INVITED COMMENTARY Postgenomic Psychiatry: Great Hopes or Great Hype? Peter McGuffin, MB, PhD* and Anita Thapar, MB, PhD Address *SGD P Research Centre, Institute of Psychiatr y, King’s College London, PO Box 80, D eCrespigny Park, London SE5 8AF, UK. E-mail: p.mcguffin@ btinternet.com Current Psychiatry Reports 2004, 6: 75–76 Current Science Inc. ISSN 1523-3812 Copyright © 2004 by Current Science Inc. Introduction The year 2003 saw the 50th anniversary of the discovery of the double helical structure of DNA and the completion of the sequencing of the entire human genome, the annotated draft of which was reported 2 years earlier in 2001 in simul- taneous “genome issues” of the journals Nature and Science. Media interest has been enormous, and it is a widely pro- claimed view that molecular genetics and its evolving off- spring, genomics, will revolutionize biomedical science and the practice of all clinical disciplines. However, much of this leaves many clinical psychiatrists cold. Psychiatric geneticists run the risk (we know from experience) of being told by clinical colleagues that their research sounds “very clever” (non-British readers should be aware that “clever” is not nec- essarily a compliment in this part of the world), but it is a pity that it is of little clinical relevance. So what then is the truth; do es the po stgeno mic era o ffer great ho pe fo r psychia- try o r is it all hype? Molecular Neurobiology We believe that, at its most basic level, progress in genomic research will lead to a profound improvement in under- standing of the neurobiology of psychiatric disorders. Knowing the structure and function of all human genes has been compared with discovering a “periodic table of life” [1], and paves the way for a shift in emphasis from the structure of the genome to a functional genomics and pro- teomics—the study of proteins at a functional level. Com- bining this type of “bottom-up” approach with top-down studies comparing human behavior with animal models would take us into an era of behavioral genomics [2]. Schizophrenia is beginning to look like a promising exam- ple. Although it has been known since ancient times that psychiatric disorders tend to run in families, it was not until the past century that twin and adoption designs were widely used, confirming the powerful role of genes. Schizo- phrenia was the most thoroughly researched disorder, with the evidence suggesting heritability in the region of 80%. Actually finding the genes involved in schizophrenia has proved a more difficult task than many predicted, but there are now several well-replicated findings implicating genes involved in glutamate, serotonin, and dopamine pathways [3,4], and these are beginning to provide new insights into pathogenesis of the disease [5,6]. Pharmacogenomics and Pharmacotherapy Genomic advances in psychiatry also will have important implications for pharmacotherapy. These will involve drug discovery resulting from finding new targets for drugs and treatment tailoring, which is the prescription of drugs based on an individual’s genotype. At present, the drugs used in the treatment of psychiatric and other central nervo us system diseases have actio ns that are lim- ited to a number of categories of targets that include cell surface receptors, nuclear receptors, ion channels, and enzymes. It is likely that identifying the genes involved in the pathogenesis of psychiatric disorders will identify new targets, some of which will fall within these catego- ries, but they also will include others that have not been thus far considered as potential sites of drug action [7]. In addition, advances in genomics will allow tailoring of pharmaceuticals that are likely to be relevant to the development of treatment response and side effects (reviewed in this issue by Basu et al. ). For example, there is already some evidence that response to an atypical antipsychotic, such as clozapine, is influenced by an individual’s genotype at a combination of loci or that the susceptibility of side effects to tricyclic antidepressants is influenced by genes in the cytochrome P450 system. By contrast, in our view, gene therapy proper, that is, using genetic engineering methods to carry out gene transfer of “healthy” genes into tissues containing mutant genes, is unlikely to have a place in psychiatric disorders. Treat- ments involving gene transfer already have proved enor- mously problematic, even in single gene disorders affecting more accessible organs such as the lungs [8], and seem unlikely to be successful in polygenic disorders involving a relatively inaccessible organ, the brain.