The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics.

INTRODUCTION: CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. METHODS: Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. RESULTS: There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. DISCUSSION: PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

Recommendation for a Therapeutic Reference Range of Cariprazine-A Short Communication.

BACKGROUND: Therapeutic reference ranges are essential for therapeutic drug monitoring to evaluate results and adjust pharmacotherapy. The measured serum concentrations of cariprazine-treated patients have frequently been found to lie beyond the currently used therapeutic reference range; furthermore, reliable data for establishing evidence-based therapeutic ranges are scarce. The current therapeutic reference ranges have only been estimated; however, real-world data on cariprazine are missing. Individual serum concentrations were analyzed, and the validity of the currently used reference ranges was assessed. METHODS: Serum concentrations of 19 psychiatric patients treated with cariprazine without pharmacokinetic abnormalities were retrospectively analyzed. Only the last measurement per patient was included in the analysis, and patients who underwent a dose adjustment in the subsequent 2 weeks after sampling were excluded (assuming that the target dose and response had been achieved at that time). Serum concentrations were compared with the therapeutic reference range (10-20 ng/mL) of the Arbeitsgemeinschaft für Neuropsychiatrie und Pharmakotherapie consensus guidelines of 2017 and with a recent recommendation for a lower therapeutic reference range (5-15 ng/mL). RESULTS: The mean serum concentration was 9.1 ± 4.1 SD ng/mL. A total of 47.4% of the values were within the therapeutic reference range of 10-20 ng/mL, and 78.9% fell within the range of 5-15 ng/mL. CONCLUSIONS: These results support previous recommendations for lowering the therapeutic reference range to 5-15 ng/mL. The calculated therapeutic reference range was 5.0-13.2 ng/mL. It may even be potentially lower because clinicians may have tried to titrate the dose to a serum concentration within the current therapeutic reference range of 10-20 ng/mL.

[Barriers for Implementation of PGx Testing in Psychiatric Hospitals in Germany: Results of the FACT-PGx Study]. / Barrieren bei der Implementierung pharmakogenetischer Testungen in der Psychiatrie in Deutschland ­ Ergebnisse aus der FACT-PGx Studie.

OBJECTIVE: The FACT-PGx study was conducted to analyze barriers to implementation of pharmacogenetic testing in psychiatric hospitals in Germany and to propose solutions for its faster and easier implementation in all hospitals. METHODS: 104 patients (50% female) were genotyped and participated in the study. 67 completed a survey. To analyze the correlation between continuous data (age) of the survey, the wilcoxon rank test and for categorial data (education level, history of treatment and episodes), t-test was used. RESULTS: No patient declined to be genotyped. 99% believed that genotyping could help to shorten their hospital stay. Patients >40 years of age and with higher educational levels were willing to pay for the PGx (p=0.009). On average, patients were willing to pay 117.42€ +/-140.49€ and to wait 15.83+/- 8.92 days for the results. Processes differed significantly between routine laboratory screening and PGx testing which could be a barrier for implementation. CONCLUSION: Patients are not barriers to but enablers of an implementation of PGx. New process flows can be barriers, but can be overcome by optimization.

Effect of CYP2D6 pharmacogenetic phenotype and phenoconversion on serum concentrations of antidepressants and antipsychotics: a retrospective cohort study.

BACKGROUND: Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking. AIM: The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care. METHOD: Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine. RESULTS: We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal-Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal-Wallis test; p < 0.001; p = 0.05). CONCLUSION: The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively.

Rates of Divergent Pharmacogenes in a Psychiatric Cohort of Inpatients with Depression-Arguments for Preemptive Testing.

Background: The international drug agencies annotate pharmacogenes for many years. Pharmacogenetic testing is thus far only established in few settings, assuming that only few patients are actually affected by drug-gene interactions. Methods: 108 hospitalized patients with major depressive disorder were genotyped for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, NAT2, DPYD; VKORC1 and TMTP. Results: We found 583 (mean 5.4, median 5) divergent phenotypes (i.e., divergent from the common phenotypes considered normal, e.g., extensive metabolizer) in the 12 analyzed pharmacokinetic genes. The rate for at least one divergent phenotype was 100% in our cohort for CYP, but also for all 12 important pharmacogenes: patients had at least two divergent phenotypes. Compared to a large Danish cohort, CYP2C9 NM and IM status, CYP2C19 UM, CYP2D6 UM and DYPD (GAS 0, 1, 2) genotypes differed statistical significantly. For CYP2D6 and CYP2C19, 13% of the patients were normal metabolizers for both enzymes in our cohort, but this value was 27.3% in the Danish cohort, which is a highly significant difference (p < 0.0001). Conclusion: Divergent phenotypes in pharmacogenes are not the exception, but the rule. Patients with divergent phenotypes seem more prone for hospitalization, emphasizing the need for pre-emptive testing to avoid inefficacy and adverse drug effects in all patients.

