Aligned with the mission of the Dutch Pharmacogenetics Working Group (DPWG) to promote the implementation of pharmacogenetics (PGx), this guideline is specifically designed to optimize pharmacotherapy of cholesterol lowering medication (statins) and glucose lowering medication (sulfonylureas). The SLCO1B1 c.521 T > C variant reduces the activity of the SLCO1B1 transporter involved in statin transport out of the blood into the liver. High blood concentrations of statins increase the risk of serious myopathy. For simvastatin, the DPWG recommends choosing an alternative in homozygotes for these gene variant and to preferably choose an alternative in heterozygotes. For atorvastatin, the DPWG recommends to preferably choose an alternative in carriers of this gene variant having additional risk factors for myopathy. For rosuvastatin, the DPWG recommends keeping the dose as low as possible in carriers of this gene variant with additional risk factors. No therapy adjustment is required for fluvastatin and pravastatin in carriers of this gene variant. Gene variants can diminish the activity of the enzyme CYP2C9, that converts sulfonylurea to less effective metabolites. Although CYP2C9 gene variants may lead to increased levels of glibenclamide, gliclazide, glimepiride, and tolbutamide, no therapy adjustments are required in patients with these variants. The main reason is that there was either no negative clinical effect or an increase in hypoglycemic, which is of less importance than the increase in effectiveness it signals. The DPWG classifies pre-emptive SLCO1B1 testing as 'essential' for simvastatin 80 mg/day, 'beneficial' for simvastatin up to 40 mg/day, and 'potentially beneficial' for atorvastatin and rosuvastatin.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being “potentially beneficial” for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.

Abstract Background Patients with a mental illness are more likely to develop, and die from, cardiovascular diseases (CVD), necessitating optimal CVD-risk (CVR)-assessment to enable early detection and treatment. Whereas psychiatrists use the metabolic syndrome (MetS)-concept to estimate CVR, GPs use absolute risk-models. Additionally, two PRIMROSE-models have been specifically designed for patients with severe mental illness. We aimed to assess the agreement in risk-outcomes between these CVR-methods. Methods To compare risk-outcomes across the various CVR-methods, we used somatic information of psychiatric outpatients from the PHAMOUS-, and MOPHAR-database, aged 40–70 years, free of past or current CVD and diabetes. We investigated: (1) the degree-of-agreement between categorical assessments (i.e. MetS-status vs. binary risk-categories); (2) non-parametric correlations between the number of MetS-criteria and absolute risks; and (3) strength-of-agreement between absolute risks. Results Seven thousand twenty-nine measurements of 3509 PHAMOUS-patients, and 748 measurements of 748 MOPHAR-patients, were included. There was systematic disagreement between the categorical CVR-assessments (all p < 0.036). Only MetS-status versus binary Framingham-assessment had a fair strength-of-agreement (κ = 0.23–0.28). The number of MetS-criteria and Framingham-scores, as well as MetS-criteria and PRIMROSE lipid-scores, showed a moderate-strong correlation (τ = 0.25–0.34). Finally, only the continuous PRIMROSE desk and lipid-outcomes showed moderate strength-of-agreement (ρ = 0.91). Conclusions The varying methods for CVR-assessment yield unequal risk predictions, and, consequently, carry the risk of significant disparities regarding treatment initiation in psychiatric patients. Considering the significantly increased health-risks in psychiatric patients, CVR-models should be recalibrated to the psychiatric population from adolescence onwards, and uniformly implemented by health care providers. Trial registration The MOPHAR research has been prospectively registered with the Netherlands Trial Register on 19th of November 2014 (NL4779).

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.

The chronicity of depressive disorders is a major problem. Dopamine stimulating agents (DSA) are suggested to hold a promising potential in depression management, particularly in older adults, in whom dopamine deficiency due to aging may be an underlying cause. More evidence is needed to support these drugs in the management of depression. Therefore, we conducted a systematic literature review and meta-analysis. Data was extracted from eighteen randomized-controlled-trials and eight open-label-studies. Additional meta-regression-analyses were performed to examine superiority of monotherapy versus augmentation, and to rule out a putative age effect. DSA were found to reduce depressive symptoms (SMD=-0.26, 95%CI(-0.43;-0.10]). Heterogeneity was high and a significant Egger's test indicated publication bias. Adjustment for missing studies, using trim-and-fill-methodology, reduced the effect size (SMD=-0.17, 95%CI(-0.39;0.05]), which lost statistical significance. Removing the outlier study from the analysis, the effect size remained marginally small, but was statistically-significant (SMD=-0.17, 95%CI(-0.31;-0.02]). Neither augmentation nor monotherapy was superior. No age effect was found. It can be concluded that off-label DSA are overall effective in reducing depressive symptoms. However, the evidence is weak, regarding the publication bias, and modest-to-weak treatment effects. Well-designed high-quality trials are highly needed, before dopamine stimulating agents can be adequately posi-tioned in future depression treatment protocols.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.

Background Shared care agreements between clinical pharmacists and physicians can improve suboptimal lithium monitoring in in- and outpatient settings. However, it is unknown whether incorporating community pharmacists in such agreements can also improve lithium monitoring in an outpatient setting. Aim To assess the necessity for a shared care agreement for lithium monitoring in our region by investigating: intervention rates by community pharmacists and whether those are sufficient; lithium monitoring by physicians in ambulatory patients; the extent of laboratory parameter exchange to community pharmacists. Method Patient files of lithium users were surveyed in a retrospective cohort study among 21 community pharmacies in the Northern Netherlands. Outcome was the intervention rate by community pharmacists and whether those were deemed sufficient by an expert panel. Additionally, we investigated both the percentages of patients monitored according to current guidelines and of laboratory parameters exchanged to community pharmacists. Results 129 patients were included. Interventions were performed in 64.4% (n = 29), 20.8% (n = 5), and 25.0% (n = 1) of initiations, discontinuations, and dosage alterations of drugs interacting with lithium, respectively. The expert panel deemed 40.0% (n = 14) of these interventions as “insufficient”. Physicians monitored 40.3% (n = 52) of the patients according to current guidelines for lithium serum levels and kidney functions combined. Approximately half of the requested laboratory parameters were available to the community pharmacist. Conclusion Intervention rates by community pharmacists and lithium monitoring by physicians can be improved. Therefore, a shared care agreement between community pharmacists, clinical pharmacists, and physicians is needed to improve lithium monitoring in ambulatory patients.

