Tryptophan MRI in People With Schizophrenia and Healthy Controls
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2/Phase 3

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). 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
    

Intervention name(s): Tryptophan; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Tryptophan
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: tryptophan; kynurenic acid; schizophrenia