The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline

Abstract

Importance of the field: Cognitive impairments associated with schizophrenia include neuropsychological deficits in attention, working memory, learning and executive function. Because these cognitive deficits precede the onset of psychosis, are present in non-affected relatives and constitute the best predictor of functional outcome, they are a cardinal clinical feature in schizophrenia. Currently, no effective treatment for the cognitive symptoms in schizophrenia exists.

Areas covered in this review: There is evidence that the inhibitory GABA system is affected in schizophrenia, suggesting that cognitive impairments associated with schizophrenia may be effectively treated by drugs that modulate the GABA_A receptor. However, classical benzodiazepines produce cognitive impairments and are associated with numerous side effects. The recent development of compounds with selective efficacy for different α subunits at the benzodiazepine site of the GABA_A receptor has renewed interest for the therapeutic potential of GABAergic drugs.

What the reader will gain: This review summarizes the involvement of the inhibitory GABA system in the cognitive abnormalities of schizophrenia and discusses putative (selective) GABAergic cognition-enhancing drugs for schizophrenia.

Take home message: If cognitive abnormalities in schizophrenic individuals are the result of GABAergic dysfunction, selectively modulating the GABA system could comprise a promising therapeutic intervention for cognitive symptoms in schizophrenia.

Keywords::

• alpha subunit
• gamma-aminobutyric acid
• benzodiazepine
• cognition
• GABA
• GABA_A receptor
• TP003
• TPA023

Notes

This box summarizes key points contained in the article.