AICM: A Genuine Framework for Correcting Inconsistency Between Large Pharmacogenomics Datasets.

Pac Symp Biocomput. 2019;24:248-259

Authors: Hu ZT, Ye Y, Newbury PA, Huang H, Chen B

Abstract
The inconsistency of open pharmacogenomics datasets produced by different studies limits the usage of such datasets in many tasks, such as biomarker discovery. Investigation of multiple pharmacogenomics datasets confirmed that the pairwise sensitivity data correlation between drugs, or rows, across different studies (drug-wise) is relatively low, while the pairwise sensitivity data correlation between cell-lines, or columns, across different studies (cell-wise) is considerably strong. This common interesting observation across multiple pharmacogenomics datasets suggests the existence of subtle consistency among the different studies (i.e., strong cell-wise correlation). However, significant noises are also shown (i.e., weak drug-wise correlation) and have prevented researchers from comfortably using the data directly. Motivated by this observation, we propose a novel framework for addressing the inconsistency between large-scale pharmacogenomics data sets. Our method can significantly boost the drug-wise correlation and can be easily applied to re-summarized and normalized datasets proposed by others. We also investigate our algorithm based on many different criteria to demonstrate that the corrected datasets are not only consistent, but also biologically meaningful. Eventually, we propose to extend our main algorithm into a framework, so that in the future when more datasets become publicly available, our framework can hopefully offer a "ground-truth" guidance for references.

PMID: 30864327 [PubMed - in process]

Pharmacogenomics of Multiple Sclerosis: A Systematic Review.

Front Neurol. 2019;10:134

Authors: Hočevar K, Ristić S, Peterlin B

Abstract
Background: Over the past two decades, various novel disease-modifying drugs for multiple sclerosis (MS) have been approved. However, there is high variability in the patient response to the available medications, which is hypothesized to be partly attributed to genetics. Objectives: To conduct a systematic review of the current literature on the pharmacogenomics of MS therapy. Methods: A systematic literature search was conducted using PubMed/MEDLINE database searching for articles investigating a role of genetic variation in response to disease-modifying MS treatments, published in the English language up to October 9th, 2018. PRISMA guidelines for systematic reviews were applied. Studies were included if they investigated response or nonresponse to MS treatment defined as relapse rate, by expanded disability status scale score or based on magnetic resonance imaging. The following data were extracted: first author's last name, year of publication, PMID number, sample size, ethnicity of patients, method, genes, and polymorphisms tested, outcome, significant associations with corresponding P-values and confidence intervals, response criteria, and duration of the follow-up period. Results: Overall, 48 articles published up to October 2018, evaluating response to interferon-beta, glatiramer acetate, mitoxantrone, and natalizumab, met our inclusion criteria and were included in this review. Among those, we identified 42 (87.5%) candidate gene studies and 6 (12.5%) genome-wide association studies. Existing pharmacogenomic evidence is mainly based on the results of individual studies, or on results of multiple studies, which often lack consistency. In recent years, hypothesis-free approaches identified novel candidate genes that remain to be validated. Various study designs, including the definition of clinical response, duration of the follow-up period, and methodology as well as moderate sample sizes, likely contributed to discordances between studies. However, some of the significant associations were identified in the same genes, or in the genes involved in the same biological pathways. Conclusions: At the moment, there is no available clinically actionable pharmacogenomic biomarker that would enable more personalized treatment of MS. More large-scale studies with uniform design are needed to identify novel and validate existing pharmacogenomics findings. Furthermore, studies investigating associations between rare variants and treatment response in MS patients, using next-generation sequencing technologies are warranted.

PMID: 30863357 [PubMed]

Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs.

Mol Psychiatry. 2019 Mar 12;:

Authors: Le-Niculescu H, Roseberry K, Levey DF, Rogers J, Kosary K, Prabha S, Jones T, Judd S, McCormick MA, Wessel AR, Williams A, Phalen PL, Mamdani F, Sequeira A, Kurian SM, Niculescu AB

Abstract
The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.

PMID: 30862937 [PubMed - as supplied by publisher]

Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.

