Clinical Utility of Pharmacogenomics of Psychotropic Medications

Overview

While the scientific understanding of pharmacogenomics is quickly accelerating, its translation to clinical decision-making (especially in psychiatric practice) has progressed more slowly. In an effort to begin to bridge this translational gap, genetic testing has been developed for various and commonly existing psychiatric disorders, such as major depression, schizophrenia, bipolar disorder, and pain syndromes to improve the safety of prescribing psychotropic medications for these disorders. This genetic testing incudes several pharmacodynamics and pharmacokinetic genetic factors, such as the cytochrome P450 1A2 gene (CYP1A2); the cytochrome P450 2B6 (CYP2B6) gene; P450 2D6 gene (CYP2D6); the cytochrome P450 2C9 gene (CYP2C9); the cytochrome P450 2C19 gene (CYP2C19); uridine-glucoronyl-transferase 2B15 (UGT2B15) gene; the serotonin transporter gene (Solute Carrier Family 6 Member; SLC6A4); p-glycoprotein ( ATP-binding cassette sub-family B member 1; ABCB1) transporter gene; the serotonin 2A receptor gene (HTR2A); the serotonin 2C receptor (HTR2C) gene; serotonin 1a receptor (5HT1a) gene; dopamine 1 receptor (DRD1) gene; dopamine 2 receptor (DRD2) gene; adrenergic alpha-2A receptor (alpha-2A) gene; opioid mu (opioid receptor mu 1; OPRM1) receptor gene; dopamine synthesis gene (ankyrin repeat and kinase domain containing 1; ANKK1); dopamine metabolizing enzyme \[Catechol-o-methyltransferase (COMT\]) gene; kainite receptor gene (glutamate ionotropic receptor kainate type subunit 4; GRIK4); folate (methylenetetrahydrofolate reductase; MTHFR) gene; sodium channels (sodium voltage-gated channel alpha subunit 2; SCN2A) gene. The interpretive report is based on copies of these multiple informative genes. The investigators are proposing to utilize comprehensive genetic testing to select more genetically-informed psychotropic medications to enhance their effectiveness in real-world patients with psychiatric illnesses such as schizophrenia, major depression, bipolar affective disorder as well as pain in a state hospital setting. The investigators plan to use genetic testing offered by Admera® for major classes of psychotropic medications. The investigators hypothesize that genetic testing will demonstrate clinical benefits by improving state hospital patients' response and decreasing their adverse effects. The proposed study will be conducted in a total sample of 60 subjects diagnosed with schizophrenia, major depression, bipolar affective disorder as well as pain at the Oregon State Hospital, Salem Oregon over a total period of 24 months

There is considerable inter-individual variability in therapeutic drug response, required dosage and adverse effects in psychotropic treatment. Few patients experience a remission of their illness when initially treated with any medications.1,2 In those who remain symptomatic, less than half will experience a significant improvement with a change in medication or with the addition of an alternative psychotropic medication.2 Variation in drug response is complex and is dependent on a number of factors, including diagnostic accuracy, the potential for drug-drug interactions, age, gender, renal and hepatic functioning, medical and psychiatric comorbidity, nutritional status, coincident substance use, genomic and related downstream translational factors and patient compliance. In recent studies examining the use of antidepressants, antipsychotics, mood stabilizers, and pain medications substantial proportions of study patients discontinue treatment as a consequence of adverse effects or symptom relapse.3-5 Similarly in community practice settings, nearly half of the patients make no follow-up visits, and only a fourth return to pursue regular primary treatment.6,7 Prolonged times to response whether caused by adverse effects or by other factors are associated with substantial increased risk for morbidity or mortality. Pharmacogenomic testing is expected to improve response, as well as minimize the likelihood of adverse effects associated with patient nonadherence and extended morbidity.8-10 While the scientific understanding of pharmacogenomics is quickly accelerating, its translation to clinical decision-making in practice has progressed more slowly.11,12 In an effort to begin to bridge this translational gap, a pharmacogenomic/pharmacogenetic testing has been developed for various and commonly existing psychiatric disorders to improve the safety of prescribing medications. This pharmacogenomic-based interpretive report is based on genotyping both copies of multiple informative genes, which are: the cytochrome P450 1A2 gene (CYP1A2); the cytochrome P450 2B6 (CYP2B6) gene; P450 2D6 gene (CYP2D6); the cytochrome P450 2C9 gene (CYP2C9); the cytochrome P450 2C19 gene (CYP2C19); uridine-glucoronyl-transferase 2B15 (UGT2B15) gene; the serotonin transporter gene (Solute Carrier Family 6 Member; SLC6A4); p-glycoprotein ( ATP-binding cassette sub-family B member 1; ABCB1) transporter gene; the serotonin 2A receptor gene (HTR2A); the serotonin 2C receptor (HTR2C) gene; serotonin 1a receptor (5HT1a) gene; dopamine 1 receptor (DRD1) gene; dopamine 2 receptor (DRD2) gene; adrenergic alpha-2A receptor (alpha-2A) gene; opioid mu (opioid receptor mu 1; OPRM1) receptor gene; dopamine synthesis gene (ankyrin repeat and kinase domain containing 1; ANKK1); dopamine metabolizing enzyme \[Catechol-o-methyltransferase (COMT\]) gene; kainite receptor gene (glutamate ionotropic receptor kainate type subunit 4; GRIK4); folate (methylenetetrahydrofolate reductase; MTHFR) gene; sodium channels (sodium voltage-gated channel alpha subunit 2; SCN2A) gene. The cytochrome P450 enzymes' genes code for the enzymes that are responsible for metabolism of most antipsychotic, antidepressant and pain medications. The UGT2B15 is for benzodiazepine metabolism. The COMT gene is for dopamine metabolism and is relevant for cognitive function, depression and smoking. The SLC6A4 and the 5HT2A have been associated with differential treatment response to specific medications. The 5HT2C is for weight gain; the ABCB1 gene is for pain; some psychotropics such as risperidone; the dopamine 2 (D2) receptor gene for psychotropic medications, weight gain and pain medications; and the opioid mu (OPRM1) receptor gene for weight and pain; Sodium channels (SCN2A) gene for autism, seizures and bipolar disorder; GRIK4 gene is for kainite receptor involvement with rapidly acting antidepressants, pain, dysphoria, and potentially psychotropic medications' ANKK1 is for smoking, weight management, and bipolar disorder. The MHTFR is for antidepressants; D1 is for psychotropic response. Such genetic testing has a significant potential to reduce healthcare costs through increased efficacy and tolerability of antidepressant medications as well as medication adherence. However, there is a relative lack of such efforts with psychotropic medications (APMs) in the treatment of various psychiatric disorders, such as schizophrenia, major depression, or bipolar disorder. This is despite significant room for improvement in efficacy and tolerability of currently available drugs in such patients. Consequently, the investigators are proposing to utilize genetic testing to select more genetically-informed medications to enhance their effectiveness in real-world patients with psychiatric illnesses such as schizophrenia, major depression, and bipolar affective disorder as well as medical problem with chronic pain in a large state hospital setting. The investigators plan to use genetic testing offered by Admera® for medications. The investigators hypothesize that utilizing such pharmacogenomic testing as a treatment decision support tool will demonstrate clinical benefits by improving patient response and decreasing adverse effects to the psychotropic medications. The proposed study will be conducted at the Oregon State Hospital, Salem Oregon over a total period of 12 months.