Possible Interaction: Clozapine and Gamma-Aminobutyric Acid

“Neurophysiological studies suggest that clozapine may facilitate & ggr;-aminobutyric acid (GABAergic) neurotransmission.”

“The curve of specific [3H]-CGP54626A binding in competition with different concentrations of GABA was left shifted in the presence of clozapine.”

“The blockade of these GABAA receptors by clozapine would be expected to increase the firing rate of the interneurons and the release of GABA onto pyramidal cells.”

“One possible explanation is that clozapine , along with its other mechanisms of action, potentiates GABA (Bragina et al., 2007; Marx et al., 2011).”

“The association between clozapine and GABA is suggested in our case by the fact that catatonia is well known to be linked with GABA dysregulation (Northoff, 2002) and that the patient developed a similar psychosis with catatonia following withdrawal of lorazepam, a benzodiazepine that potentiates GABA.”

“This case suggests that clozapine may potentiate GABA ; and clozapine withdrawal psychosis and clozapine withdrawal catatonia may be associated with downregulation of GABA receptors.”

“This potential link between GABA dysregulation and clozapine withdrawal psychosis has not been previously postulated and possibly has important clinical implications.”

“It is associated with deficits in γ‐aminobutyric acid (GABA) neurotransmission; clozapine , regarded as the most effective antipsychotic, is associated with potentiation of GABA.”

“The possibility that this effect of clozapine is mediated via its interference with the activity of central noradrenaline and/or GABA neurons is discussed.”

“ Clozapine at 10 μM reverses 1 μM GABA 25 ± 4.0% (n = 23) (its “core” fraction).”

“These non-additivities also suggest that Clozapine at 10 μM fully saturates a subset of GABAA receptors blocked by 1 μM GABA.”

“Sixteen known 5-HT3 receptor blockers, including clozapine , fully or partially reverse the inhibitory effect of 1 μM GABA on [35S]TBPS binding, indicating that they are also GABAA antagonists, some of them selective for subsets of GABAA receptors.”

“These complementary results obtained from in vivo neurochemistry and presynaptic neurotransmitter labeling suggest that systemic clozapine suppresses neuronal GABA release within the GP.”

“Reverse dialysis of the atypical APD, clozapine (1–100 μM), produced a concentration dependent decrease in extracellular GABA.”

“Compatible with a post-synaptic mechanism, we found that membrane currents evoked by exogenous applications of GABA were similarly dose-dependently inhibited by clozapine.”