Psychiatry Res. 2018 11;269:746-752

Authors: Miljević ČD, Nikolić-Kokić A, Blagojević D, Milovanović M, Munjiza A, Jukić MM, Pešić V, Lečić-Toševski D, Spasić MB

Abstract
To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.

PMID: 30273900 [PubMed - indexed for MEDLINE]

Variants at HLA-A, HLA-C, and HLA-DQB1 Confer Risk of Psoriasis Vulgaris in Japanese.

J Invest Dermatol. 2018 03;138(3):542-548

Authors: Hirata J, Hirota T, Ozeki T, Kanai M, Sudo T, Tanaka T, Hizawa N, Nakagawa H, Sato S, Mushiroda T, Saeki H, Tamari M, Okada Y

Abstract
Psoriasis vulgaris (PsV) is an autoimmune disease of skin and joints with heterogeneity in epidemiologic and genetic landscapes of global populations. We conducted an initial genome-wide association study and a replication study of PsV in the Japanese population (606 PsV cases and 2,052 controls). We identified significant associations of the single nucleotide polymorphisms with PsV risk at TNFAIP3-interacting protein 1and the major histocompatibility complex region (P = 3.7 × 10-10 and 6.6 × 10-15, respectively). By updating the HLA imputation reference panel of Japanese (n = 908) to expand HLA gene coverage, we fine-mapped the HLA variants associated with PsV risk. Although we confirmed the PsV risk of HLA-C*06:02 (odds ratio = 6.36, P = 0.0015), its impact was relatively small compared with those in other populations due to rare allele frequency in Japanese (0.4% in controls). Alternatively, HLA-A*02:07, which corresponds to the cysteine residue at HLA-A amino acid position 99 (HLA-A Cys99), demonstrated the most significant association with PsV (odds ratio = 4.61, P = 1.2 × 10-10). In addition to HLA-A*02:07 and HLA-C*06:02, stepwise conditional analysis identified an independent PsV risk of HLA-DQβ1 Asp57 (odds ratio = 2.19, P = 1.9 × 10-6). Our PsV genome-wide association study in Japanese highlighted the genetic architecture of PsV, including the identification of HLA risk variants.

PMID: 29031612 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/12

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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/12

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Verification of pharmacogenomics-based algorithms to predict warfarin maintenance dose using registered data of Japanese patients.

Eur J Clin Pharmacol. 2019 Mar 09;:

Authors: Sasano M, Ohno M, Fukuda Y, Nonen S, Hirobe S, Maeda S, Miwa Y, Yokoyama J, Nakayama H, Miyagawa S, Sawa Y, Fujio Y, Maeda M

Abstract
PURPOSE: Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9 (CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences.
METHODS: Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097-1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC).
RESULTS: For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy.
CONCLUSION: The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.

PMID: 30852642 [PubMed - as supplied by publisher]

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.

Clin Ther. 2019 Mar 06;:

Authors: Jeffrey MG, Nathanson L, Aenlle K, Barnes ZM, Baig M, Broderick G, Klimas NG, Fletcher MA, Craddock TJA

Abstract
PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
METHODS: Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
FINDINGS: The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
IMPLICATIONS: The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies. (Clin Ther. 2019;41:XXX-XXX) © 2019 Elsevier Inc.

PMID: 30851951 [PubMed - as supplied by publisher]

Apolipoprotein E gene polymorphism and renal function are associated with apolipoprotein E concentration in patients with chronic kidney disease.

Lipids Health Dis. 2019 Mar 09;18(1):60

Authors: Czaplińska M, Ćwiklińska A, Sakowicz-Burkiewicz M, Wieczorek E, Kuchta A, Kowalski R, Kortas-Stempak B, Dębska-Ślizień A, Jankowski M, Król E

