Treatment of Cognitive and Negative Symptoms in Schizophrenia With N-acetylcysteine
Condition: Schizophrenia; Cognitive Deficits; Schizophrenia; Negative Type
MeSH terms: Schizophrenia; Cognition Disorders; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to attempt to treat cognitive and negative symptoms of
      schizophrenia, with the nutritional supplement N-acetylcysteine (NAC).

      Schizophrenia is a chronic mental disorder that affects approximately 65 million people
      worldwide, and causes significant disability and suffering. Patients with schizophrenia often
      hear voices and have persecutory delusions. Though these are the most recognizable features
      of the illness, the deficits most closely linked to disability are known as cognitive
      deficits and negative symptoms. Cognitive abilities refer to the ability to perform mental
      tasks that require focus and attention, and also include memory and verbal skills. Negative
      symptoms refer to a lack of interest in the world, and decreased social interactions. In our
      study, the investigators aim to improve these symptoms and deficits by targeting the
      glutamate system.

      Glutamate is the major excitatory neurotransmitter in the brain, and its regulation is
      abnormal in schizophrenia: glutamate levels are too low at some receptors, and too high at
      others. As well, free radicals surrounding glutamate receptors also interfere with their
      proper function. N-acetylcystine (NAC) is a safe and widely-available dietary supplement that
      may restore glutamate to its correct levels in the brain, and may also help protect the brain
      from antioxidant damage.

      In our study, patients with schizophrenia will be randomly assigned to receive either NAC or
      placebo for 8 weeks. Brain levels of glutamate and an important antioxidant, glutathione,
      will be measured before and after treatment, using a neuroimaging technique known as magnetic
      resonance spectroscopy. Cognitive and negative symptoms will also be assessed before, during
      and after treatment. The investigators hypothesize that glutamate and glutathione will be
      normalized in patients' brains, and that their negative and cognitive symptoms will be
      improved, too.
    

Detailed description: 
      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

           o 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

           o 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).
    

Intervention name(s): N-acetylcysteine; Treatment as Usual
Intervention type(s): Drug; Other
Intervention description(s): N-acetylcysteine is a safe, widely available supplement currently FDA-approved for treatment of acetaminophen antidote and as a mucolytic. It has effects on glutamate in the brain via the NMDA receptor as well as the glutathione antioxidant system (it is a precursor to glutathione).; Treatment for schizophrenia which may include medications, therapy, or other types of treatment as determined by the subject's VA or community psychiatrist or mental health treatment team
Other intervention name(s): NAC, acetylcysteine, cysteine, Acetadote
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: schiozphrenia; cognition; negative symptoms; glutamate; glutathione; N-acetylcysteine