The Effects of Antipsychotic Drugs on Brain Metabolism in Healthy Individuals

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.

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 or mood 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 25

- 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