Future Directions

Better drugs are clearly needed for the treatment of schizophrenia and these are most likely to come from a better understanding of disease origin and pathophysiology, and better novel molecular targets. Without these advances, it is likely that only incremental improvements on existing drugs will be possible. Indeed, all existing antipsychotic drugs and many drugs currently in development represent modest clinical and chemical improvements on earlier drugs; variations on a theme (olanzapine versus clozapine); metabolites of existing drugs (9-hydroxyrisperidone (paliperidone) versus risperidone); or attempts to mimic a limited set of models (aripiperazole (partial DA agonism) and asenapine (5HT2A/D2 antagonism)).

Evolving information on the polygenic nature of schizophrenia and the fact that the atypical antipsychotics have polypharmic actions have led to the suggestion that 'magic bullets' for schizophrenia should be replaced by 'magic shotguns'22 or 'selectively' nonselective agents.75 In addition to considerations of the genetics and neurochemistry of schizophrenia, it has been proposed10 that disrupted cortical circuitry, a consequence of neuronal apoptosis, may be a key event in the pathophysiology of schizophrenia. Changes in enzymes involved in the apopotic cascade, Bax/Bcl2, have been observed in the brains of patients with schizophrenia.48 Such changes have been discussed in terms of proapoptoic stress in schizophrenia, a theme that Spedding etal. have developed regarding stress-related dysfunction of neuronal plasticity mechanism and neurogenesis in psychiatric disorders and that may reflect a 'failure to recover'.76 Neurogenesis appears to be a key event in the delayed onset of antidepressants77 and may also be involved in the delayed onset of action of antipsychotics.78 The information revolution driven by genomics and understanding of the neurocircuitry and plasticity of the brain is just beginning to impact antipsychotic drug discovery efforts. Whether this information will be able to usefully provide new insights into the molecular targeting of the next generation of antipsychotic drugs remains to be seen.

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