The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia

Schizophrenia Clinical Trial

— TrypNAC-II  

Official title:

The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04013555
• Other study ID #: HP-00086009
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 20, 2020
• Est. completion date: June 30, 2024

Study information

• Verified date: December 2023
• Source: University of Maryland, Baltimore
• Contact: Jennifer Zaranski, MA
• Phone: 410-402-6060
• Email: jzaranski[@]som.umaryland.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

The overall goal of the study is to examine how the medication N-acetylcysteine (NAC), when added to tryptophan, affects various cognitive functions, such as verbal and visual memory. The investigators will also use magnetic resonance imaging (MRI) to examine how NAC affects brain activity and chemicals.

Description:

The purpose of the study is to examine whether high dose N-acetylcysteine (NAC) blocks the adverse effects of increased kynurenic acid (KYNA) on selected measures of brain chemistry, function and behavior, through the inhibition of kynurenine aminotransferase (KAT) II, which converts kynurenine to KYNA. The study will be a double-blind, placebo-controlled, randomized cross-over challenge study, in which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a maximum of 15 g, or placebo, then receive tryptophan (TRYP), 6 gms. The tryptophan challenge method robustly increases peripheral measures of kynurenine and KYNA in humans and putatively increases brain KYNA levels, through the CNS conversion of kynurenine to KYNA; a process that is observed in both rodents and nonhuman primates. The investigators will evaluate the ability of NAC to inhibit the conversion of kynurenine to KYNA with the following primary outcome measures: 1) the investigators will measure serum kynurenine and KYNA before and after NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA; 2) the investigators will use the arterial spin labeling (ASL) technique to measure whole brain and frontal gray matter cerebral blood flow (CBF) before and after NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo attenuates the effects of TRYP on ASL CBF measures; 3) the investigators will use magnetic resonance spectroscopy (MRS) to measure glutamate and glutathione levels in the medial prefrontal cortex (mPFC) before and after NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo increases MRS glutathione and glutamate measures; and 4) the investigators will use diffusion tensor imaging (DTI) to measure white matter fractional anisotropy (FA) before and after NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo increases white matter FA.

The investigators will have two secondary endpoints. First, if the investigators observe that NAC attenuates the effects of TRYP on ASL and/or increases mPFC glutamate levels or white matter DTI FA, then the investigators will examine whether these effects are related to changes in cognitive measures of attention, verbal and visual memory, and working memory. Second, the investigators will use measures of serum KYNA and peripheral blood mononuclear cell (PBMC) kynurenine 3-monooxygenase (KMO) activity levels to examine whether the level of these measures is related to the observed effects of NAC on our neuroimaging and cognitive outcome measures.

The investigators hypothesize that NAC will inhibit KAT II, which will be reflected in the:

1) decreased peripheral conversion of kynurenine to KYNA; and 2) increased CBF, glutamate, and white matter fractional anisotropy (FA). In addition, the investigators hypothesize that the NAC effects on the neuroimaging measures will be related to improved performance on cognitive measures of attention, verbal and visual memory and working memory. These observed effects of NAC will be greater than those seen with placebo. The investigators further hypothesize that the NAC effects on ASL CBF, glutamate, and FA measures will be independent of NAC-induced changes in MRS glutathione, i.e., not due to the NAC oxidative stress mechanism, but, rather, will be correlated with NAC-induced reductions in the peripheral conversion of kynurenine to KYNA. Finally, the investigators hypothesize that the observed effects of NAC on CBF, glutamate, and FA will be related to baseline serum KMO activity and KYNA levels. The demonstration that NAC reverses the adverse impact of increased KYNA levels will importantly support the development of KAT II inhibitors for the enhancement of cognition in schizophrenia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Males and females

• Age: 18 to 55 years

• DSM-5 Criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder (documented by SCID)

• 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)

• Female participants must agree to use a medically accepted means of contraception

Exclusion Criteria:

• DSM-5 alcohol or substance misuse disorder in the last 3 months (documented by SCID)

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

• 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; Brune and Pflughaupt 1975; Torres et al 2007).

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

• Pregnancy or lactation

• No metal in body that will interfere with MR imaging

• Monoamine oxidase inhibitors, migraine headache medications (triptans) and dextromethorphan

• Forensic or legal issues

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia
• Schizophreniform Disorder

Intervention

Drug:
• N-acetylcysteine (NAC)
Flavored effervescent formulation
• Placebo
Flavored effervescent formulation designed to mimic NAC
• Tryptophan
Oral slurry form

Locations

Country	Name	City	State
United States	Maryland Psychiatric Research Center (MPRC) ; the Treatment Research Program (TRP)	Catonsville	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum kynurenine levels	The investigators will use the kynurenine serum measures to examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA.	Change from baseline after 4 hours, 5.5 hours, and 7 hours on each Challenge Day.
Primary	Kynurenic acid levels	The investigators will use the KYNA serum measures to examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA.	Change from baseline after 4 hours, 5.5 hours, and 7 hours on each Challenge Day.
Primary	Whole brain gray matter and frontal gray matter cerebral blood flow (CBF)	The investigators will use a Pseudo-continuous Arterial Spin Labeling (pCASL) sequence, which provides full brain coverage with high spatial resolution and excellent WM signal-to-noise ratio (SNR) (SNR>15), to measure whole brain gray matter and frontal gray matter cerebral blood flow (CBF). The investigators will use the pCASL CBF measures to examine whether NAC compared to placebo attenuates the effects of TRYP on ASL CBF measures.	Change from baseline after 3 hours on each Challenge Day.
Primary	Medial prefrontal cortex glutamate levels using magnetic resonance spectroscopy (MRS)	The MRS glutamate measure will be used to examine whether NAC compared to placebo increases glutamate levels in the pre-specified brain region.	Change from baseline after 3 hours on each Challenge Day.
Primary	Medial prefrontal cortex glutathione metabolite levels using magnetic resonance spectroscopy (MRS)	The MRS glutathione measure will be used to evaluate whether the NAC effects on ASL CBF, glutamate, and DWI indices are independent of NAC-induced changes in MRS glutathione, i.e., not due to the NAC oxidative stress mechanism.	Change from baseline after 3 hours on each Challenge Day.
Secondary	Improvement in cognitive function	Measured by the MATRICS battery	Change from baseline after 5 hours on each Challenge Day.
Secondary	Electrophysiological measure	The investigators will use visual evoked potentials (VEP) to measure interhemispheric transfer times (IHTT) to examine whether NAC produces functional changes in white matter integrity.	Change from baseline after 3 hours on each Challenge Day.
Secondary	Serum kynurenic acid (KYNA) level	The investigators will use the baseline KYNA serum measure to examine whether the effects of NAC on our primary neuroimaging and secondary cognitive and electrophysiological outcome measures are related to baseline KYNA serum levels.	The measure will be collected at baseline.
Secondary	Peripheral Blood Mononuclear Cell (PBMC) kynurenine 3-monooxygenase (KMO) activity	The investigators will use the baseline KMO activity measure to examine whether the effects of NAC on our primary neuroimaging and secondary cognitive and electrophysiological outcome measures are related to this measure.	The measure will be collected at baseline.