The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia

NCT04013555 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: HP-00086009
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

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). 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.

Conditions

Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder

Outcome Measures

Primary Outcomes (3)

• 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.

  Baseline, 1 hour and 4 hours on each Challenge Day

• 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.

  Baseline, 1 hour and 4 hours on each Challenge Day

• Whole Brain 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 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.

  Baseline, 2 hours on each Challenge Day

Study Arms (2)

N-acetylcysteine & Tryptophan

EXPERIMENTAL

N-acetylcysteine 140 mg/kg up to a maximum of 15 g. Thirty minutes after N-acetylcysteine administration participants will receive Tryptophan, 6 grams.

Drug: N-acetylcysteine (NAC); Drug: Tryptophan

Placebo & Tryptophan

PLACEBO COMPARATOR

Placebo 140 mg/kg up to a maximum of 15 g. Thirty minutes after placebo administration participants will receive Tryptophan, 6 grams.

Drug: Placebo; Drug: Tryptophan

Interventions

N-acetylcysteine (NAC) DRUG

Flavored effervescent formulation

Also known as: Cetylev

N-acetylcysteine & Tryptophan

Placebo DRUG

Flavored effervescent formulation designed to mimic NAC

Placebo & Tryptophan

Tryptophan DRUG

Oral slurry form

N-acetylcysteine & Tryptophan; Placebo & Tryptophan

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

Maryland Psychiatric Research Center (MPRC) ; the Treatment Research Program (TRP)

Catonsville, Maryland, 21228, United States

Location

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

Acetylcysteine; Tryptophan

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids, Essential

Results Point of Contact

• Title: Dr. Robert Buchanan
• Organization: Maryland Psychiatric Research Center

rwbuchanan@som.umaryland.edu

410-402-7876

Study Officials

• Robert W Buchanan, M.D.

  University of Maryland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All raters, investigators and other staff will be blind to treatment assignment except for the research pharmacist. The research pharmacist does not participate in assessing any of the primary symptom or side effect dependent variables and conveys no information about treatment assignment to participants or staff except in a medical emergency.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This will be a double-blind, placebo-controlled, randomized cross-over challenge study. Participant randomization will use a permuted block randomization system (block sizes 2 or 4), in which treatment assignment order is random within each block, with an equal number of participants assigned to each treatment, to generate a list of treatment assignments. Thus, it will be difficult to ascertain the next treatment assignment, even if a participant becomes unblinded, while any imbalance in the number of participants between the treatment groups will be kept within tight limits.

Study Record Dates

• First Submitted: June 27, 2019
• First Posted: July 9, 2019
• Study Start: January 20, 2020
• Primary Completion: August 14, 2024
• Study Completion: August 14, 2024
• Last Updated: February 11, 2026
• Results First Posted: February 11, 2026

Record last verified: 2026-01

Locations

US (1)