Initial human safety and tolerance study of a GABA uptake inhibitor, Cl‐966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania

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Abstract
An initial double‐blind, placebo‐controlled safety and tolerance study of single doses of a GABA uptake inhibitor (CI‐966) being developed for the treatment of epilepsy was conducted in healthy volunteers. Drug doses of 1 to 10 mg were well tolerated. A volunteer who received 25 mg of CI‐966 developed transient short‐ and long‐term memory deficits. Both volunteers following administration of 50 mg drug doses presented with a constellation of physical and mental disturbances. Physical abnormalities including tremor, myoclonus, increased muscle rigidity, cogwheeling, and short‐ and long‐term memory impairment of 12–24 hr duration were observed. In addition, striking psychiatric symptoms of many days' duration resembling those seen in patients with mania and schizophrenia were evident. These findings suggest that GABA may modulate memory and dopaminergic pathways responsible for posture and muscle control. In addition, GABA may be a potentially important mediator in the pathogenesis of schizophrenia and mania.