The Influence of Pharmacogenetics on the Clinical Relevance of Pharmacokinetic Drug-Drug Interactions: Drug-Gene, Drug-Gene-Gene and Drug-Drug-Gene Interactions.

Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical relevance of drug-drug interactions also depends on the genetic profile of the patient. If inhibitors or inducers of drug metabolising enzymes (e.g., CYP and UGT) are added to the drug therapy, phenoconcversion can occur. This leads to a genetic phenotype that mismatches the observable phenotype. Drug-drug-gene and drug-gene-gene interactions influence the toxicity and/or ineffectivness of the drug therapy. To date, there have been limited published studies on the impact of genetic variations on drug-drug interactions. This review discusses the current evidence of drug-drug-gene interactions, as well as drug-gene-gene interactions. Phenoconversion is explained, the and methods to calculate the phenotypes are described. Clinical recommendations are given regarding the integratation of the PGx results in the assessment of the relevance of drug interactions in the future.

Current use of anticholinergic medications in a large naturalistic sample of psychiatric patients.

Due to the high number of psychotropic drugs with anticholinergic potential, patients taking psychotropic drugs are at high risk for anticholinergic adverse drug reactions (ADRs). The aim of this study was to analyze the prevalence and type of pharmacodynamic anticholinergic drug-drug interactions in psychiatric patients. The retrospective longitudinal analysis used data from a large pharmacovigilance study conducted in ten German psychiatric hospitals. Anticholinergic burden of drugs was defined as "strong" or "moderate" based on current literature. Number and type of anticholinergic drugs were assessed. In total, 27,396 patient cases (45.6% female) with a mean age of 47.3 ± 18.3 years were included. 17.4% (n = 4760) of patients were ≥ 64 years. 35.4% of the patients received between one and four anticholinergic drugs simultaneously. A combination of drugs with anticholinergic potential was detected in 1738 cases (6.3%). Most prescribed drugs were promethazine (n = 2996), olanzapine (n = 2561), biperiden (n = 1074), and doxepin (n = 963). Patients receiving anticholinergic combinations were younger (45.7 vs. 47.4 years, p < 0.01) and had a longer inpatient stay (median 18 vs. 26.5 days, p < 0.001). The prevalence of anticholinergic drug use in psychiatry is high. Further efforts need to focus on reducing the rate of anticholinergics and inappropriate medication especially in the elderly. Anticholinergic ADRs can be prevented by avoiding high-risk drug combinations. Replacing tricyclic antidepressants and first-generation antihistamines with drugs with lower anticholinergic potential and avoiding biperiden could reduce 59.3% of anticholinergic drug application.

Pharmacodynamic Drug-Drug interactions of QT-prolonging drugs in hospitalized psychiatric patients.

At least 170 approved drugs are linked to QT prolongation, which can lead to serious adverse drug reactions (ADRs), such as Torsade de Pointes (TdP). The aim of this study was to analyze the prevalence and type of pharmacodynamic drug-drug interactions (DDIs) between QT-prolonging drugs in psychiatry. The present retrospective analysis used data from a large pharmacovigilance study, conducted in 10 psychiatric hospitals in Germany. Patients medication lists were screened for QT-prolonging drugs, classified according to the Arizona Center for Education and Research on Therapeutics (AZCERT). In total, 27,396 patient cases (46% female) with a mean (± standard deviation) age of 47 ± 18 years were included in the study. Altogether, 83% of the cases received at least one and up to eight QT-prolonging drugs at the same time. Combination of drugs with a known or possible risk for TdP (according to the AZCERT) was detected in 13,670 cases (50%). Most frequently prescribed psychotropic high-risk drugs (n = 48,995) were the antipsychotics pipamperone (n = 6202), quetiapine (n = 5718), prothipendyl (n = 4298), and risperidone (n = 4265). The replacement of high-risk drugs such as tricyclic antidepressants, levomepromazine, melperone, and promethazine with more tolerable drugs could avoid 11% of QT-prolonging drugs and increase the tolerability of psychopharmacological treatment. More than 80% of psychiatric patients receive at least one QT-prolonging drug during their hospital stay, and almost 50% of these drugs are combined in clinical practice. For the prevention of cardiac ADRs, the physician should evaluate the risk for QT prolongation for each drug and patient-specific risk factors before prescribing these drugs or drug combinations.

Potentially inappropriate medication in older psychiatric patients.

