Review article
Neuropsychopharmacology and the genetics of schizophrenia
A history of the diagnosis of schizophrenia
Thomas A. Ban
Department of Psychiatry, Vanderbilt University, Nashville, TN, USA
Accepted 10 May 2004 - Available online 25 July 2004
8. Neuropsychopharmacology
Neuropsychopharmacology is a combined discipline of neuropharmacology and psychopharmacology. By its unique capability of linking the effect of psychotropic drugs on mental illness with their action on brain structures, neuropsychopharmacology provides a means for bridging the gap between psychiatric nosology and the genes (approximately 30,000) expressed in the human brain (Ban, 2002; Faraone et al., 1999).
All the primary targets of psychotropic drugs are molecular structures involved in neuronal transmission, e.g., G-protein-coupled receptors, nuclear (hormonal) receptors, enzymes, and all these structures are encoded by genes which have been identified. Hence, any psychopathology-based clinical syndrome or nosological entity that corresponds in a treatment-responsive population to a psychotropic drug is suitable for the generation of genetic hypotheses with the employment of the candidate gene approach.
Based on the pharmacological action of drugs with a therapeutic effect in schizophrenia, various genes have been implicated in the pathophysiology of the disease. First, Arinami et al. (1994) reported that a functional variant of the dopamine-D2 gene was associated with schizophrenia. Then Williams et al. (1996, 1997) detected an association between a mutation in the serotonin-5HT2A receptor gene and schizophrenia.
More recently, Dubertret et al. (1998), and Williams et al. (1998), found an association between a functional polymorphism of the dopamine-D3 receptor subtype and schizophrenia. Despite of these findings, the fact remains that association studies have failed so far to present replicable differences in mutations (polymorphism) between normal subjects and schizophrenic patients (Malhotra and Goldman, 1999).
In view of this, Faraone et al. (2002) suggest that the findings in association studies demonstrate the complexity and heterogeneity of the genetic etiology of schizophrenia. They contend that more research is needed to identify other genes associated with schizophrenia and to determine how they affect the brain, and whether the genes identified combine in additive or interactive fashion to modify the risk for schizophrenia.
But is this really the case? Would it not be more correct to say that in working with a biologically heterogenous population like schizophrenia, the clinical prerequisite for molecular genetic research is not fulfilled? Given that the findings of Astrup (1959) and Fish (1964), and Leonhard's (1957) classification of endogenous psychoses have been ignored for 40 years, there is no subpopulation within schizophrenia that qualifies for molecular genetic research. If Fish's (1964) findings could be verified, affect-laden paraphrenia, a syndrome, characterized by paranoid delusions with affective loading and mood swings (Ban, 1982), would become the first subpopulation within schizophrenia that qualifies for molecular genetic research.
There is also another possible lead that could yield a suitable population. Patients with systematic hebephrenia, a population in Leonhard's (1957) classification, with a low (23%) responsiveness to typical antipsychotics in Fish's (1964) study, seem to fare better when switched from a typical to an atypical antipsychotic. If the difference in therapeutic responsiveness between atypical and typical neuroleptics in systematic hebephrenia could be verified, it would render another subpopulation within schizophrenia accessible for molecular genetic research (Ban, 1999, 2002).