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SNP Combos in Three CYP450 Genes Affect Psychotropic Rx Response, Genomas Finds

Patients with major depressive disorders who carry combinations of the CYP2C9, CYP2C19, and CYP2D6 genes have limited ability to metabolize at least 14 psychotropic medications, according to a recent study performed by researchers at Genomas and Hartford Hospital, both located in Connecticut.
“We found clear evidence that there were significantly more innate drug metabolism deficiencies based on the gene variants predominantly observed in the population experiencing side effects,” said Genomas CEO Gualberto Ruaño in a statement. “Our goal is to enhance patient safety by preventing predictable side effects and at the same time build the case for DNA typing in the optimized utilization of health-care resources.”
The study, which appeared last month in Personalized Medicine, involved 73 patients with major depressive disorder who were on one of 14 different drugs, including antipsychotics (Abilify, Risperdal, Seroquel), antidepressants (Prozac, Wellbutrin, Effexor, Paxil, Zoloft), anticonvulsants (Lamictal, Depakote, Trileptal, Klonopin, Topamax), and the stimulant (Concerta).
These patients were referred to Genomas for diagnostic DNA typing after their doctors found that they have low response or an adverse response to treatments.
As part of the study, Genomas genotyped the same genes on samples obtained from 120 control participants who were being treated at Hartford Hospital for dysllipidemia but were not psychiatrically ill.
The study was conducted at the Institute of Living at Hartford Hospital, where Genomas’ CLIA-certified Laboratory of Personalized Health is also located. The Laboratory of Personalized Health performs DNA typing to diagnose drug metabolism capacities of patients referred by local doctors. The referrals used in the study came from local Connecticut doctors.
Ruaño, who is also the director of genetics research at Hartford Hospital and a founder of Genaissance, now part of Clinical Data, told Pharmacogenomics Reporter this week that the company is incorporating this clinical experience to help it develop its PhyzioType Systems for DNA-Guided Medicine.

“When these patients were referred to us they were already in trouble.”

The Personalized Medicine studyused the Tag-It assay and the Luminex xMap system to detect polymorphisms in the CYP2C9, CYP2C19, and CYP2D6 genes. The researchers found the proportion of psychiatric patients versus control patients who had two wild-type alleles for CYP2C9, CYP2C19, and CYP2D6, was 50 percent versus 74 percent, 71 percent versus 73 percent, and 36 percent versus 43 percent, respectively.
Approximately 57 percent of the psychiatric population carried non-wild-type alleles for two to three genes compared to 36 percent in the control population, the study found. Carriers of non-wild-type alleles for none or one gene comprised 43 percent of the psychiatric population and 64 percent of the controls.
“These findings reveal that clinically relevant CYP2C9 polymorphisms occur more frequently in depressed psychiatric patients than in nonpsychiatric controls,” the researchers concluded. “The significant enrichment of CYP2C9-deficient alleles in the psychiatric population validates a previously reported association of this gene with the risk for depression disorders.”
The researchers found the same trend for polymorphisms in the CYP2D6 gene, but found no difference in CYP2C19 allele frequencies between psychiatric and control groups. According to the researchers, the CYP2C19 gene is less polymorphic than the other two CYP genes, and thus, did not have enough statistical power to detect difference in the frequency of this particularly gene.
“We found a significant cumulative metabolic deficiency in the psychiatric population for combinations of the CYP2C9, CYP2C19, and CYP2D6 genes,” the researchers concluded. “The high prevalence of carriers with deficient and null alleles suggests that CYP450 DNA typing may play a role in the management of psychiatric patients at tertiary care institutions.”
Ruaño pointed out that the study does have a referral bias. “When these patients were referred to us they were already in trouble,” he said. “But the results of the study suggest that perhaps with DNA typing their adverse reactions could have been controlled earlier.”
The researchers also said in the paper they hope the study demonstrates that targeted genotyping of psychiatric patients will lead to better treatment outcomes than with screening the general population.
“Comprehensive, combinatorial genotyping and targeted applications to populations with the greatest medical need stand in sharp contrast to limited genotyping for broad population screening,” the researchers said in the paper.
“We believe the definition of a novel drug-sensitivity syndrome is warranted in carriers of multiple null and deficient alleles of CYP450 genes,” the authors wrote. “Such individuals are multiply deficient in CYP450 metabolic routes which place them at risk for adverse reactions with several psychotropics.”
The researchers also conceded that among the study’s limitations included the fact that it followed predominantly Caucasian individuals and enrolled a disproportionate number of females. 
Genomas is targeting recruitment of minority patients, who were under-represented in this study. Ruaño noted that Genomas will continue working with other centers and regional doctors to provide DNA typing to gauge metabolic functions of referred patients.  

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