO), 
crossover study in which the metabolic effects of olanzapine were investigated. 30 healthy men aged 
between 18-49 years underwent 10 mg/d olanzapine treatment for 15 days (5 mg/d for 3 days, then 10 
mg/d for 12 days) in this study 
15. There are also some other multiple-dose studies in which the 
participants were given daily olanzapine to investigate metabolic effects up to 15 days 
16, 17, 18 19. None of 
the participants in these studies had major, severe side effects of olanzapine. Based on these studies we 
determined the duration of medication as 15 days in this study. We determined the daily olanzapine 
dosage as 5 mg in this study. We aimed 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. 
 
To assess the potential side effects of olanzapine, we set up 5 separate visits on the 1st, 2nd, 5th, 10th, 14th 
days of medication period. A physician will be present to monitor all participants’ reactions to the 
medication and stop the medication if they are affected adversely. 
 
MRI/MRS Scan: We have found that most subjects find that remaining in the scanner is somewhat 
uncomfortable but acceptable. An MRI technologist will be able to communicate with subjects at all 
times via intercom. Subjects are informed that they are free to stop at any point. Padding around the 
head will protect subjects from minor mechanical injuries and reduce head motion. Earplugs will 
be used to minimize the scanning noise of MR scanner. Women of childbearing potential must 
undergo a negative urine pregnancy test prior to completing the MR procedure on each day of MR 
scanning.  
 
Women of childbearing age: Pregnant women and nursing mothers cannot participate to this study. If 
the participant is a woman of childbearing potential, she must be using a metal-free IUD, oral 
contraceptive, or barrier methods (for at least 3 months) or must be abstinent (for at least 1 month: time 
to get the most reliable result with pregnancy test) prior to this study. In addition, they must have a 
negative blood pregnancy test (instead of urine pregnancy test) at the beginning of the study.  
 
Blood Draw: Subjects will be monitored for 15 minutes following the blood draw to ensure they are 
doing well. To minimize the possibility of bruising and infection from the blood draw, proper sterile 
phlebotomy techniques will be used. 
 
Psychiatric Evaluation: Some subjects might feel uncomfortable answering questions during the 
psychiatric evaluation. They will not be forced to answer if they do not wish to answer any particular 
question. 
 
Neuropsychiatric Assessment: Fatigue, frustration, or boredom may occur during the assessment; 
however, participants will be offered the option to discontinue testing or training sessions and resume at 
a later time in order to minimize these effects. 
 
To minimize potential breach of confidentiality, subject data are coded with unique research numbers. 
The code linking the research number with personal identifiers is kept in binders separate from both 
clinical and imaging data and also in password- protected computer files on computers in a locked 
office at McLean. Subject interview records and imaging data are identified by research numbers and 
will be collected and stored via the secure web-based application REDCap. The application complies 

 
with HIPAA regulations and will store the information securely, protected by web authentication, and 
Secure Sockets Layer (SSL) encryption. Dietary information captured from the ASA24 is stored in an 
NIH-designed database that is completely deidentified. The only document linking the participant’s 
username and study number will be kept in a password-protected computer file in a locked office at 
McLean.
 
Statistical Analysis: There is no published literature on the effects of olanzapine on the brain measures 
we plan to study. Therefore, it is not possible to calculate a sample size that would detect a 
given between-group difference in this study. In fact, our hypothesis is that olanzapine administration 
does not cause significant abnormalities in brain metabolism. Therefore, we plan to recruit a sample that 
is large enough to establish the absence of a moderate or large effect. Our proposed sample size of 30 
subjects will allow us to detect a difference with effect sizes of 0.45 or greater as significant at the 
p<0.05 level with 80% power. Note that effect sizes of 0.5 are generally considered moderate and 0.8 
considered large. Therefore, a non-statistically significant finding with our sample size will suggest that 
any effects of olanzapine on brain metabolism are at best small. We will examine deviations induced by 
the study drug on brain metabolism using paired t-tests for before and after measurements. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
In terms of olanzapine treatment, the medication may be unsafe for some people and cause some 
unwanted side effects (neurological, gastrointestinal, dermatological, ocular, musculoskeletal, 
hematologic, endocrine, metabolic, psychiatric). 
 
