Psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: a review of old and new targets.

Neurocognitive impairments significantly contribute to disability and the overall clinical picture in schizophrenia spectrum disorders. There has therefore been a concerted effort, guided by the discovery of neurotransmitter and synaptic systems in the central nervous system, to develop and test compounds that may ameliorate neurocognitive deficits. The current article summarizes the results of efforts to test neurocognitive-enhancing agents in schizophrenia. Overall, existing clinical trials provide little reason to be enthusiastic about the benefits of psychopharmacological agents at enhancing neurocognition in schizophrenia-a state of affairs that may reflect the inadequacy of single neurotransmitter or receptor models. The etiologic and phenomenological complexity of neurocognitive deficits in schizophrenia may be better served by psychopharmacological agents that (i) target neurotransmitter systems proximal in the causal chain to neurocognitive deficits; (ii) enhance distal survival processes in the central nervous system-neurogenesis, neuronal growth, synaptogenesis, and connectivity; and (iii) counteract the negative effects of aberrant neurodevelopment in schizophrenia, such as neuroinflammation and oxidative stress. Future efforts to develop psychopharmacological agents for neurocognitive impairment in schizophrenia should reflect the knowledge of its complex etiology by addressing aberrations along its causal chain. Clinical trials may benefit methodologically from (i) an appreciation of the phenomenological heterogeneity of neurocognitive deficits in schizophrenia; (ii) a characterization of the predictors of treatment response; and (iii) a recognition of issues of sample size, statistical power, treatment duration, and dosing.