Sodium Butyrate For Improving Cognitive Function In Schizophrenia

The purpose of this grant is to evaluate the efficacy of sodium butyrate as a novel
treatment for cognitive deficits in schizophrenia (SZ). Sodium butyrate is a short chain
fatty acid and binds to the zinc site of histone deacetylases (HDAC). The inhibition of HDAC
results in histone hyperacetylation.

The proposal consists of a small preliminary open label study to assess tolerability and
side effects of sodium butyrate in schizophrenic patients receiving antipsychotic treatment
( in 5 patients with SZ treated with sodium butyrate for 8 weeks), followed by a larger
double-blind study of the effects of sodium butyrate on cognitive function and symptoms, in
SZ patients who are not in an acute exacerbation of the primary symptoms and show continued
cognitive deficits. Secondary aims will be to evaluate its effects on improving symptoms and
functioning in SZ, and the relationship of the drug's clinical effects to epigenetic and
inflammation related biochemical changes. In the double-blind phase we plan a study at 3
sites: 2 US, 1 China, but only the US site at the Nathan Kline Institute ( NKI) will be
active in the initial phase of the study.

We will provide a brief overview of the importance of these questions, some previous
interventional treatment approaches, and the potential of HDAC inhibitors and sodium
butyrate in particular to improve cognitive function.

The persistent cognitive deficits which can be appreciated across the course of SZ, from
prodromal to chronic SZ, may be the most important underlying dysfunction in preventing
functional, occupational, and social recovery in SZ compared to other symptom domains. There
is no effective treatment for these cognitive deficits which persist after antipsychotic
medication has reduced or resolved the positive symptoms of SZ. Although some exploratory
studies of nicotinic agonist drugs showed promise for improvement of cognitive deficits
associated with SZ , later larger and better-controlled studies with nicotinic agonist drugs
have not shown markedly positive effects for this type of pharmacologic intervention,
although one recent study is promising.

There is increasing interest in epigenetic mechanisms involving in DNA methylation and
histone acetylation involved in the pathology underlying SZ and related disorders ). There
is also interest in activation of inflammatory process as a part of the underlying
pathophysiology of SZ, and there is research showing that effects on inflammatory markers
may be partially mediated though epigenetic mechanisms of histone acetylation and DNA
methylation. There is growing evidence that HDAC inhibitor drugs (HDACi) have properties of
being cognitive enhancers and potential treatments for psychiatric disorders where cognitive
deficits are prominent, such as SZ and Alzheimer's disease. Graff and Tsai suggest they may
be particularly important in the process of promoting memory consolidation or conversion of
short-term to longer- term memory and increasing memory retention or consolidation. Memory
consolidation is demonstrated by the temporal gradient of retrograde amnesia (severity of
amnesia most severe for events that occurred shortly before the amnesic event), as well as
improvements in delayed recall of previously learned information after a retention interval.
A specific deficit in memory consolidation has been demonstrated in SZ . Delayed recall
performance may be used as an index of consolidation. For example, Goff et al found evidence
of a beneficial effect of d-cycloserine on delayed but not immediate thematic recall using
the Logical Memory Test (LMT) from the Revised Wechsler Memory Scale (WMS-R).