Nervous system side effects have frequently included somnolence, tremor, insomnia, dizziness, speech 
disorder, abnormal gait, amnesia, paresthesia, apathy, confusion, tremor, akathisia, hypertonia, 
articulation impairment, incoordination, abnormal dreams, emotional lability, agitation, nervousness, 
and hostility. Akinesia, alcohol misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, 
delirium, dementia, depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, 
incoordination, stimulant misuse, stupor, stuttering, tardive dyskinesia, vertigo, and withdrawal 
syndrome have also been reported. Circumoral paresthesia, coma, encephalopathy, neuralgia, 
neuropathy, nystagmus, paralysis, subarachnoid hemorrhage, tobacco misuse, and sleep related eating 
disorder have been reported rarely 
22, 23, 24, 25, 26. Almost all antipsychotics have been associated with a 
risk of epileptic seizure provocation. Olanzapine can lower seizure threshold. However, in patients on 
olanzapine for the treatment of a primary psychiatric disorder, clinical seizure is a rare occurrence. In 
most of these cases, a history of seizure or risk factors for seizures were reported. 
 
All antipsychotics have been associated with the risk of sudden cardiac death due to an arrhythmia. In 
clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500 
milliseconds [msec] at any time post-baseline in patients with baseline QTcF 
< 500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant 
differences in associated cardiac events compared to placebo. 
 
Metabolic side effects have frequently included weight gain. Binge eating and increases in food craving 
have been associated with olanzapine. Additional studies have confirmed that patients receiving 
atypical antipsychotics are at an increased risk of developing hyperglycemia and/or diabetes mellitus. 

 
 
Hepatic side effects have rarely included hepatitis, liver fatty deposit, and cholestatic or mixed liver 
injury. Transient and moderate, asymptomatic elevations in liver function tests have been reported.  
 
Gastrointestinal side effects have frequently included dry mouth, increased appetite, thirst, constipation, 
dyspepsia, increased salivation, vomiting, and flatulence. Dysphagia, esophagitis, fecal impaction, fecal 
incontinence, gastritis, gastroenteritis, gingivitis, melena, mouth ulceration, nausea and vomiting, oral 
moniliasis, periodontal abscess, rectal hemorrhage, stomatitis, tongue edema, taste perversion, and tooth 
caries have also been reported. Isolated cases of olanzapine-induced acute pancreatitis have been 
reported during post marketing use 
33. 
 
Musculoskeletal side effects have included extremity pain (other than joint pain) and joint pain in 5% 
of patients. Joint stiffness and twitching have been reported frequently. Arthritis, arthrosis, leg 
cramps, and myasthenia have also been reported. Bone pain, bursitis, myopathy, osteoporosis, 
rheumatoid arthritis, and rhabdomyolysis have been reported rarely 
34. 
 
Hematologic side effects have rarely included anemia, leukocytosis, leukopenia, lymphadenopathy, 
thrombocytopenia, normocytic anemia, neutropenia, leukopenia, agranulocytosis, eosinophilia, 
agranulocytosis, and thrombocythemia
35, 36, 37, 38. 
 
Ocular side effects have frequently included amblyopia, abnormal vision, and conjunctivitis. 
Abnormality of accommodation, blepharitis, cataract, diplopia, dry eyes, eye hemorrhage, eye 
inflammation, eye pain, ocular muscle abnormality have also been reported. Glaucoma, corneal lesion, 
keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, esotropia, and pigment deposits in 
the lens have been reported rarely 
39, 40, 41. 
 
Psychiatric side effects have frequently included depression, euphoria, delusions, manic, and psychotic 
symptoms. Obsessive-compulsive symptoms and suicide attempts have also been reported 
42. One of the 
important side effects of antipsychotic drugs is neuroleptic malignant syndrome. Neuroleptic malignant 
syndrome (NMS) is a rare (incidence rates; range from 0.02 to 3 percent among patients taking 
neuroleptic agents) but life-threatening, idiosyncratic reaction to neuroleptic medications.  
 
