Benzodiazepines and GABA hypothesis of schizophrenia

Abstract

Clinical and experimental studies pertinent for demonstrating the antipsychotic potential of benzodiazepines (BDZ) and the involvement of γ-aminobutyric acid (GABA) in the origin of schizophrenia are reviewed. It is shown that, due to severe methodological problems and pitfalls, placebo-controlled, double-blind studies do not permit unequivocal conclusions on the efficacy of BDZs, but neither do they completely disprove it. Furthermore, at first glance, confusing and controversial findings in animal models indicate a bi-directionality of effects of full BDZ agonists on dopamine-mediated functions, which may perhaps be explained by (i) anatomical and functional organization of the GABA-dopamine system in the nigro-striatal and ventro tegmental area, and (ii) the regional non-selectivity of action of these drugs. The recent demonstration of structural polymorphism of the GABA(A)-BDZ receptor complex and heterogeneous distribution of sets of subunits of the GABA( A)-BDZ receptor in the brain, suggests possibilities for development of partial BDZ agonists showing greater regional selectivity of action and thus potentially more specific antipsychotic action. Initial clinical results with bretazenil (Ro 16-6028), a partial BDZ agonist, in acute schizophrenia are, in this respect, an encouraging lead to be followed further.

Auditory hallucinations: phenomenology, neuropsychology and neuroimaging update

“…The availability of benzodiazepine receptor ligands for PET and SPECT permits the assessment of GABA, receptors, the main subtype of CABA receptors in the brain, in living schizophrenic patients. This is also of relevance to the study of hallucinations, given the interactions between the inhibitory transmitter GABA and dopamine in the brain (101), and the clinical evidence that benzodiazepines may be effective against positive symptoms of schizophrenia (102). Busatto et al (103) recently conducted a '2'l-Iomazenil SPECT study on 15 schizophrenic patients and 12 healthy controls, and found weak evidence of reduced GABA, binding in several cortical regions in the schizophrenic group.…”

Cortical Cholinergic Transmission and Cortical Information Processing in Schizophrenia

“…Our previous research on the regulation of BF cholinergic neurons also suggests that positive GABA modulators, particularly BZR agonists, are capable of normalizing an overreactive cortical cholinergic input system (Sarter and Bruno 1994). While chronic treatment with such drugs appears limited by rapid BZR downregulation, several studies demonstrated the usefulness and potency of BZR agonists in exhibiting antipsychotic effects (Llorca et al 1991;Delini-Stula et al 1992;Jaspert and Ebert 1994;Delini-Stula and Berdah-Tordjman 1995;Delini-Stula and Berdah-Tordjman 1996) in preventing symptom progression (Carpenter et al 1999) and relapse (Kirkpatrick et al 1989), and, when coadministered with typical antipsychotic drugs, in enhancing the therapeutic efficacy and reducing the daily doses of the antipsychotic drug required (Bodkin 1990;Wolkowitz and Pickar 1991;Wassef et al 1999).…”

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

“…Additionally, several studies have indicated that glutamatemediated disruption of fast-spiking PV GABAergic interneuron pathways play a major role in the generation of synchronicity and gamma oscillation in the brain. Subjects with SCZ exhibit altered gamma-band activity that often correlates with symptoms and cognitive deficit, suggesting that GABAergic transmission and PV interneurons are responsible for the cognitive decline in SCZ [27,234,235].…”