Effects of Lacosamide on Human Motor Cortex Excitability: a Transcranial Magnetic Stimulation Study

This study has been designed to explore dose-depended effects of lacosamide (LCM) on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in young healthy human subjects, and to compare the pattern of excitability changes induced by LCM with those of carbamazepine (CBZ). LCM selectively enhances slow inactivation of voltage-gated sodium channel, and, in contrast to CBZ, does not affect steady-state fast inactivation (Errington et al., 2006). The enhancement of slow inactivation of sodium channels by LCM is a novel manner to modulate sodium channels and leads to normalization of activation thresholds and a reduced pathophysiological hyper-responsiveness, thereby effectively controlling neuronal hyperexcitability without affecting physiological activity (Beyreuther et al., 2007). Therefore, it is thought that LCM, compared to CBZ, will be better tolerated in clinical settings while being as or even more effective in controlling seizure activity. On the basis of the results from nonhuman studies, it is hypothesized that the TMS profile of LCM will be distinguishable from that of CBZ. CBZ, like other 'classical' sodium channel blockers such as phenytoin, predominantly demonstrated elevated TMS motor thresholds indicating reduced neuronal membrane excitability, without developing significant changes of synaptic intracortical inhibition and facilitation (Ziemann et al., 1996; Chen et al., 1997; Lee et al., 2005). Because of its novel mode of action it can only be speculated which TMS parameters LCM might affect. For example, more than exclusively affecting neuronal membrane excitability, LCM could possibly also affect inhibitory mechanisms such as short- and long-latency intracortical inhibition (Valls-Sole et al., 1992; Kujirai et al., 1993). This would in line with other well-tolerated modern antiepileptic drugs (Ziemann et al., 1996; Reis et al., 2002; Lang et al., 2006).

• Drug: Lacosamide
  Lacosamide 200 or 400 mg
• Drug: Placebo
  Placebo
• Drug: Carbamazepine
  Carbamazepine 600 mg

• Placebo Comparator: Placebo
  Placebo arm
  Intervention: Drug: Placebo
• Experimental: Lasosamide 200
  Lacosamide 200 mg
  Intervention: Drug: Lacosamide
• Experimental: Lacosamide 400
  Lacosamide 400 mg
  Intervention: Drug: Lacosamide
• Active Comparator: Carbamazepine 600
  Carbamazepine 600 mg
  Intervention: Drug: Carbamazepine

Inclusion Criteria:

• healthy
• male
• right-handed
• aged 18-45 years

Exclusion Criteria:

• cardiac pacemaker
• metal implants in the head
• intake of any medication
• previous neurologic, psychiatric, or chronic internal diseases
• pregnancy or breastfeeding; drug, nicotine, or alcohol abuse
• known or expected intolerance to soy beans, peanuts, LCM or CBZ; abnormal ECG with prolonged PQ-interval
• participation in another clinical trial within the previous 8 weeks