Treatment of Cognitive and Negative Symptoms in Schizophrenia With N-acetylcysteine

Schizophrenia is a severe mental illness associated with hallucinations and delusions (positive symptoms), emotional withdrawal and decreased expressivity (negative symptoms), and problems with memory, attention, and social interaction (cognitive impairment). Positive symptoms, the most recognizable characteristics of the illness, can be treated effectively with available antipsychotic medications. Cognitive deficits and negative symptoms, however, are more closely related to functional outcome in schizophrenia, and yet, there is no approved treatment for these types of deficits (1,2).

One prominent theory proposes that these deficits and symptoms arise from dysfunctional receptors for the major excitatory neurotransmitter in the brain, glutamate (3), in two different ways. First, it is believed that decreased signaling from glutamate receptors on inhibitory neurons leads to excessive glutamate activity in the prefrontal cortex, resulting in cognitive impairment (2). This decreased signaling from glutamate receptors may result from too little glutamate present at receptors with mGlu2/3 subunits on inhibitory neurons. In a second mechanism, excessive oxidizing species surrounding glutamate receptors in schizophrenia cause receptor hypofunction (2). Glutathione, the most important protective molecule against oxidative stress in the brain, is protective against this. Importantly, glutathione was found to be 52% lower in medial prefrontal cortex of schizophrenia patients compared to controls (4). In rats, inhibition of glutathione synthesis produced cognitive deficits, and a recent study showed an inverse correlation between glutathione and negative symptoms in patients (5,6). Remarkably, there is an agent that affects both glutamate and glutathione: the dietary supplement N-acetylcysteine, or NAC.

NAC is a safe and widely available dietary supplement that may be able to alter the pathophysiology of schizophrenia by affecting both glutamate and glutathione. Within the glutamate system, NAC acts on inhibitory neurons to restore inhibitory tone on glutamatergic neurons in the frontal cortex (7). A study published in 2012 showed NAC normalized glutamate levels in cingulate cortex of cocaine-dependent patients (8). Remarkably, NAC is also the precursor to glutathione, and NAC administration increases serum glutathione concentrations (9,10). In one randomized, placebo-controlled study, NAC administration correlated with improvement in negative symptoms in schizophrenia patients (11). We propose to investigate the mechanisms of the putative therapeutic benefit of NAC for patients with schizophrenia, and to explore its impact on negative symptoms and cognition.

In this study, we will use magnetic resonance spectroscopy (MRS) to measure glutamate levels in prefrontal cortex, hypothesizing that NAC will normalize, and therefore reduce, levels of glutamate. We will measure glutathione levels with both MRS and serum levels, hypothesizing that NAC will increase glutathione levels in the brain and systemically. We will measure negative symptoms before, during and after treatment with NAC, hypothesizing an improvement in the NAC treatment group compared to placebo, based on findings in the literature. Finally, as an exploratory aim, we will measure performance on the MATRICS Consensus Cognitive Battery (MCCB), before and after NAC treatment, to test effects of NAC on cognition in schizophrenia.

In 40 subjects with a diagnosis of schizophrenia or schizoaffective disorder, we will conduct a randomized, double-blind, placebo-controlled study with NAC (total daily dose 2400mg) or placebo over an 8-week period.

• Specific Aim 1: Compare glutamate in bilateral dorsolateral prefrontal cortex before and after NAC vs. placebo treatment using MRS
• Hypothesis 1: Prefrontal glutamate concentration will be normalized (reduced) after treatment with NAC, but not after treatment with placebo.
• Specific Aim 2: Compare glutathione in medial prefrontal cortex before and after NAC vs. placebo treatment using MRS
• Hypothesis 2a: Medial prefrontal cortical glutathione concentration will be improved (increased) after treatment with NAC, but not placebo
• Hypothesis 2b: Serum glutathione levels will be increased after treatment with NAC, but not placebo
• Specific Aim 3: Compare negative symptoms before, during and after NAC vs. placebo treatment
• Hypothesis 3: Negative symptoms will be improved after treatment with NAC, but not placebo
• Exploratory Aim: Assess performance on the MCCB before and after treatment with NAC vs. placebo

References

1. Green, M. F. \& Nuchterlein, K. H. Should Schizophrenia Be Treated as a Neurocognitive Disorder? Schizophrenia bulletin 25, 309-318 (1999).
2. Moghaddam, B. \& Javitt, D. From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment. Neuropsychopharmacology 37, 4-15 (2011).
3. Moghaddam, B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174, (2004).
4. Do, K. Q. et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. European Journal of Neuroscience 12, 3721-3728 (2000).
5. Castagné, V., Rougemont, M., Cuenod, M. \& Do, K. Q. Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia. Neurobiology of Disease 15, 93-105 (2004).
6. Matsuzawa, D. et al. Negative Correlation between Brain Glutathione Level and Negative Symptoms in Schizophrenia: A 3T 1H-MRS Study. PLoS ONE 3, e1944 (2008).
7. Berk, M., Malhi, G. S., Gray, L. J. \& Dean, O. M. The promise of N-acetylcysteine in neuropsychiatry. Trends in Pharmacological Sciences 34, 168-178 (2013).