PURPOSE: Many psychotropic drugs are listed as potentially inappropriate medication (PIM) in the older population. Potentially inappropriate means that prescription of those drugs in older adults may cause significant harm. The objective of this study was to analyze the prevalence and sort of PIM prescribing in a naturalistic, real-world psychiatric setting. METHODS: The retrospective analysis gathered data from a large pharmacovigilance study, conducted at 10 psychiatric hospitals. Data from inpatients aged ≥ 65 years were included for the analysis. The number and sort of PIM, as defined by the German PRISCUS list, were controlled by analyzing the patients' medication profile. RESULTS: In total, 4760 patient cases (59.2% female) with a mean (mean ± standard deviation (SD)) age of 77.33 ± 7.77 years were included into the study. Altogether, 1615 cases (33.9%) received at least 1 PRISCUS-PIM per day (regular and as-needed medication included). The most frequently prescribed PRISCUS-PIM (n = 2144) were zopiclone > 3.75 mg/day (n = 310), lorazepam > 2 mg/day (n = 269), haloperidol > 2 mg/day (n = 252), and diazepam (n = 182). Cases with PRISCUS-PIM were younger (75.7 vs. 78.2 years, p < 0.001) and had a longer (26 vs. 22 days, p < 0.001) hospital length of stay. Replacing benzodiazepines and z-substances, haloperidol > 2 mg, tricyclic antidepressants, first generation antihistaminergic drugs, and clonidine by non-PIM could reduce 69.9% of PRISCUS-PIM-prescribing. CONCLUSIONS: The prevalence of PRISCUS-PIM is high in the hospitalized psychiatric setting. Rational deprescribing of inappropriate anticholinergics, benzodiazepines, and antipsychotics in the older population is a key component to reduce the risk of adverse drug reactions. More tolerable medications should be prescribed.

Frequencies of Genetic Polymorphisms of Clinically Relevant Gene-Drug Pairs in a German Psychiatric Inpatient Population.

INTRODUCTION: Genetic variation is known to affect enzymatic activities allowing differentiating various metabolizer types (e. g., slow or rapid metabolizers), in particular CYP2C19 and CYP2D6. METHODS: PGx-testing was conducted in adult major depressive disorder inpatients admitted to the Vitos Klinik Eichberg between 11/2016 and 7/2017 (n=108, 57% female). We conducted a two-sided Z-Test (p=0.05) to analyze and compare frequencies of CYP2D6, CYP2C19, CYP3A4, CYP3A5 and CYP2C9 metabolizer groups with other European and psychiatric inpatient cohorts. The HLA-A and -B genes were also analyzed. RESULTS: Non-normal metabolizer status of CYP2D6 were present in 47%. More specifically, 35 % were intermediate, 7% poor and 4% ultra-rapid metabolizers. 68% were CYP2C19 non-normal metabolizers. 8% were ultra-rapid and 31% rapid metabolizers. Notably, only 13% were NM for CYP2C19 and NM for CYP2D6 (activity score of 1 or more). For CYP2C9 we found 16% to be intermediate metabolizers, 1.0% poor metabolizer. CYP3A4 and CYP3A5 genetic polymorphisms were present in 25% and 19% respectively. HLA-B TAG- SNPs for *15:01 was positive in 25 patients, showing the need for different Tag-SNPs in Caucasians. HLA-B *57:01 TAG-SNP was positive in 8% of the patients, HLA-A TAG-SNP for *31:01 in Caucasians was positive in 9%. Z-Test showed statistical significance for our results. DISCUSSION: Our results suggest that our psychiatric inpatients were enriched with genotypes consistent with non-normal drug metabolism compared to reference populations. We therefore conclude that pharmacogenetic testing should be implemented in clinical practice to guide drug therapy.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

BACKGROUND: The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. METHODS: The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. RESULTS: Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. CONCLUSIONS: Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Prevalence and sort of pharmacokinetic drug-drug interactions in hospitalized psychiatric patients.

Psychiatric patients are high-risk patients for the development of pharmacokinetic drug-drug interactions (DDIs), leading to highly variable (victim) drug serum concentrations. Avoiding and targeting high-risk drug combinations could reduce preventable adverse drug reactions (ADRs). Pharmacokinetic cytochrome P450 (CYP)-mediated DDIs are often predictable and, therefore, preventable. The retrospective, longitudinal analysis used informations from a large pharmacovigilance study (Optimization of pharmacological treatment in hospitalized psychiatric patients study, study number 01VSF16009, 01/2017), conducted in 10 psychiatric hospitals in Germany. Medication data were examined for the co-prescription of clinically relevant CYP inhibitors or inducers and substrates of these enzymes (victim drugs). In total, data from 27,396 patient cases (45.6% female) with a mean (mean ± standard deviation (SD)) age of 47.3 ± 18.3 years were available for analysis. CYP inhibitors or inducers were at least once prescribed in 14.4% (n = 3946) of the cases. The most frequently prescribed CYP inhibitors were melperone (n = 2504, 28.1%) and duloxetine (n = 1324, 14.9%). Overall, 51.0% of the cases taking melperone were combined with a victim drug (n = 1288). Carbamazepine was the most frequently prescribed CYP inducer (n = 733, 88.8%). Combinations with victim drugs were detected for 58% (n = 427) of cases on medication with carbamazepine. Finally, a DDI was detected in 43.6% of the cases in which a CYP inhibitor or inducer was prescribed. The frequency of CYP-mediated DDI is considerably high in the psychiatric setting. Physicians should be aware of the CYP inhibitory and inducing potential of psychotropic and internistic drugs (especially, melperone).

