30 June 2009. One of the most highly anticipated payoffs of the post-genomic era is personalized medicine, the ability to develop more precise diagnoses and customized treatments based on a patient’s genetic makeup. Progress on this front in psychiatry has been slow, but two new studies, one on bipolar disorder and the other on major depressive disorder, may nudge the field a bit closer to this elusive goal.
A cornerstone of personalized medicine is pharmacogenomics, which aims to uncover the relationships between genetic differences and drug efficacy. This approach has made significant inroads in oncology, where treatment regimens for breast cancer based on HER2 tumor typing have become commonplace, as has genetic testing to predict the effectiveness of Gleevec (imatinib mesylate) and related compounds in leukemia and gastrointestinal cancer. Preliminary studies of genetically tailored first-line treatments for non-small cell lung cancer have also been promising (see, e.g., Rosell et al., 2009; Sequist et al., 2008).
In psychiatry, however, the impact of pharmacogenomics has so far been limited, and more oriented toward genetic effects on the kinetics of drugs (metabolism, bioavailability, etc.) than their direct physiological actions (drug dynamics), and thus more applicable to avoiding undesirable side effects than enhancing therapeutic efficacy. For example, tests for cytochrome P variants affecting drug metabolism that are associated with tardive dyskinesia and other side effects of antipsychotics are now available, though the extent of the penetration of these tests into clinical practice is unknown (for a review, see Arranz and Kapur, 2008; also see SRF related news story).
The two new studies focus squarely on drug dynamics. In the first, Julio Licinio and colleagues from the University of Miami performed exonic sequencing on a 22-kb region containing the BDNF (brain-derived neurotrophic factor) gene and flanking regions in 272 Mexican Americans diagnosed with major depressive disorder (MDD) and 264 controls (Licinio et al., 2009). Their analyses identified 83 novel SNPs (254 had been identified previously), one of which, rs12273539, retained a significant (p = 0.002) association with MDD. The group also identified two haplotype blocks that were significantly associated with MDD.
In addition, the Miami team reports that eight SNPs were associated with patients’ response to antidepressants, though none of these associations retained statistical significance after multiple quality-control tests. The authors write that their findings “further implicate BDNF in the susceptibility to MDD and in the therapeutic response to antidepressants.”
In the second new study, Roy Perlis of Harvard led a multi-institution collaboration, with colleagues also from MIT, University College London (UCL), and the University of Pittsburgh, in a genomewide association study (GWAS) of the efficacy of lithium in the prevention of recurrent mood episodes in bipolar disorder (BD).
The Perlis team first examined samples from 1,177 patients who took part in the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) study, 458 of whom had been treated with lithium. No SNPs achieved genomewide significance for association with response to lithium, but five suggestive regions were included in further analyses of a cohort from UCL. One SNP that showed additional evidence of association in the UCL cohort, rs9784453, lies on chromosome 4q32 near GRIA2, which codes for a subunit of a glutamate receptor that has been shown to be downregulated by chronic lithium treatment of human cell lines in vitro. A comparison of rs9784453 alleles in lithium-treated patients revealed a significant (p = 0.001) difference in the time to recurrence.
In a mostly cautionary editorial on psychiatric pharmacogenomics that accompanies the paper by Perlis and colleagues, John Nurnberger argues that the paper is “not perfect”: among the methodological flaws he notes are the fact that the definition of lithium response used in the study is not based on a single group of patients followed over many years, and that patients’ blood levels of lithium—a crucial measure in clinical practice—were not factored into the study’s assessment of response. Nonetheless, Nurnberger writes, the new study is “a good start [that] by presenting the first data...becomes the reference paper for the field.” He proposes that converging, complementary pharmacogenomic evidence from GWASs, candidate gene studies, and functional studies will eventually coalesce, resulting not only in translation into new clinical guidelines, but also shedding light on the poorly understood mechanisms underlying many drugs for mental illness.
Citing the Perlis group’s data on recurrence in rs9784453 carriers as an example of the sort of finding that could someday bring pharmacogenomic insights into mainstream psychiatry, Nurnberger writes, “[T]he median time to recurrence is about 230 days for homozygote carriers with the ‘poor response’ allele and about 520 days for homozygote carriers of the ‘good response’ allele, with heterozygote carriers falling in between. Differences such as this are of clinical interest.”—Peter Farley.
Licinio J, Dong C, Wong ML. Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry. 2009 May;66(5):488-97. Abstract
Perlis RH, Smoller JW, Ferreira MA, McQuillin A, Bass N, Lawrence J, Sachs GS,
Nimgaonkar V, Scolnick EM, Gurling H, Sklar P, Purcell S. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry. 2009 Jun;166(6):718-25. Epub 2009 May 15. Abstract