Abstracts

Rationale: Divalproex DR (delayed-release) and divalproex ER (extended-release) (DVP ER) are FDA approved for Bipolar Disorder, Epilepsy and Migraine prophylaxis. Divalproex ER is given once daily, improving compliance. Also more even absorption may reduce side effects. Overnight switch to DVP ER advised in the package insert, could however produce more side effects in this susceptible population. We compared tolerability of overnight versus gradual switching to DVP ER in adults with Intellectual and Developmental Disabilities (IDD) receiving DVP for Epilepsy and/or Bipolar Disorder. Methods: The study design was open with parallel groups and a blinded side effects rater. Subjects were randomized to Overnight Conversion (n= 7) or Gradual Conversion (n= 8). The switch to DVP ER began 7 days after baseline, either overnight or gradually. Dosing of DVP ER was increased by 8-20% as recommended due to lower bioavailability. Subjects attended 3 visits following switch commencement, at Day +1, +4, and +8. CBC, chemistry profile, and DVP levels were drawn at baseline, and Day +8 post-switch. Caregivers recorded any seizures. Concomitant medications were allowed provided dosing remained constant. We used the Monitoring of Side Effects Scale (MOSES) (Sturmey, 2003) rated at each visit as the primary outcome measure. This has 64 items rated 0-4 in 8 groups. Results: Seven males and 8 females participated. Mean age was 35.6 years (range 22 to 49). The 2 groups were comparable demographically. Mean DVP ER dose in the Overnight Group was 1607 mg/day, and in the Gradual Group was 1875 mg/day. MOSES ratings in both groups were extremely low at baseline, +1, +4, and +8 days. Side effects were judged significant if they worsened or if they were of new onset. Tremor was present at baseline in 1 subject from each group but improved after conversion began in each case. One subject had mild abdominal pain at visit +4, in the Gradual Conversion Group. One subject (#4) in the Overnight Group rated minimal on agitation at baseline, but moderate at +1, followed by mild agitation and minimal irritability at +4, and +8 visits, however there were also environmental changes, a 24-hour gastroenteritis with vomiting and a brief tonic seizure (1 second) in his left leg. One Gradual Group subject had increase in agitation and irritability, from mild at baseline and +1 days, to moderate at day +4, but improved to minimal by day +8. Another Gradual Group subject had increased agitation after baseline following a decrease in DVP ER dose made due to a low WBC, probably unrelated to DVP but made prior to hematology referral for this and anemia. Neither group had any sedation. Conclusions: This pilot study found no significant increase in DVP ER side effects or seizures in the Overnight Conversion Group in comparison with a more Gradual Conversion over 4-6 days. Side effect rates following conversion to DVP ER at days +1, +4, and +8 were extremely low in both the Overnight and Gradual Conversion Groups. (Funded by Abbott Laboratories)