Pharmacogenetic Testing in Depressed Patients and Interdisciplinary Exchange between a Pharmacist and Psychiatrists Results in Reduced Hospitalization Times.

INTRODUCTION: Pharmacogenetics (PGx) is a well-researched tool to improve pharmacotherapy. So far, it has not been implemented into daily practice in Germany. In psychopharmacology, substantial benefit can be expected by using PGx due to the excessive CYP metabolism of the psychotropic drugs as well as already discovered target polymorphisms (e. g., serotonin receptor). METHODS: An evaluation of a naturalistic pharmacist-led pilot implementation of PGx testing in a psychiatric hospital in patients undergoing inpatient treatment for major depressive disorder was conducted. Length of stay, number of antidepressant switches, and rehospitalization rates were analyzed. A PGx-tested intervention cohort of n=49 was retrospectively compared to a control cohort of n=94 patients. RESULTS: The intervention cohort showed significantly shorter stays than the control, after correction of the length of hospital stay and the time to genotyping results (mean intervention: 36.3 d (SD: ±19.3 d); control: 46.6 d (±19.1 d); p=0.003). Antidepressant- naïve patients had the largest benefit from the PGx testing (intervention: 24.7 d (±13.5 d); control: 50.2 d (±22.5 d); p < 0.001. The number of antidepressant switches during the entire stay did not differ between the groups: 0.41 (0.64) vs. 0.21 (0.46); p=0.063 [95% CI -0.01-0.40]). DISCUSSION: Depressed patients, especially treatment-naïve, seem to benefit from PGx testing prior to treatment. Although the results of this retrospective evaluation are promising, more systematic prospective studies are needed to assess the effect of PGx testing on the treatment of major depressive disorder.

QTc Time Correlates with Amitriptyline and Venlafaxine Serum Levels in Elderly Psychiatric Inpatients.

INTRODUCTION: Many antidepressants cause QT prolongation but the classification of cardiac risk of these drugs varies markedly in different published lists. This retrospective study analyzed the correlation of QTc time with amitriptyline and venlafaxine serum level in elderly psychiatric inpatients. METHODS: Elderly inpatients aged≥65 years for whom venlafaxine or amitriptyline serum level had been measured were selected retrospectively from a therapeutic drug monitoring database and screened for an electrocardiogram measurement at the time of blood withdrawal. The correlation of amitriptyline or venlafaxine serum levels with QTc time was examined by using Pearson's correlation analysis. RESULTS: Amitriptyline serum levels (n=11) correlated significantly with QTc time (r=0.918, p<0.001, CI 95%). Venlafaxine serum levels (n=27) also correlated significantly with QTc time (r=0.382, p<0.05, CI 95%). DISCUSSION: Amitriptyline and venlafaxine induce QT prolongation depending on drug concentrations in blood. Its extent, however, is very low when drug serum levels are within the therapeutic range. Future pharmacokinetic studies that correlate drug serum level and QT time should classify the cardiac risk of drugs based on the grade of the regression line in relation to the therapeutic range.

Validation of pharmacist-physician collaboration in psychiatry: 'the Eichberger-model'.

Background Collaboration between physicians and pharmacists can increase medication safety. In the "Eichberger model" a clinical pharmacist is employed and working full time in a psychiatric hospital. Objective The aim of this study was to determine the expected type of expertise from a clinical pharmacist in psychiatry and the acceptance of the pharmacist's recommendations. Method All email requests to the clinical pharmacist from January 1st to April 30th 2015 were screened retrospectively and type of requester and content of request were extracted. Maintenance rate of drug therapy was analyzed by reviewing patient charts 2 weeks after medication prescription. Results A total of 147 requests were included. 85 (57.8%) requests were from attending physicians and 62 (42.2%) from residents. 82.1% of all physicians were contacting the clinical pharmacist during the study period. Most common reasons for requests were: appropriate drug selection (31.3%), drug interactions (25.2%), possible adverse drug events (17%) and switching drugs (12.2%). The acceptance rate by the physicians was 100%, with an implementation and maintenance rate of both 98.6%. Conclusion We found a high acceptance level of the pharmacist's recommendations. The pharmacist's skills were requested by the majority of physicians and included a in a large variety of specific questions. A pharmacist can play an important role to optimize patient care in collaboration with the physician in psychiatry.