Olanzapine, like all other drugs, can cause hypersensitivity syndrome which is seen very rarely. Drug 
Hypersensitivity Syndrome (DHS) is unpredictable but potentially life- threatening with significant 
morbidity. This syndrome is a severe, idiosyncratic multi- system reaction defined by the clinical triad 
of fever, rash and internal organ involvement (e.g., hepatitis, myocarditis, nephritis or pneumonitis), 
which may occur 1 - 8 weeks after medicine exposure. Fever is a common early feature, usually 
preceding a widespread and long-lasting papulopustular or erythematous skin eruption, which often 
progresses to exfoliative dermatitis. The severity of the skin-related changes does not correlate with the 
extent of internal organ involvement, which may remain asymptomatic or be life- threatening. 
Treatment consists of immediate withdrawal of all suspect medicines, followed by supportive care of 
symptoms. Hospitalization may be required. The mortality from drug hypersensitivity syndrome is 
estimated at around 8% 
51. 
 
In terms of the MRI and MRS scans, unlike X-rays or CAT scans, magnetic resonance (MR) 
technology does not use ionizing radiation. The MR system requires the use of rapidly varying 
magnetic gradient fields and strong radio frequency fields, which conform to the guidelines established 

 
by the US FDA for time varying magnetic fields in MR devices. This study uses a standard clinical 
MRI scanner (3 Tesla or 3T), as well as a high field (4 Tesla or 
4T) MRI scanner. The 4T scanner is not used for routine clinical studies in children or adults, but 
the FDA has determined (July 14, 2003) that scanners with magnetic field strengths of less than 8 
Tesla (double this scanner) or less do not represent a significant risk to adults, children, or infants 
aged more than 1 month. There could be adverse effects that are delayed or very mild, such that they 
have not yet been recognized. Most people experience no ill effects from 3T or 4T scans, but some 
people do report claustrophobia dizziness, mild nausea, headaches, a metallic taste in their mouth, 
double vision, or sensation of flashing lights. These symptoms, if present, disappear shortly after 
leaving the scanner. No serious adverse effects have been reported to date at any site operating at 3T or 
4T field strength. 
 
Blood draw may lead to a small arm bruise and, in rare cases clot or infection at the site the blood was 
drawn. Some people become light-headed during or immediately after a blood draw. These are rare 
occurrences, and, in our experience, the vast majority of subjects tolerate blood draws well. 
 
In terms of the psychiatric evaluation, some subjects might feel uncomfortable answering questions, 
but they will not be forced to answer if they do not wish to do so. 
 
In terms of the neuropsychiatric assessment, some participants may experience fatigue, frustration, or 
boredom; however, participants will be offered the option to discontinue testing or training sessions and 
resume at a later time in order to minimize these effects. 
 
To minimize potential breach of confidentiality, subject data are coded with unique research numbers. 
The code linking the research number with personal identifiers is separate from both clinical and 
imaging data and also in password- protected computer files on computers in a locked office at 
McLean. Subject interview records and imaging data are identified by research numbers and will be 
collected and stored via the secure web-based application REDCap. The application complies with 
HIPAA regulations and will store the information securely, protected by web authentication, and Secure 
Sockets Layer (SSL) encryption. Dietary information captured from the ASA24 is stored in an NIH-
designed database that is completely deidentified.
RECRUITMENT PROCEDURES 
For subject recruitment, the research coordinators/assistants will post online advertisements and flyers 
around the McLean campus and local universities describing the study and the procedures involved. 
The participants will come in and go through the consent process and be administered the Informed 
Consent by a licensed physician investigator. The subject is then provided with a copy of their signed 
consent form to review and keep. 
 
Subjects will be compensated by check for the procedures that they complete. If the subject does not 
complete the entire study, he/she will be compensated for the procedures that were completed. The 
subjects will be compensated a total of up to $680 for all study procedures. Travel costs above $5, as 
authenticated by a receipt, will be reimbursed up to $25 per visit. 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date: July 2015 
CONSENT PROCEDURES 
For participants, consent is obtained in a private interview room. The physician and a research assistant 
will thoroughly review the consent form with the participant. Subjects are given as much time as 
they need to look over the consent for before signing it. 
 
DATA AND SAFETY MONITORING
Subjects are thoroughly screened by a research assistant and a qualified physician prior to their 
enrollment in the study to ensure subject safety. The physician closely monitors the participants during 
the medication period. Subjects are carefully assessed before, during, and after the MRI scans by the 
research assistant and MR technologist or authorized personnel to ensure that they suffer no adverse 
reactions. The physician will be present in all phases of the screening process. The PI closely oversees 
all of the study activities and intervenes wherever necessary.