BACKGROUND:Clinical practice guidelines (CPGs) recommend the monitoring of somatic parameters in patients treated with antipsychotic drugs in order to detect adverse effects. The objective of this study was to assess, in adult and (frail) elderly populations, the consistency and applicability of the somatic monitoring instructions recommended by established CPGs prior to and during antipsychotic drug use. METHODS:A search for national and international CPGs was performed by querying the electronic database PubMed and Google. Somatic monitoring instructions were assessed for adult and (frail) elderly populations separately. The applicability of somatic monitoring instructions was assessed using the Systematic Information for Monitoring (SIM) score. Somatic monitoring instructions were considered applicable when a minimum SIM score of 3 was reached. RESULTS:In total, 16 CPGs were included, with a total of 231 somatic monitoring instructions (mean: 14; range: 0-47). Of the somatic monitoring instructions, 87% were considered applicable, although critical values and how to respond to aberrant values were only present in 28 and 52% of the available instructions respectively. Only 1 CPG presented an instruction specifically for (frail) elderly populations. CONCLUSIONS:We emphasize the need for a guideline with somatic monitoring instructions based on the SIM definition for both adult and (frail) elderly populations using antipsychotic drugs. In addition, CPGs should state that clear agreements should be made regarding who is responsible for interventions and somatic monitoring prior to and during antipsychotic drug use.

Additional file 2: Supplementary Table 2. Clinical Practice Guidelines.

Additional file 1: Supplementary Table 1. Clinical Practice Guidelines.

Background Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. Objectives To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. Methods Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 weeks (n = 81). We genotyped ABCB1 at rs1045642 [3435C>T], rs1128503 [1236C>T], rs2032582 [2677G>T/A] and rs2235040 [2505G>A]. For our primary aim, we modeled mean SERT-occupancy in an E-max nonlinear regression model with PSC and assessed whether the model improved by genetic subgrouping. For our secondary aim, we used multivariate linear regression analysis. Results The rs1128503 and rs2032582 SNPs modified the relationship between PSC and SERT-occupancy in both our intention-to-treat and sensitivity analyses at the carriership level. However, we could not detect significant differences in clinical response between any of the genetic subgroups. Conclusion Pharmacokinetic influences of the ABCB1 rs1128503 and rs2032582 represent a potentially relevant pharmacogenetic mechanism to consider when evaluating paroxetine efficacy. Future studies are needed to support the role of ABCB1 genotyping for individualizing SSRI pharmacotherapy.

Summary Treatment with psychotropic medication may sometimes be jeopardised because of the COVID-19 pandemic. One underlying reason is the lack of COVID-19-specific psychopharmacology guidelines. Here, we discuss five considerations arising from our clinical experience and pharmacological background knowledge to enable safe and well-informed psychopharmacotherapy during the COVID-19 pandemic.

Journal of Clinical Psychopharmacology: 9/10 2020 - Volume 40 - Issue 5 - p 443 doi: 10.1097/JCP.0000000000001273

PURPOSE/BACKGROUND:The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES:In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS:No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS:The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.

People with intellectual disabilities are one of the most heavily medicated population in society. This issue is compounded by the general vulnerability of this group and the frequent medical complications that they display. Especially psychotropic drugs are frequently prescribed. These agents may cause serious side-effects, while people with intellectual disability have increased vulnerability for these side-effects. As a result, the monitoring of psychotropic drug side-effects for this population should be a top priority. Topics covered in this chapter will be a definition of side-effects, a description of the various methods and procedures used to assess psychotropic drugs' side-effects, including standardized tests, and the monitoring and management of side-effects. Current status and future directions with respect to these issues will be covered.

OBJECTIVE To identify discrepancies between actual drug use by outpatients with mood and anxiety disorders and medication overviews from health care providers as well as to investigate the clinical relevance of those discrepancies. METHODS A cross-sectional study in adults visiting 1 of 4 participating outpatient departments for mood and anxiety disorders was conducted between March and November 2014. DSM-5 criteria were used to assign the psychiatric diagnosis. The primary outcome was the number of discrepancies between the actual medication use, as determined by medication reconciliation with the patient, and the medication overview from the outpatient department, general practitioner, and community pharmacy. Our secondary outcome was the clinical relevance of discrepancies, as assessed by an expert panel that reviewed all discrepancies for their potential to cause patient harm. RESULTS Of 367 patients included, 94.8% had at least 1 discrepancy in the medication overview from the outpatient department. A mean of 3.9 discrepancies existed per patient. Most discrepancies (74.5%) related to omitted drugs (drugs taken regularly by patients but absent from the medication overview). Of all discrepancies at the outpatient departments, 22.7% had the potential to cause moderate to severe discomfort or clinical deterioration, affecting 49.3% of the patients. Both total number and number of clinically relevant discrepancies were lower in medication overviews from general practitioners and pharmacies. CONCLUSION Patients from outpatient departments for mood and anxiety disorders may be at substantial risk for medication discrepancies that are often clinically relevant. Medication reconciliation at mental health care outpatient departments is in need of improvement.