The critical node assumption has not (yet) yielded better drugs for schizophrenia Based on the “critical node” assumption, a large number of potential nodes have been identified for therapeutic drug discovery.

These have been identified via the three general strategies outlined above (eg, molecular genetic, neuronal network, or signal transduction) and a large number of these candidate nodes have been a theme of research Inhibitors,research,lifescience,medical over the past decade. As we have recently summarized as part of a larger study of psychiatric drug discovery, nearly 150 investigational compounds directed against many individual molecular targets (“nodes”) have been subjected to at Inhibitors,research,lifescience,medical least early-phase clinical trials (Roth

and Conn, unpublished report). Representative compounds for each node are listed in Table I. In this table, antipsychotic drugs have been classified based on molecular target (eg, “node”)/targets (“nodes”) and whether the compounds were validated with preclinical and clinical studies. Lastly, it is indicated whether the compounds were found, based on clinical trials, to be superior to a standard comparator medication (typically haloperidol). Based on the currently available data, we were unable to find any evidence to support the hypothesis that targeting Inhibitors,research,lifescience,medical any single molecular target (“node”) other than D2 dopamine receptors will yield a drug which effectively treats the core symptoms of schizophrenia.

Additionally, we were unable to find any support for the hypothesis that drugs targeting a single node are more effective Inhibitors,research,lifescience,medical at treating schizophrenia than drugs targeting a large number of nodes. Indeed, clozapine, which targets at least 50 nodes, remains superior to all other medications.3,5 The results obtained arc consistent with the proposal that Inhibitors,research,lifescience,medical “D2 dopamine receptors represent the critical node in schizophrenia pathogenesis.”13 It is unknown whether any single molecular target of greater promise will ever be found. There are many ways in which these findings can be interpreted, although each interpretation relies mainly on untested assertions. A typical criticism one can make of these findings is that “we have not yet found the critical Nature Cell Biology node” and that once this key node is discovered, the pathway towards drugs with greater efficacy and fewer side effects will be clarified. The untested assumptions are (i) that such a special node associated with efficacy exists; (ii) that it can be discovered; and (iii) that, once discovered, using techniques of molecular biology, a drug can be designed to target it. An implicit assumption underlying this argument relates to the need for an enhanced understanding of the molecular pathogenesis of schizophrenia in order to discover and validate suitable molecular targets.