Abstracts

Rationale: Unlike blood levels, the neurophysiological effects of anticonvulsants are seldom measured over time-- although they are likely more relevant to the duration of drug action. Lamotrigine (LTG) and other sodium channel agents are known to elevate the motor threshold (MT) to transcranial magnetic stimulation (TMS), consistent with an increased proportion of inactive voltage-gated sodium channels at the neuronal membrane. This effect is well-defined and allows painless, non-invasive assessment of single-dose pharmacodynamics. Methods: We administered a single oral dose of LTG-XR 300 mg to 10 healthy volunteers, and tracked the resting MT to TMS for 80 hours using a parameter estimation (PEST) algorithm. This dose was predicted to produce blood levels in the therapeutic range. In addition, we recorded sitting and standing blood pressures and subjective side effects on a visual-analog scale. With an expectation only of increased MT after LTG, sequential MT measures were analyzed by one-tailed paired t-tests. Results: Possible neurotoxicities were rare and mild. Orthostasis was not observed. In one subject, MT at 6-32 hours exceeded the output of the stimulator. For the remaining 9 subjects, MT increased monotonically to an average of 21% above baseline at 12 hours (p = .0013.) Although there appeared to be individual variations in the magnitude and duration of effect, average MT remained significantly elevated out to 56 hours (p < .05). Results, including significant and near-significant differences from baseline, are illustrated in Figure 1. Conclusions: TMS effects from a single dose of LTG-XR are remarkably robust, and contrast with an absence of subjective toxicity. Neurophysiological changes from LTG-XR are detectable up to 56 hours after a single dose.