Tryptophan MRI in People With Schizophrenia and Healthy Controls

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02067975
Recruitment Status : Recruiting
First Posted : February 20, 2014
Last Update Posted : May 16, 2018
Mitsubishi Tanabe Pharma Corporation
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Robert W. Buchanan, University of Maryland

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Tryptophan Drug: Placebo Phase 2 Phase 3

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Detailed Description:

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Neuroimaging of Tryptophan Challenge in People With Schizophrenia and Healthy Controls
Study Start Date : September 2014
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Tryptophan

Arm Intervention/treatment
Active Comparator: tryptophan
6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3
Drug: Tryptophan
Placebo Comparator: Placebo
Placebo will be a liquid drink without tryptophan. 6mg at least two weeks apart at time zero of the 7 hour visits 2 and 3.
Drug: Placebo

Primary Outcome Measures :
  1. Visual memory, attention, and processing speed scores on the Relational and Item Specific Encoding Task (RISE). [ Time Frame: at least two weeks ]
    Tryptophan-induced elevated KYNA levels transiently impair performance on neuropsychological measures of verbal and visual memory, attention, and processing speed.

Secondary Outcome Measures :
  1. Dorsolateralhippcampal fMRI activation and connectivity using the Relational and Item Specific Encoding Task (RISE). [ Time Frame: at least two weeks ]
    Tryptophan-induced elevated KYNA levels alters dorsolateralhippcampal fMRI activation and connectivity during the performance of the relational memory task RISE.

Other Outcome Measures:
  1. Glutamate levels using fMRI [ Time Frame: at least two weeks ]
    Tryptophan-induced elevated KYNA levels alter 1H-MRS measures of glutamate levels in the medial prefrontal cortex (mPFC), a brain region involved in attention and processing speed behaviors, default mode network activity, and sensitive to changes in KYNA levels.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

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 identifier (NCT number): NCT02067975

Contact: Catherine Kilday 410-402-6412

United States, Maryland
Maryland Psychiatric Research Center Recruiting
Catonsville, Maryland, United States, 21228
Principal Investigator: Robert W. Buchanan, M.D.         
Sponsors and Collaborators
University of Maryland
Mitsubishi Tanabe Pharma Corporation
National Institute of Mental Health (NIMH)
Principal Investigator: Robert W Buchanan, M.D. University of Maryland

Responsible Party: Robert W. Buchanan, Interim Director, University of Maryland Identifier: NCT02067975     History of Changes
Other Study ID Numbers: HP-00057861
1P50MH103222-01 ( U.S. NIH Grant/Contract )
First Posted: February 20, 2014    Key Record Dates
Last Update Posted: May 16, 2018
Last Verified: May 2018

Keywords provided by Robert W. Buchanan, University of Maryland:
kynurenic acid

Additional relevant MeSH terms:
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs