Abstract Details

5HT may play a pathophysiologic role or have therapeutic potential in focal epilepsy.  5HT1A receptor activation hyperpolarizes hippocampal Ca1 neurons.  Several anti-seizure drugs, including carbamazepine, may block 5HT reuptake.  PET 5HT1A receptor ligand studies found reduced binding in mesial temporal seizure foci and depression.  Fenfluramine, a drug recently approved for Dravet’s Syndrome but not focal epilepsy, increases 5HT synaptic availability by disrupting 5HT vesicular storage. 

We performed a pilot trial of PRX-00023 (Nalutozan), a high affinity 5HT1A agonist , in patients with focal epilepsy that showed promise in trials for anxiety and depression (Investigator initiated IND 110522; NCT01281956).  Ten patients with at least 4 seizures over a six-week baseline  were randomized in a double-blind cross-over design with two 12 week treatment periods and a four week washout.  Subjects on benzodiazepines, phenobarbital, or phenytoin were excluded.  Study endpoints were seizure counts, neuropsychological tests, mood, anxiety ratings, and the Columbia Suicide Severity Rating Scale.  The maximum dose of PRX-00023 was 240 milligrams per day.   After  completion, patients could participate in a similar follow-on study of buspirone (maximum dose 60 milligrams per day), a high affinity 5HT1A agonist, with lesser activity at 5HT2, 6, 7 and dopamine D2 receptors (NCT01496612) with the same outcome measures.

Nine patients completed both, and one only the placebo study arm. There was  no significant difference in seizure frequency, depression and anxiety ratings, or adverse events between PRX and placebo treatment phases.  No patient had a 50% or greater seizure frequency reduction.  Nine patients participated in, and five competed both buspirone follow-on trial phases.  There were no significant differences in any of the outcome measures or in adverse events.

Our two small pilot trials do not provide any suggestion that 5HT1A agonists have a treatment role in focal epilepsy.