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

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 alpha 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.