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

  title={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},
  author={Allen J. Sedman and Gregory P. Gilmet and A J Sayed and Edward L. Posvar},
  journal={Drug Development Research},
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… 
Preclinical toxicology of the GABA uptake inhibitor CI‐966
Preclinical toxicology of Cl‐996 was evaluated in male and female B6C3F1 mice, Wistar rats, and beagle dogs and enhanced GABAergic activity was considered to be the cause of most of the clinical signs elicited by Cl‐966 in rodents and dogs.
Neuropharmacological evidence for an interaction between the GABA uptake inhibitor Cl‐966 and anxiolytic benzodiazepines
HCl (Cl‐966, Parke‐Davis), a new specific inhibitor of GABA uptake to neurons that is severalfold more potent than for inhibition of glycine or glutamate uptake, produces a modest reversal of punished‐suppressed drinking behavior in thristy rats both in the conflict and phenylenetetrazole (PTZ)‐induced proconflict Vogel test.
Assessment of zolpidem and Cl‐966 for anxiolytic and anxiogenic properties by using the discrimination of pentylenetetrazole by rats
The present data suggest that the discriminative stimulus produced by PTZ is not related to its ability to produce convulsions, and the partial substitution of CI‐966 given in high doses is consistent with clinical reports that this compound may produce anxiogenic effects.
GABA Levels in the Brain: A Target for New Antiepileptic Drugs
A new class of antIEpileptic drugs such as vigabatrin, which blocks GABA degradation enzymes, have been developed as effective antiepileptics and are associated with minimal side effects.
Building a bridge between neurobiology and mental illness.
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  • 1992
Atypical Antipsychotic Drugs: Clinical and Preclinical Studies
Data which indicate that nondopaminergic systems may be essential for the activity of atypical antipsychotoic drugs are summarized, and some of the compounds discussed here will not, in fact, prove to be antipsychotic in humans.
GABA and mood disorders: a brief review and hypothesis.
  • F. Petty
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Hallucinogenic drugs are of interest to psychiatrists as possible models of schizophrenia. Possibly some of the mechanisms by which these drugs elicit altered mental states might lead to a better
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Summary: Antiepileptic drug discovery has made enormous progress from the serendipity and screening processes of earlier days to the rational drug development of today. The modern era of research


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Tetrahydroisoxazolopyridinol (THIP) is not an effective new treatment for tardive dyskinesia, but more specific GABA agonists should be evaluated in future studies of this syndrome.
The interaction between GABA and dopamine: implications for schizophrenia.
Interest in GABA research in schizophrenia appears to have waned, but several areas nevertheless appear promising for clinical investigation.
γ-Acetylenic GABA in Tardive Dyskinesia
Tardive dyskinesia was significantly reduced, and preexisting parkinsonism increased slightly, suggesting an interaction between GABA and dopamine, in patients receiving higher neuroleptic doses.
Novel inhibitors of gamma-aminobutyric acid (GABA) uptake: anticonvulsant actions in rats and mice.
The studies indicate that the family of compounds represented by SK&F 89976A andSK&F 100330A may have clinically relevant anticonvulsant activity.
Sodium Valproate in Schizophrenia: Some Biochemical Correlates
Summary Sodium valproate given in doses of 750–3000 mg daily to eight schizophrenic patients produced a qualitatively similar increase in symptoms in five. CSF showed no significant change in
Medical treatment of mental illness.
Psychotherapeutic drugs have dramatically improved the prognosis for patients with severe mental illness and involve psychiatry in modern biological science.