Abstract
BACKGROUND: Chronic kidney disease (CKD) associates with complex lipoprotein disturbances resulting in high cardiovascular risk. Apolipoprotein E (APOE) is a polymorphic protein with three common isoforms (E2; E3; E4) that plays a crucial role in lipoprotein metabolism, including hepatic clearance of chylomicrons and very low-density lipoprotein (VLDL) remnants, and reverse cholesterol transport. It demonstrates anti-atherogenic properties but data concerning the link between polymorphism and level of APOE in CKD patients are inconclusive. The aim of our research was to assess the relationship between APOE gene polymorphism and APOE concentration and its redistribution among lipoproteins along with CKD progression.
METHODS: 90 non-dialysed CKD patients were included into the study. Real time PCR was used for APOE genotyping. APOE level was measured in serum and in isolated lipoprotein fractions (VLDL; IDL + HDL; HDL). Kidney function was assessed using eGFR CKD-EPI formula.
RESULTS: The population was divided into three APOE genotype subgroups: E2(ε2ε3), E3(ε3ε3) and E4(ε3ε4). The highest APOE level was observed for the E2 subgroup (p < 0.001). APOE concentration positively correlated with eGFR value in the E2 subgroup (r = 0.7, p < 0.001) but inversely in the E3 subgroup (r = - 0.29, p = 0.02).). A lower concentration of APOE in the E2 subgroup was associated with its diminished contents in HDL and IDL + LDL particles. In the E3 subgroup, the higher concentration of APOE was related to the increased number of non-HDL lipoproteins.
CONCLUSION: In patients with CKD, APOE genotype as well as renal function are associated with the concentration of APOE and its redistribution among lipoprotein classes.

PMID: 30851738 [PubMed - in process]

Genetic determinants of dabigatran safety (CES1 gene rs2244613 polymorphism) in the Russian population: multi-ethnic analysis.

Mol Biol Rep. 2019 Mar 08;:

Authors: Sychev DA, Abdullaev SP, Mirzaev KB, Ryzhikova KA, Shuyev GN, Sozaeva ZA, Grishina EA, Mammaev SN, Gafurov DM, Kitaeva EY, Shprakh VV, Suleymanov SS, Bolieva LZ, Sozaeva MS, Zhuchkova SM, Gimaldinova NE, Sidukova EE, Asoskova AV, Mumladze RB

Abstract
This study was aimed to investigate the prevalence of the CES1 gene (c.1168-33A > C, rs2244613) polymorphism among 12 different ethnic groups living in Russia to provide a basis for future clinical studies concerning genetic determinants of dabigatran safety. The study involved 1630 apparently healthy, unrelated, and chronic medication-free volunteers of both genders from 12 different ethnic groups in Russia: 136 Russians, 90 Avars, 50 Dargins, 46 Laks, 120 Kabardians, 112 Balkars, 244 Ossetians, 206 Mari, 204 Mordvinians, 238 Chuvashes, 114 Buryats and 70 Nanays. Genotyping was performed by using real-time polymerase chain reaction-based methods. The allelic prevalence of the ethnic groups was compared with Caucasus population participating in the RE-LY study. Statistically significant differences for the following gene polymorphism were found between all ethnic groups and RE-LY participants. Based on obtained results, it can be assumed that patients of all ethnic groups living in Russia taking dabigatran have a lower risk of bleeding.

PMID: 30850966 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenetic algorithm for individualized controlled ovarian stimulation in assisted reproductive technology cycles.

Panminerva Med. 2019 Mar;61(1):76-81

Authors: Roque M, Bianco B, Christofolini DM, Barchi Cordts E, Vilarino F, Carvalho W, Valle M, Sampaio M, Geber S, Esteves SC, Parente Barbosa C

Abstract
Controlled ovarian stimulation (COS) is crucial for optimizing in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) success. Multiple factors influence the ovarian response to COS, making predictions about oocyte yields not so straightforward. As a result, the ovarian response may be poor or suboptimal, or even excessive, all of which have negative consequences for the affected patient. There is a group of patients that present with a suboptimal response to COS despite normal biomarkers of ovarian reserve, such as AFC and AMH. These patients have a lower number of retrieved oocytes than what was expected based on their ovarian reserve, thus showing the inadequacy of using only the traditional ovarian reserve biomarkers to predict the ovarian response. Suboptimal response to COS might be related to ovarian sensitivity to exogenous gonadotropins modulated by genetic factors. The understanding of the gene polymorphisms related to reproductive function can help to improve the clinical management of this patient population and to explain some of the individual patient variability in response to COS. The development of a pharmacogenetic approach concerning COS in the context of assisted reproduction seems attractive as it might help to understand the relationship between genetic variants and ovarian response to exogenous gonadotropins. The patient's genetic profile could be used to select the most appropriate gonadotropin type, predict the optimal dosage for each drug, develop a cost-effective treatment plan, maximize the success rates, and lastly, decrease the time-to-pregnancy.

