Progress in drug discovery for schizophrenia in the 60 years since chlorpromazine was discovered as a treatment for psychosis has been disappointing. Andrade and colleagues[2
] describe many of the problems. I have critiqued this issue elsewhere (Carpenter and Koenig 2008,[7
] Carpenter 2004[6
]). The rationale for development of drugs for schizophrenia depends on understanding the molecular pathophysiology in order to identify molecular targets for compound development. This challenge has not been met, in part because schizophrenia is a heterogeneous syndrome and the human brain has been difficult to access for molecular studies at the tissue level. Neuroimaging techniques can identify involved pathways, but do not address what has caused aberrant structure or function. Genetic studies identify candidate genes, but validation is difficult and, in any case, particular genetic contributions make a very small contribution to manifest illness and associated genetic findings will vary from case to case.
Another major reason for the shortfall in discovery relates to treating schizophrenia as a disease defined by psychosis. This has led to antipsychotic drugs approved for the treatment of schizophrenia but limited in the breath of therapeutic effect with cognition impairment and negative symptoms being the two leading unmet therapeutic needs (Buchanan et al
] and Kirkpatrick et al
]). Commercial considerations may have also played a major role. Methods for developing an antipsychotic compound have been well established including rodent models that predict the human effect and a known mechanism of action—dopamine D2 antagonism. Based on this model scores of drugs are now on the market, but without novel mechanism or substantial advance in efficacy. An image of second generation antipsychotic drugs being superior to first generation drugs including efficacy for negative symptoms and cognition was created, but is not substantiated with data with the exception of clozapine superiority for treating the psychotic component of the disorder in patients inadequately responsive to other dopamine antagonists. The cost of treatment with second generation antipsychotic drugs created a strong incentive to produce “me-too” drugs.
Clinicians now have a wide range of adverse effects to guide selection for individual patients, but still only one drug with established superiority. Major pharmaceutical companies are now abandoning the search for new drugs for schizophrenia. Pessimism is understandable, but is the field ready to overcome pessimism regarding drug discovery for persons with schizophrenia?
My answer is yes, based on the following considerations.