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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Vinkers
Christiaan H
CH
Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands .c.h.vinkers@uu.nl
Mirza
Naheed R
NR
Olivier
Berend
B
Kahn
René S
RS
D001288:Attention / Q000187:drug effects; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018682:GABA Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009422:Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D018079:Receptors, GABA / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
D015507:Drugs, Investigational; D018682:GABA Agents; D058785:GABA-A Receptor Agonists; D018079:Receptors, GABA