New drug targets in psychiatry: Neurobiological considerations in the genomics era

• Published in: Neuroscience and biobehavioral reviews 2022-08, Vol.139, p.104763-104763, Article 104763
• Main Authors: Harrison, Paul J., Mould, Arne, Tunbridge, Elizabeth M.
• Format: Article
• Language: English
• Subjects: Catechol O-Methyltransferase - genetics; Dopamine; Drug development; Genomics; Humans; Kruppel-Like Transcription Factors - genetics; Neurobiology; Psychiatry; Schizophrenia - genetics
• ISSN: 0149-7634; 1873-7528
• DOI: 10.1016/j.neubiorev.2022.104763

After a period of withdrawal, pharmaceutical companies have begun to reinvest in neuropsychiatric disorders, due to improvements in our understanding of these disorders, stimulated in part by genomic studies. However, translating this information into disease insights and ultimately into tractable therapeutic targets is a major challenge. Here we consider how different sources of information might be integrated to guide this process. We review how an understanding of neurobiology has been used to advance therapeutic candidates identified in the pre-genomic era, using catechol-O-methyltransferase (COMT) as an exemplar. We then contrast with ZNF804A, the first genome-wide significant schizophrenia gene, and draw on some of the lessons that these and other examples provide. We highlight that, at least in the short term, the translation of potential targets for which there is orthogonal neurobiological support is likely to be more straightforward and productive than that those relying solely on genomic information. Although we focus here on information from genomic studies of schizophrenia, the points are broadly applicable across major psychiatric disorders and their symptoms. •Neurobiological and genomic studies have provided insights into the biology of psychiatric disorders, including schizophrenia.•Genomic findings have the potential to identify novel therapeutic targets, but the pathway from gene to target is not straightforward.•We outline the steps needed to move from gene to therapeutic target using exemplars from both neurobiology and genomics.•A at least in the short term, targets for which there is both neurobiological and genomic evidence are likely to be the most promising and tractable.