This study will examine whether lithium carbonate, given alone or with divalproex, increases
the amount of brain-derived neurotrophic factor (BDNF) in the spinal fluid of patients with
Huntington's disease (HD), a hereditary disorder of the central nervous system. Patients
with this fatal degenerative disease have lower amounts of substances in the brain and
spinal fluid called trophic or growth factors. One of these factors is BDNF. A possible
treatment for HD may be to increase the levels of BDNF. Lithium carbonate, a drug used to
treat bipolar disorder, and divalproex, a drug used to treat mood disorders and seizure
disorders, have both been shown to increase the amount of BDNF protein in laboratory
Patients 18 to 70 years old with a DNA-confirmed diagnosis of Huntington's disease may be
eligible for this study. Candidates are screened with a medical history and physical
examination, neurological evaluation, blood and urine tests, and electrocardiogram (EKG).
Participants take lithium carbonate with and without divalproex. They also receive placebo
(an inactive substance) for portions of the study. On the first day of the study, patients
are given a supply of pills with instructions on how to take them. Blood pressure and pulse
are measured, and blood and urine tests may be done. Patients are evaluated with
standardized tests and scales for assessment of various aspects of HD.
Patients return to the clinic once a week for follow-up evaluations, including blood and
urine tests, physical examinations, disease assessments, and a review of medication side
effects. Each week, they receive a new supply of medications and instructions on how to take
them. At the end of the sixth week, they finish taking the medications.
During the study, patients undergo three lumbar punctures (spinal taps) - at weeks 2, 4, and
6 - to measure BDNF and various other brain chemicals. For this test, a local anesthetic is
given and a needle is inserted in the space between the bones in the lower back where the
CSF circulates below the spinal cord. A small amount of fluid is collected through the
needle. The procedure generally takes from 5 to 20 minutes.
Patients return to the clinic 2 weeks after completing the study medication for a final
evaluation, including a physical examination and blood and urine tests.
Objective: The overall objective of this study is to examine the acute effects of lithium
alone and/ or in combination with divalproex on markers of neuroprotective activity in
patients with Huntington's disease (HD). It is hypothesized that at safe and tolerable doses
these drugs will enhance depleted levels of brain-derived neurotrophic factor (BDNF), a
neurotrophin which is necessary for the survival of striatal neurons.
Study population: Patients suffering from Huntington's disease will be study participants.
Design: The acute effects of lithium and divalproex on surrogate measures of neuroprotective
activity will be evaluated in up to 24 HD patients. The study, lasting approximately 6
weeks, will be conducted on an outpatient basis.
Outcome measures: In this proof-of-principle study, efficacy in restoring BDNF
concentrations will be assessed through cerebrospinal fluid (CSF) measurements. Safety will
be monitored by means of frequent clinical evaluations and laboratory test.
1. Subject is between the ages of 18 and 70 (inclusive);
2. Subject will have a diagnosis of HD confirmed by DNA testing [prior to enrollment
into the study].
3. Only those subjects will be eligible, who with or without a caregiver, can be assumed
to be able to comply with study requirements and to report on their condition by
4. Subjects with minimental status examination score of greater than and equal to 24.
Patients meeting any of the following exclusion criteria during screening or during the
study will not be immediately excluded from the study, as appropriate:
1. Patient has a history of any medical condition such as diabetes, cardiac disease,
renal impairment, liver disease, pancreatitis and other chronic medical problems that
can reasonably be expected to subject the patient to unwarranted risk;
2. Patient has clinically significant laboratory abnormalities that would preclude
administration of lithium and divalproex;
3. Patient is taking a prohibited concomitant medication;
4. Patient has not been using an adequate contraceptive method for the last 30 days or
unwilling to continue contraception throughout the study, or is not at least one year
post menopausal (if female);
5. Patient is pregnant or breastfeeding;
6. Patient has participated in a clinical study with an investigational drug within the
last 30 days;
7. Patient has a condition (such as active drug or alcohol abuse) that, in the opinion
of the investigators, would interfere with compliance or safety;
8. Patient has known hypersensitivity to lithium or divalproex;
9. Patients inability to swallow tablets or to comply with medication schedule;
10. Patient and / or caregiver are unwilling to sign an informed consent or to comply
with protocol requirements;
11. Patient is unwilling to have lumbar puncture.
12. Patient with history of severe depression, or past suicide attemps.