PMID: 29916218 [PubMed - indexed for MEDLINE]

Genetic polymorphisms in aquaporin 1 as risk factors for malignant mesothelioma and biomarkers of response to cisplatin treatment.

Radiol Oncol. 2019 Mar 03;53(1):96-104

Authors: Senk B, Goricar K, Kovac V, Dolzan V, Franko A

Abstract
Background Malignant mesothelioma (MM) is an asbestos related aggressive tumor with poor prognosis. The aim of this study was to investigate if aquaporin 1 (AQP1) genetic polymorphisms influence the risk of MM and the response to cisplatin based MM treatment. Patients and methods The case-control study included 231 patients with MM and a control group of 316 healthy blood donors. All subjects were genotyped for three AQP1polymorphisms (rs1049305, rs1476597 and rs28362731). Logistic and Cox regression were used in statistical analysis. Results AQP1 rs1049305 polymorphism was significantly associated with MM risk in dominant model adjusted for gender and age (OR = 0.60, 95% CI = 0.37-0.96, Padj = 0.033). This polymorphism was also significantly associated with cisplatin based treatment related anaemia (unadjusted: OR = 0.49, 95% CI = 0.27-0.90, P = 0.021; adjusted: for CRP: OR = 0.52, 95% CI = 0.27-0.99, P = 0.046), with leukopenia (OR = 2.09, 95% CI = 1.00-4.35, P = 0.049) in dominant model and with thrombocytopenia (OR = 3.06, 95% CI = 1.01-9.28, P = 0.048) and alopecia (OR = 2.92, 95% CI = 1.00-8.46, P = 0.049) in additive model. AQP1 rs28362731 was significantly associated with thrombocytopenia (unadjusted: OR = 3.73, 95% CI = 1.00-13.84, P = 0.049; adjusted for pain: OR = 4.63, 95% CI = 1.13-19.05, P = 0.034) in additive model. Conclusions AQP1 may play a role in the risk of MM. Furthermore, AQP1 genotype information could improve the prediction of MM patients at increased risk for cisplatin toxicity.

PMID: 30840592 [PubMed - in process]

Combined evaluation of genotype and phenotype of thiopurine S-methyltransferase (TPMT) in the clinical management of patients in chronic therapy with azathioprine.

Drug Metab Pers Ther. 2019 Mar 06;:

Authors: Rucci F, Cigoli MS, Marini V, Fucile C, Mattioli F, Robbiano L, Cavallari U, Scaglione F, Perno CF, Penco S, Marocchi A

Abstract
Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.

PMID: 30840585 [PubMed - as supplied by publisher]

Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders.

Front Pharmacol. 2019;10:99

Authors: Aldrich SL, Poweleit EA, Prows CA, Martin LJ, Strawn JR, Ramsey LB

Abstract
In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. Slower CYP2C19 metabolizers experienced more untoward effects than faster metabolizers (p = 0.015), including activation symptoms (p = 0.029) and had more rapid weight gain (p = 0.018). A larger proportion of slower metabolizers discontinued treatment with es/citalopram than normal metabolizers (p = 0.007). Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.

PMID: 30837874 [PubMed]

Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications.

Front Pharmacol. 2019;10:83

Authors: Veldic M, Ahmed AT, Blacker CJ, Geske JR, Biernacka JM, Borreggine KL, Moore KM, Prieto ML, Vande Voort JL, Croarkin PE, Hoberg AA, Kung S, Alarcon RD, Keeth N, Singh B, Bobo WV, Frye MA

Abstract
Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

PMID: 30837869 [PubMed]