This study will explore the possible effectiveness of levetiracetam in patients with bipolar
illness who have not responded adequately to standard treatments. Levetiracetam was
recently approved to treat seizures. Other drugs in the same class as levetiracetam,
including carbamazepine and valproate, are widely recognized as substitute medications for
lithium or are used as an adjunct to it, and other anticonvulsants have also shown promise
in improving bipolar symptoms.
Patients with bipolar illness whose manic, depressed or unstable moods are not adequately
controlled by their current treatment and who have not responded previously to two standard
treatments (i.e., lithium, valproate, carbamazepine or neuroleptics) may be eligible for
Participants will take levetiracetam starting at 500 mg daily. If this dose is well
tolerated, it will be increased to 500 mg twice a day. Every 3 days, doses may be increased
until the target dose of 3000 mg/day is reached. Higher doses, not to exceed 4000 mg/day,
may be tried in patients who do not respond fully to the lower doses. Patients and
observers will use standard ratings to evaluate the patients' response to therapy during the
8-week study. If, after 8 weeks, the results appear promising, patients may continue
treatment for an additional 6 months to evaluate longer-term effects.
Almost all of the approved anticonvulsant compounds (with the exception of gabapentin and
tiagabine) have now been suggested to have acute antimanic or more long-term mood
stabilizing properties. Carbamazepine and valproate have gained a widely recognized role
in treatment algorithms of bipolar illness, and lamotrigine has shown promising
antidepressant effects. Levetiracetam (Keppra® (Registered Trademark)) is the most recently
approved anti-epileptic drug available, and deserves pilot exploration in bipolar illness
for a variety of reasons. These include: its positive side-effects profile; it is a
derivative of the nootropic agent piracetam which has memory-enhancing properties in animal
studies; it likely has a unique mechanism of action since it is not active on most of the
traditional excitatory and inhibitory neurotransmitter systems; it is not active on
traditional anticonvulsant models such as pentylenetetrazol (PTZ) or maximum electroshock
(MES) seizures, but is able to stop both the development and completed phase of
amygdala-kindled seizures; and it is not metabolized by hepatic enzymes and thus has few
adverse pharmacokinetic interactions.
We propose pilot exploration of levetiracetam as an adjunctive agent in patients with
bipolar illness who are inadequately responsive to routine psychopharmacological agents for
bipolar illness. At the NIMH we will study a maximum of 10 acutely depressed, 10 manic, and
10 cycling patients enrolled in Protocol 97-M-0039. We would start at Levetiracetam doses
of 500 mg/day, and not to exceed 4000 mg/day. Response will be based primarily on the
percentage of patients showing "much" or "very much" improvement on the GCI-BP score in each
of the three groups as augmented by the percentage decrement on cross-sectional scales such
as the Inventory of Depressive Symptomatology (IDS) and Young Mania Rating Scale (YMRS) in
conjunction with prospective ratings on the NIMH-LCMp. Should preliminary evidence of
efficacy be observed in this open add-on clinical trial, more systematic controlled studies
will then be designed for confirmation of promising target areas of efficacy.
Patients meeting DSM -IV criteria for bipolar I, bipolar II, bipolar NOS, and
schizoaffective illness-bipolar type will be eligible for study. They will be enrolled in
approved Protocol #97-M-0039 and thus will not have H.I.V. and will have provided consent
for all of the rating forms utilized in this study.
Patients with inadequate response to two standard agents (i.e., lithium, valproate,
carbamazepine, or neuroleptics) in the treatment of bipolar illness will be eligible for
open adjunctive levetiracetam.
If serum creatinine is above normal, a creatinine clearance will be preformed; this must
be above 85 in order for a patient to be eligible for this study.
Women of child-bearing age who are not on an active method of birth control or who are
likely to become pregnant will be excluded.
Men or women with significant renal disease will also be excluded.
For the depressed phase, patients will have an IDS score of 18 or greater, an LCM
depression score of low moderate or greater, and a GCI-BP severity score of moderate or
greater for more than 2 weeks, i.e., the DSM-IV durational criteria.
For the hypomanic/manic phase, patients will have an YMRS score of 8 or greater, an LCM
mania rating of mild or greater, and a CGI-BP severity score of moderately ill or greater
for 7 days or more.
Those in the cycling group would meet the severity criteria for depression and mania.
They would have four or more mood "switches," and have an overall illness rating on the
CGI-BP severity score of moderate or greater.