SchizophreniaPhase 2/3NCT02067975
Tryptophan MRI in People With Schizophrenia and Healthy Controls
A Phase 2/3 study testing Tryptophan in people with Schizophrenia, 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 yearsHealthy volunteers can take part
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Tryptophan
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 93 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2014to 31 Dec 2019
- Phase
- Phase 2/3
- 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
- Healthy volunteers accepted
- Adult
Who may be able to join
- Males and females between the ages of 18 and 55 years
- Has met DSM-IV-TR/DSM-5 Criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder
- 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)
- Women must be in the first half of their menstrual cycle at the time of the 2 challenge visits
- Males and females between the ages of 18 and 55 years
- No DSM-IV-TR/DSM-5 Axis I Disorder (documented by SCID)
- Women must be in the first half of their menstrual cycle at the time of the 2 challenge visits
Who cannot join
- DSM-IV-TR/DSM-5 substance abuse in the last month or substance dependence in the last 6 months (documented by SCID)
- Calgary Depression Scale total score ≥ 10 at baseline
- Current smoker (expired CO ≥ 10 ppm)
- Current use of nicotine replacement therapy or other nicotine products
- Pregnancy or breast feeding
- Post-menopausal women will not be included due to changes in the HPA axis expression and hormonal effects on cognition. In women over the age of 45, menopausal status will be evaluated clinically
Show all 12Show fewer
- Excessive self-reported daily caffeine intake, defined as intake exceeding 1000 mg or the equivalent of 8 cups of coffee
- 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
- History of an organic brain disorder; mental retardation; or a medical condition, whose pathology or treatment could alter cognition
- Claustrophobia
- Metal in body that will interfere with MR imaging
- Treatment with monoamine oxidase inhibitors, migraine headache medications (triptans) and dextromethorphan
Trial locations and contacts
1 site in 1 country.
United States1 site
Maryland Psychiatric Research Center
Catonsville, Maryland, 21228
About this study
Official title: Neuroimaging of Tryptophan Challenge in People With Schizophrenia and Healthy Controls
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). 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.
Read the 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 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.
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
- Conditions
- Schizophrenia
- Being tested
- Tryptophan, Placebo
- Keywords
- tryptophan, kynurenic acid, schizophrenia
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TryptophanDrug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Healthy Controls | Other | All participants will receive both 6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3, and will also receive 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. The order in which participants receive either placebo or tryptophan will be randomized (ie. placebo first study visit day tryptophan on second study day, or tryptophan on first study day and placebo on second study day) Receives: Drug: Tryptophan; Drug: Placebo |
| Schizophrenia Related Disorders | Other | All participants will receive both 6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3, and will also receive 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. The order in which participants receive either placebo or tryptophan will be randomized (ie. placebo first study visit day tryptophan on second study day, or tryptophan on first study day and placebo on second study day) Receives: Drug: Tryptophan; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Verbal Memory Scores From Baseline to 4 Hours Post-Treatment
The following assessment was used to assess the outcome measure: the Hopkins Verbal Learning Test-Revised (HVLT-R). HVLT total scores range from 0 to 36. In order to conduct group comparisons, the HVLT raw total scores are converted to a t-score (range: -10 to 80). The mean t-scores for each condition are below (see outcome measure data table). Higher scores represent better performance. Participants performed the same task before pre- and post-treatment with Tryptophan and again with placebo (2 weeks between conditions). Change in scores pre- and post-treatment were compared between the Tryptophan and placebo conditions.
Measured: The order in which participants received either the tryptophan or placebo was randomized. The HVLT was administered 90 minutes prior to treatment and 4 hours post treatment. There were at least two weeks between the challenge days.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2014 (estimated)
- Study start14 Aug 2014
- Primary completion31 Dec 2019
- Study completion31 Dec 2019
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.
- Publications (1)Papers the sponsor has linked to this study.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Maryland, Baltimore
- Sponsor type
- University, hospital or other
- Collaborators
- Tanabe Pharma Corporation, National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Robert Buchanan, University of Maryland, Baltimore
- Investigators
- Robert W Buchanan, M.D., Principal investigator, University of Maryland, Baltimore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02067975
- Sponsor's protocol ID
- HP-00057861
- Other IDs
- 1P50MH103222-01
- Status last verified
- Jul 2024
- First submitted
- 11 Feb 2014
- Last updated
- 30 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Hare SM, Adhikari BM, Mo C, Chen S, Wijtenburg SA, Seneviratne C, Kane-Gerard S, Sathyasaikumar KV, Notarangelo FM, Schwarcz R, Kelly DL, Rowland LM, Buchanan RW. Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow. Neuropsychopharmacology. 2023 Oct;48(11):1594-1601. doi: 10.1038/s41386-023-01587-3. Epub 2023 Apr 28.
