Psychiatric genetics and the future of personalized treatment.

Abstract

Well before the sequencing of the human genome in 2003, family and twin studies had established that psychiatric disorders are both familial and heritable. But identifying the genes involved has been a formidable challenge. At the same time, there has been an urgent need to unlock the biological basis of psychiatric disorders. While psychotropic drugs are helpful for many and life-saving for some, there is a striking fact about available drug therapies: they are all based on serendipitous discoveries and biological insights that date to the 1950s and 1960s. When it comes to treating psychiatric disorders, we are still living in the “Mad Men” era. Lithium has been the gold standard treatment for bipolar disorder ever since John Cade reported its mood stabilizing effects in 1949. All current antipsychotic medications target the D2 dopamine receptor, just as the first medicines in this class did in the 1950s. Antidepressants have relied on variations of the monoamine hypothesis that was articulated in the mid-1960s. The shortcomings of available psychotropics are well-known. The results of large-scale effectiveness studies of mood and psychotic disorders (STAR*D, CATIE, and STEP-BD) are sobering: roughly 30% of depressed patients treated for 14 weeks with an SSRI achieved remission [1];25% of patients with schizophrenia remained on their initial medication by 18 months [2]; and 50% of bipolar patients who achieved recovery from a mood episode relapsed within two years despite best-practice treatment. [3] A major hope hanging on genetic studies has been that they can break this therapeutic impasse, There are three main avenues by which genetic research may inform efforts towards personalized medicine. First, by identifying DNA variants associated with risk of disease, genetic studies may point us toward new treatment targets. The discovery that a specific gene or set of genes confers risk for illness raises the possibility that drugs that target that gene (or genes) may have therapeutic effects. Second, genetic studies may clarify diagnostic boundaries in ways that could inform treatment selection or identify etiologically-related subgroups that might preferentially benefit from a given treatment. And third, pharmacogenetic studies may yield genetic profiles that predict response to available treatments. The following sections address each of these avenues and the state of the science to date.