The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia

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.

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