Ignite Creation Date:
2024-05-06 @ 2:32 AM
Last Modification Date:
2024-10-26 @ 11:20 AM
Study NCT ID:
NCT02067975
Status:
COMPLETED
Last Update Posted:
2021-12-23
First Post:
2014-02-11
Brief Title:
Tryptophan MRI in People With Schizophrenia and Healthy Controls
Sponsor:
University of Maryland Baltimore
Organization:
University of Maryland Baltimore
Study Overview
Official Title:
Neuroimaging of Tryptophan Challenge in People With Schizophrenia and Healthy Controls
Status:
COMPLETED
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 metabolizedchanged 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
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 23-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 79
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-5DSM-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 andor 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
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-5DSM-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 andor 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 1P50MH103222-01 | NIH | None | httpsreporternihgovquickSearch1P50MH103222-01 |