L-Carnosine for Bipolar I Disorder

OBJECTIVE:

It is our hypothesis that L-carnosine treatment of persons with bipolar illness will improve
their cognitive outcomes, more specifically, measures of attention and executive function,
verbal and visuospatial memory and psychomotor performance, relative to placebo treatment.
We also hypothesize that L-carnosine treatment may secondarily improve any residual
affective symptoms.

RESEARCH PLAN:

We aim to test these hypotheses by conducting a randomized, placebo controlled, add on
treatment trial of L-carnosine (added to ongoing prescribed pharmacological treatment, for
example - lithium, anticonvulsants, antipsychotic agents and depressants) for a period of 12
weeks. Measures of cognition, and psychopathology will be utilized for evaluating primary
and secondary outcomes, along with safety assessments.

METHODS:

Up to 48 subjects with DSM IV TR bipolar I disorder will be recruited from Western
Psychiatric Institute and Clinic, Mayview State Hospital and Mon Yough Community Services,
Inc. using a 1:1 randomization, subjects who sign a informed consent document will be
randomized to receive L-carnosine or placebo.

It is expected that 12 of the 48 subjects may not meet inclusion/exclusion criteria, leaving
36 consenting adults (18 to 65 years) with DSM IV-TR Bipolar Disorder who will be assessed
for euthymia (Young Mania Rating Scale Score ≤ 10, Montgomery Asberg Depression Rating Scale
Score of ≤ 10) over a one month period (2 assessments) while receiving stable doses of their
current medications. They will also be assessed for cognitive dysfunction
(attention/executive function, immediate and declarative memory, and psychomotor
performance) using Cogtest - a proprietary neuropsychological library of 19 tests. These
subjects will be characterized for normal pre-morbid IQ, no ECT treatment in past 6 months,
no alcohol or substance dependence in past 6 months, mini-mental state score ≥ 24.

L-carnosine (or placebo) will be administered using random assignment at a dose of 500
mg/day, increasing each week by 500 mg to a dose of 2000 mg/day (twice daily schedule) in 4
weeks; as an adjunct to existing psychotropic medicines. The dose of 2000 mg (or less, i.e.
a minimum of 500 mg if tolerability is an issue) will be continued for 8 additional weeks.
L-carnosine is not known to have interactions with psychotropic drugs but mood-stabilizer
levels will be monitored.

Standard psychopathology rating scales will be administered to evaluate secondary aims such
as impact on residual symptoms of bipolar disorder. Safety will be assessed by tailing a
careful medical history and physical examination at screening and evaluating results of
laboratory measures. Any adverse effects will be assessed by asking questions at each visit,
and if required bring subjects in for assessments outside the scheduled visits, and by
telephone contact in between longer scheduled visits.

SIGNIFICANCE:

Cognitive dysfunction can seriously hinder improved functional outcomes in persons with
schizophrenia or bipolar disorder. If this short term intervention with L-carnosine shows
promise, more definitive studies using adequate powered sample sizes, and of longer duration
can be conducted. If improvements in cognitive problems are linked to improved functional
outcomes using such supplemental treatments, an important therapeutic milestone in bipolar
disorder will have been achieved.

Inclusion Criteria:

- DSM IV - TR diagnosis of bipolar I disorder or

- Ages 18 to 65 years

- Men or Women

- Ability to read and communicate in English

- 8th grade education or greater

- Ability to provide informed, competent and written consent

- Current medication and mood status (Y-MRS and MADRS scores less than or equal to 10)
is stable for greater than or equal to 4 weeks.

Exclusion Criteria:

- Medically unstable conditions

- Known allergy to L-carnosine

- Current cognitive decline is attributable to a diagnosis of dementia or other
neurological disorder, including HIV dementia or cognitive decline

- Pregnant or lactating women

- Mini-mental state examination score (MMSE) less than or equal to 23.