Tryptophan MRI in People With Schizophrenia and Healthy Controls
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|ClinicalTrials.gov Identifier: NCT02067975|
Recruitment Status : Recruiting
First Posted : February 20, 2014
Last Update Posted : May 16, 2018
|Condition or disease||Intervention/treatment||Phase|
|Schizophrenia||Drug: Tryptophan Drug: Placebo||Phase 2 Phase 3|
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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.
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|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|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|
Active Comparator: tryptophan
6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3
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.
- 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.
- 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.
- 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.
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02067975
|Contact: Catherine Kildayfirstname.lastname@example.org|
|United States, Maryland|
|Maryland Psychiatric Research Center||Recruiting|
|Catonsville, Maryland, United States, 21228|
|Principal Investigator: Robert W. Buchanan, M.D.|
|Principal Investigator:||Robert W Buchanan, M.D.||University of Maryland|