Neuropharmacology beyond reductionism - A likely prospect.

Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier. The decline of drug discovery output in the last decades, quite obvious in neuropharmacology, coincided with the advent of the single target-focused search of potent ligands selective for a well-defined protein, deemed critical in a given pathology. However, all the widespread neuro-psychic troubles are multi-mechanistic and polygenic, their complex etiology making unsuited the single-target drug discovery. An evolving approach, based on systems biology considers that a disease expresses a disturbance of the network of interactions underlying organismic functions, rather than alteration of single molecular components. Accordingly, systems pharmacology seeks to restore a disturbed network via multi-targeted drugs. This review notices that neuropharmacology in fact relies on drugs which are multi-target, this feature having occurred just because those drugs were selected by phenotypic screening in vivo, or emerged from serendipitous clinical observations. The novel systems pharmacology aims, however, to devise ab initio multi-target drugs that will appropriately act on multiple molecular entities. Though this is a task much more complex than the single-target strategy, major informatics resources and computational tools for the systemic approach of drug discovery are already set forth and their rapid progress forecasts promising outcomes for neuropharmacology.