Tryptophan MRI in People With Schizophrenia and Healthy Controls



Status:Recruiting
Conditions:Schizophrenia
Therapuetic Areas:Psychiatry / Psychology
Healthy:No
Age Range:18 - 55
Updated:2/3/2019
Start Date:September 2014
End Date:December 2019
Contact:Catherine Kilday
Email:ckilday@mprc.umaryland.edu
Phone:410-402-6412

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Neuroimaging of Tryptophan Challenge in People With Schizophrenia and Healthy Controls

Kynurenic acid (KYNA) is a naturally occurring chemical in the brain. Studies with rodents
indicate that levels of KYNA can impact levels of the neurotransmitters glutamate and
dopamine. One way to reliably increase KYNA levels is by ingesting the amino acid tryptophan.
Tryptophan is a normal part of the human diet. Tryptophan gets metabolized/changed to other
chemicals in the body- including KYNA. By giving people 6 grams of tryptophan, the
investigators will be able to increase the KYNA level in a controlled way. The investigators
will then be able to study the effects of KYNA on neurotransmitters by using cognitive tests
and magnetic resonance imaging techniques (measuring brain activity and brain chemistry using
the MRI magnet). They will test people using tryptophan and also using a placebo to look for
differences. The investigators will test healthy controls and people with schizophrenia to
look for differences.

There is emerging evidence to suggest that disturbances in the kynurenine pathway may be
related to the pathophysiology of schizophrenia. Several post-mortem studies have documented
specific abnormalities in the kynurenine pathway, including increased levels of kynurenine
and kynurenic acid (KYNA) in the prefrontal cortex of people with schizophrenia (1-4).
Increased levels of kynurenine and KYNA have also been observed in the cerebral spinal fluid
(CSF) of people with this illness (5). In addition, post-mortem studies have documented
changes in key enzymes, including increased expression of tryptophan 2,3-dioxygenase (2, 6)
(TDO), which converts tryptophan to kynurenine, and reduced activity of kynurenine
3-monooxygenase (KMO) (4), which may shift metabolism towards enhanced KYNA formation.
Finally, a number of genetic studies have implicated the KYNA pathway in this disease. Wonodi
et al. (7) found decreased KMO gene expression in the frontal eye field of people with
schizophrenia, and Holtze et al. (8) recently reported an association between a KMO SNP and
CSF levels of KYNA. Notably, although the exact mechanism underlying the KP impairment in
people with schizophrenia is unknown, immune and stress mechanisms have been implicated
(7,9).

Increased KYNA may have a number of adverse consequences of importance in schizophrenia. In
particular, KYNA is an antagonist of the α7 nicotinic and NMDA glutamate receptors.
Dysfunctions of these receptors have been linked to the cognitive impairments and symptom
manifestations observed in people with schizophrenia. The purpose of the proposed project is
to examine the impact of increased brain KYNA on performance of cognitive tasks and related
neuroimaging measures in people with DSM-5/DSM-IV-TR schizophrenia, schizophreniform, or
schizoaffective disorder patients and healthy controls. In addition, the investigators will
secondarily investigate the relationship of peripheral inflammatory markers and
glucocorticoid levels as part of the HPA stress axis to examine relationships and shift to a
Type 2 immune response in schizophrenia. Using tryptophan loading to increase KYNA levels,
the study will test the hypothesis, based on complementary preliminary studies in rodents,
that disease-related cognitive deficits in people with schizophrenia are preferentially
susceptible to (further) elevations in KYNA levels.

The investigators hypothesize that tryptophan-induced elevations in brain KYNA levels will:
1) acutely impair performance on measures of verbal and visual memory, attention, working
memory, and processing speed in people with schizophrenia; 2) alter dorsolateral-hippocampal
activation and connectivity, which underlies the performance of the relational memory task;
and 3) decrease mPFC MRS measures of glutamate, consistent with preclinical microdialysis
data. In an exploratory framework, the investigators hypothesize that increased brain KYNA
levels alter default network activation and connectivity, an effect which may be mediated by
the action of KYNA on α7 nicotinic and/or NMDA receptors. The investigators will also
investigate the extent to which cytokine and HPA axis peripheral measures are related to the
effect of tryptophan-induced elevated KYNA levels on cognitive performance and fMRI and MRS
measures. Comparisons with results from healthy controls will determine if participants with
schizophrenia have an aberrant or exaggerated response to increased KYNA levels.

Funding Information:

Funded by the National Institute of Mental Health (NIMH)

Grant Number- 1P50MH103222-01

Principal Investigator- Robert Schwarcz, PhD

Project Title- Kynurenic Acid and Cognitive Abnormalities in Schizophrenia

Program Officer Full Name- Steven Zalcamn

External Org# Name- University of Maryland, Baltimore

Inclusion Criteria (Schizophrenia:

- Males and females between the ages of 18 and 55 years

- Has met DSM-IV-TR/DSM-5 Criteria for schizophrenia, schizoaffective disorder or
schizophreniform disorder

- Prescription of antipsychotic medication for at least 60 days and constant dose for 30
days prior to study entry (either first or second generation antipsychotics permitted)

- Women must be in the first half of their menstrual cycle at the time of the 2
challenge visits

Inclusion Criteria (Healthy Controls):

- Males and females between the ages of 18 and 55 years

- No DSM-IV-TR/DSM-5 Axis I Disorder (documented by SCID)

- Women must be in the first half of their menstrual cycle at the time of the 2
challenge visits

Exclusion Criteria:

- DSM-IV-TR/DSM-5 substance abuse in the last month or substance dependence in the last
6 months (documented by SCID)

- Calgary Depression Scale total score ≥ 10 at baseline

- Current smoker (expired CO ≥ 10 ppm)

- Current use of nicotine replacement therapy or other nicotine products

- Pregnancy or breast feeding

- Post-menopausal women will not be included due to changes in the HPA axis expression
and hormonal effects on cognition. In women over the age of 45, menopausal status will
be evaluated clinically

- Excessive self-reported daily caffeine intake, defined as intake exceeding 1000 mg or
the equivalent of 8 cups of coffee

- Active disorders that have been reported to affect tryptophan metabolism or interfere
with absorption will be excluded (Acute Intermittent Porphyria, Celiac Disease,
Crohn's Disease, Irritable Bowel Syndrome

- History of an organic brain disorder; mental retardation; or a medical condition,
whose pathology or treatment could alter cognition

- Claustrophobia

- Metal in body that will interfere with MR imaging

- Treatment with monoamine oxidase inhibitors, migraine headache medications (triptans)
and dextromethorphan
We found this trial at
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Catonsville, Maryland 21228
Principal Investigator: Robert W. Buchanan, M.D.
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Catonsville, MD
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