Sodium butyrate is a chemical compound found in foods and sold as a health food supplemental
(a nutraceutical) which is a strong HDAC inhibitor (predominantly class I HDAC) and has
anti-inflammatory and neuroprotective properties). Previous studies suggest it may have
potential as a treatment for cognitive deficits in several psychiatric disorders, and have
potential ameliorative effects on depression, and on human inflammatory diseases. Research
with animal models show that sodium butyrate and phenylbutyrate have potential to improve
cognition, including rescue of fear and spatial memories and enhancement of contextual
memory, spatial memory and object recognition and improved memory in a mouse model of
Alzheimer's disease. Sodium butyrate also decreased depressive-like behaviors in models of
maternal deprivation and chronic stress . One human study with a butyrate congener improved
cognitive outcome, including improvements in a test of working memory, in treatment of a
urea cycle hyperammonia disorder. Sodium butyrate has also been used in clinical trials of
inflammatory bowel diseases (Crohn's disease, ulcerative colitis) with positive effects on
clinical state and also with improvement on indicators of inflammation . In the Crohn's
disease study it also significantly decreased an immunological component interleukin-1 beta
(IL-1 β). It has been used and sold widely as health food supplement nutraceutical in humans
and has a good safety profile . It also reduces insulin resistance and lipid metabolic
abnormalities as documented in both an animal model of fat induced insulin resistance and in
an experimental human study preventing lipid induced insulin resistance . This effect may be
relevant as a beneficial effect for metabolic abnormalities that are frequently reported in
obese SZ. Sodium butyrate is lipophilic compound that passes the blood-brain barrier. This
is reported in previous studies and reviews stating that sodium butyrate crosses the blood
brain barrier). For example, in a mouse model oral sodium butyrate increased histone
acetylation both in brain and periphery. This fulfills a criterion the Stanley granting
organization requests be reported for proposed pharmacological studies.

The above background provides a rationale for a trial of sodium butyrate as a cognitive
enhancer in SZ.

The specific aims of the double-blind will be to test the following hypotheses.

Primary Aim:

1. Treatment with sodium butyrate will improve cognition in SZ as measured by the
composite and domain scores of the Measurement and Treatment Research to Improve
Cognition in Schizophrenia battery (MATRICS [MCCB]) . The primary outcome measure will
be the MCCB composite score.

Secondary Aims:

2. Treatment with sodium butyrate will improve memory consolidation as measured by delayed
recall performance.

3. Improvement in cognitive function induced by sodium butyrate in SZ will be correlated
with improvement in a measure of performance on real world functional tasks as assessed
by the University of California San Diego (USCD) Performance- Based Skills Assessment
Battery (UPSA).

We will also explore whether improvement in cognition is related to change in HDAC activity
in peripheral blood cells and changes in inflammatory makers in the blood (CRP, IL-1 β ),
and assess whether there is any improvement in psychopathology as measured by PANSS scale.

The study will be conducted in two phases, an open-label study of the safety and
tolerability of sodium butyrate in patients with schizophrenia followed by a randomized
placebo controlled experimental study of the effects of adjunctive 6.57 gms of sodium
butyrate per day for 12 weeks

Inclusion Criteria:

1. Diagnosis by DSM-5 (Diagnostic Statistical Manual) diagnosis of SZ or schizoaffective
disorder (SA), by consensus diagnosis using chart histories and interviews.

2. Age 18-60 years of age.

3. Patients will be stably treated with antipsychotic medications and are not in acute
illness exacerbation of their symptoms.

For the double-blind phase only qualification for cognitive deficits will use the
following criteria:

4. Subjects will have baseline MCCB battery scores which meet the following criteria.
Subjects will meet the following cognitive performance criteria: a). Maximum
performance level: Performance at least 1.0 standard deviation (SD) from perfect on
the following three measures: Letter-number span (< 24), Hopkins Verbal Learning Test
(HVLT) total (<31), Continuous Performance Test (CPT) d-prime (< 3.47) and b.

5. Minimum performance level: subject must be able to validly complete the baseline
MATRICS assessment.

Exclusion Criteria:

1. History of mental retardation or pervasive developmental disorder.

2. Subjects with a current serious neurological/central nervous system (CNS) disorder
(such as seizure disorder, stroke or multiple sclerosis) or brain trauma.

3. Current treatment with valproic acid, butyrate drugs, sulforaphane, or other drugs or
chemicals known to have high HDAC inhibitory activity.

4. Pregnancy.

5. Severe unstable current medical condition.

6. Current suicidal or homicidal thoughts.

7. Current alcohol or substance abuse (other than nicotine or occasional marijuana) in
the last month.

8. Subjects with diagnosis of congestive heart failure, or those on sodium restricted
diet.