SchizophreniaPhase 1/2TrypNAC-IINCT04013555
The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia
A Phase 1/2 study testing N-acetylcysteine (NAC) and Tryptophan in people with Schizophrenia and Schizoaffective Disorder, run by University of Maryland, Baltimore at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder
- What is being tested?
- N-acetylcysteine (NAC) and Tryptophan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 88 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Jan 2020to 14 Aug 2024
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Maryland Psychiatric Research Center (MPRC) ; the Treatment Research Program (TRP)
Catonsville, Maryland, 21228
About this study
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.
Read the detailed 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.
- Being tested
- N-acetylcysteine (NAC), Placebo, Tryptophan
- Medical subject headings
- Schizophrenia, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-acetylcysteine (NAC)Drug
Also called Cetylev
Flavored effervescent formulation
PlaceboDrug
Flavored effervescent formulation designed to mimic NAC
TryptophanDrug
Oral slurry form
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Placebo; Drug: Tryptophan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Baseline, 2 hours on each Challenge Day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2019
- Study start20 Jan 2020
- Primary completion14 Aug 2024
- Study completion14 Aug 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by University of Maryland, BaltimoreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Robert Buchanan, University of Maryland, Baltimore
- Investigators
- Robert W Buchanan, M.D., Principal investigator, University of Maryland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04013555
- Sponsor's protocol ID
- HP-00086009
- Acronym
- TrypNAC-II
- Status last verified
- Jan 2026
- First submitted
- 27 Jun 2019
- Last updated
- 11 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia
- ClinicalTrials.gov ID
- NCT04013555
- Acronym / sponsor ID
- TrypNAC-II / HP-00086009
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Study start
- 20 Jan 2020 (actual)
- Primary completion
- 14 Aug 2024 (actual)
- Study completion
- 14 Aug 2024 (actual)
- First posted
- 9 Jul 2019 (actual)
- Results
- Posted 11 Feb 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| N-acetylcysteine & Tryptophan | Experimental | Drug: N-acetylcysteine (NAC), Drug: TryptophanN-acetylcysteine 140 mg/kg up to a maximum of 15 g. Thirty minutes after N-acetylcysteine administration participants will receive Tryptophan, 6 grams. |
| Placebo & Tryptophan | Placebo comparator | Drug: Placebo, Drug: TryptophanPlacebo 140 mg/kg up to a maximum of 15 g. Thirty minutes after placebo administration participants will receive Tryptophan, 6 grams. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| N-acetylcysteine (NAC)Also: CetylevFlavored effervescent formulation | Drug | N-acetylcysteine & Tryptophan |
| PlaceboFlavored effervescent formulation designed to mimic NAC | Drug | Placebo & Tryptophan |
| TryptophanOral slurry form | Drug | N-acetylcysteine & Tryptophan, Placebo & Tryptophan |
Primary outcome
Serum Kynurenine Levels
Time frame: Baseline, 1 hour and 4 hours on each Challenge Day
The investigators will use the kynurenine serum measures to examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA.
Kynurenic Acid Levels
Time frame: Baseline, 1 hour and 4 hours on each Challenge Day
The investigators will use the KYNA serum measures to examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA.
Whole Brain Gray Matter Cerebral Blood Flow (CBF)
Time frame: Baseline, 2 hours on each Challenge Day
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert W Buchanan, M.D. principal investigator
University of Maryland
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing N-acetylcysteine (NAC) and Tryptophan in people with Schizophrenia and Schizoaffective Disorder, run by University of Maryland, Baltimore at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Feb 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Kynurenine Levels (time frame: Baseline, 1 hour and 4 hours on each Challenge Day). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2026.