PubMed 37118058
Study at a glance
From the registry record, last updated by the sponsor on 30 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neuroimaging of Tryptophan Challenge in People With Schizophrenia and Healthy Controls
- ClinicalTrials.gov ID
- NCT02067975
- Acronym / sponsor ID
- HP-00057861
- Conditions
- Schizophrenia
- Keywords
- tryptophan, kynurenic acid, schizophrenia
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 93 participants (actual)
- Lead sponsor
- University of Maryland, BaltimoreUniversity, hospital or other
- Collaborators
- Tanabe Pharma Corporation, National Institute of Mental Health (NIMH)
- Study start
- 14 Aug 2014 (actual)
- Primary completion
- 31 Dec 2019 (actual)
- Study completion
- 31 Dec 2019 (actual)
- First posted
- 20 Feb 2014 (estimated)
- Results
- Posted 26 Aug 2021
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). 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 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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Healthy Controls | Other | Drug: Tryptophan, Drug: PlaceboAll participants will receive both 6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3, and will also receive 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. The order in which participants receive either placebo or tryptophan will be randomized (ie. placebo first study visit day tryptophan on second study day, or tryptophan on first study day and placebo on second study day) |
| Schizophrenia Related Disorders | Other | Drug: Tryptophan, Drug: PlaceboAll participants will receive both 6gm of tryptophan at least two weeks apart at time zero of 7 hour visits 2 and 3, and will also receive 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. The order in which participants receive either placebo or tryptophan will be randomized (ie. placebo first study visit day tryptophan on second study day, or tryptophan on first study day and placebo on second study day) |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Males and females between the ages of 18 and 55 years
- Has met DSM-IV-TR/DSM-5 Criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder
- 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)
- Women must be in the first half of their menstrual cycle at the time of the 2 challenge visits
- Males and females between the ages of 18 and 55 years
Key exclusion criteria (12 listed)
- DSM-IV-TR/DSM-5 substance abuse in the last month or substance dependence in the last 6 months (documented by SCID)
- Calgary Depression Scale total score ≥ 10 at baseline
- Current smoker (expired CO ≥ 10 ppm)
- Current use of nicotine replacement therapy or other nicotine products
- Pregnancy or breast feeding
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 |
|---|---|---|
| Tryptophan | Drug | Healthy Controls, Schizophrenia Related Disorders |
| Placebo | Drug | Healthy Controls, Schizophrenia Related Disorders |
Primary outcome
Change in Verbal Memory Scores From Baseline to 4 Hours Post-Treatment
Time frame: The order in which participants received either the tryptophan or placebo was randomized. The HVLT was administered 90 minutes prior to treatment and 4 hours post treatment. There were at least two weeks between the challenge days.
The following assessment was used to assess the outcome measure: the Hopkins Verbal Learning Test-Revised (HVLT-R). HVLT total scores range from 0 to 36. In order to conduct group comparisons, the HVLT raw total scores are converted to a t-score (range: -10 to 80). The mean t-scores for each condition are below (see outcome measure data table). Higher scores represent better performance. Participants performed the same task before pre- and post-treatment with Tryptophan and again with placebo (2 weeks between conditions). Change in scores pre- and post-treatment were compared between the Tryptophan and placebo conditions.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37118058Hare SM, Adhikari BM, Mo C, Chen S, Wijtenburg SA, Seneviratne C, Kane-Gerard S, Sathyasaikumar KV, Notarangelo FM, Schwarcz R, Kelly DL, Rowland LM, Buchanan RW. Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow. Neuropsychopharmacology. 2023 Oct;48(11):1594-1601. doi: 10.1038/s41386-023-01587-3. Epub 2023 Apr 28.
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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, Baltimore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Tryptophan in people with Schizophrenia, 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 7 inclusion and 12 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 30 Jul 2024. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 26 Aug 2021). 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?
Change in Verbal Memory Scores From Baseline to 4 Hours Post-Treatment (time frame: The order in which participants received either the tryptophan or placebo was randomized. The HVLT was administered 90 minutes prior to treatment and 4 hours post treatment. There were at least two weeks between the challenge days.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02067975, which also lists 1 linked publication.
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 30 Jul 2024.