Implementation of Pharmacogenetics in First-Line Care: Evaluation of Its Use by General Practitioners.

Pharmacogenetics (PGx) can explain/predict drug therapy outcomes. There is, however, unclarity about the use and usefulness of PGx in primary care. In this study, we investigated PGx tests ordered by general practitioners (GPs) in 2021 at Dept. Clinical Chemistry, Erasmus MC, and analyzed the gene tests ordered, drugs/drug groups, reasons for testing and single-gene versus panel testing. Additionally, a survey was sent to 90 GPs asking about their experiences and barriers to implementing PGx. In total, 1206 patients and 6300 PGx tests were requested by GPs. CYP2C19 was requested most frequently (17%), and clopidogrel was the most commonly indicated drug (23%). Regarding drug groups, antidepressants (51%) were the main driver for requesting PGx, followed by antihypertensives (26%). Side effects (79%) and non-response (27%) were the main indicators. Panel testing was preferred over single-gene testing. The survey revealed knowledge on when and how to use PGx as one of the main barriers. In conclusion, PGx is currently used by GPs in clinical practice in the Netherlands. Side effects are the main reason for testing, which mostly involves antidepressants. Lack of knowledge is indicated as a major barrier, indicating the need for more education on PGx for GPs.

Oral antibiotics lower mycophenolate mofetil drug exposure, possibly by interfering with the enterohepatic recirculation: A case series.

Mycophenolate mofetil has an important role as immunosuppressive agent in solid organ transplant recipients. Exposure to the active mycophenolic acid (MPA) can be monitored using therapeutic drug monitoring. We present three cases in which MPA exposure severely decreased after oral antibiotic coadministration. By diminishing gut bacteria ß-glucuronidase activity, oral antibiotics can prevent deglucuronidation of the inactive MPA-7-O-glucuronide metabolite to MPA and thereby possibly prevent its enterohepatic recirculation. This pharmacokinetic interaction could result in rejection, which makes it clinically relevant in solid organ transplant recipients, especially when therapeutic drug monitoring frequency is low. Routine screening for this interaction, preferably supported by clinical decision support systems, and pragmatic close monitoring of the MPA exposure in cases is advised.

Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder.

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 Emax 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.

Design and methods of the 'monitoring outcomes of psychiatric pharmacotherapy' (MOPHAR) monitoring program - a study protocol.

BACKGROUND: At many outpatient departments for psychiatry worldwide, standardized monitoring of the safety of prescribed psychotropic drugs is not routinely performed in daily clinical practice. Therefore it is unclear to which extent the drugs used by psychiatric outpatients are prescribed effectively and safely. These issues warrant structured monitoring of medication use, (pre-existing) co-morbidities, effectiveness and side effects during psychiatric outpatient treatment. Improvement of monitoring practices provides an opportunity to ensure that somatic complications and adverse drug effects are detected and dealt with in a timely manner. Structural support for data collection and follow-up tests seems essential for improvement of monitoring practices in psychiatric outpatients. The implementation of a structured somatic monitoring program as part of routine clinical practice, as we describe in this study protocol, may be a solution. METHODS: In order to address these issues, we developed the innovative program 'Monitoring Outcomes of Psychiatric Pharmacotherapy (MOPHAR)'. MOPHAR is an infrastructure for implementation of standardized routine outcome monitoring (ROM; including standardized monitoring of treatment effect), monitoring of adverse psychotropic medication effects in psychiatric outpatients, encompassing both somatic adverse effects (e.g. metabolic disturbances) and subjective adverse effects (e.g. sedation or sexual side effects) and medication reconciliation. DISCUSSION: In the MOPHAR monitoring program, a nurse performs general and psychotropic drug-specific somatic screenings and provides the treating mental health care providers with more and better information on somatic monitoring for treatment decisions. Given our experience regarding implementation of the MOPHAR program, we expect that the MOPHAR program is feasible and beneficial for patients in any MHS organisation. This paper describes the objectives, target population, setting and the composition and roles of the treatment team. It also indicates what measurements are performed at which time points during outpatient treatment in the MOPHAR monitoring program, as well as the research aspects of this project. TRIAL REGISTRATION: MOPHAR research has been prospectively registered with the Netherlands Trial Register on 19th of November 2014. ( NL4779 ).

Metabolic Syndrome at an Outpatient Clinic for Bipolar Disorders: A Case for Systematic Somatic Monitoring.

OBJECTIVES: The primary objective of the study was to determine whether the Monitoring Outcomes of Psychiatric Pharmacotherapy (MOPHAR) program improved somatic monitoring practices at an outpatient clinic for bipolar disorders in the Netherlands. The secondary objective was to determine in MOPHAR the frequency of metabolic syndrome (compared with its measurability before MOPHAR) and treatment thereof. METHODS: Frequencies of physical examinations and laboratory tests before (retrospectively) and after (prospectively) the active introduction of MOPHAR were compared among adult patients (N=155). RESULTS: A median of three measurements (range 0-19) per patient were performed before MOPHAR, compared with 24 measurements (range 3-24) after MOPHAR (p<0.001). MOPHAR revealed somatic abnormalities previously unknown to treating physicians. Metabolic syndrome was present in 53% of patients; of these, 98% were not known to have metabolic syndrome before MOPHAR. CONCLUSIONS: Introducing a monitoring program largely improved knowledge regarding metabolic abnormalities, which are frequently present among patients with bipolar disorder.

Monitoring of somatic parameters at outpatient departments for mood and anxiety disorders.

INTRODUCTION: Somatic complications account for the majority of the 13-30 years shortened life expectancy in psychiatric patients compared to the general population. The study aim was to assess to which extent patients visiting outpatient departments for mood and anxiety disorders were monitored for relevant somatic comorbidities and (adverse) effects of psychotropic drugs-more specifically a) metabolic parameters, b) lithium safety and c) ECGs-during their treatment. METHODS: We performed a retrospective clinical records review and cross-sectional analysis to assess the extent of somatic monitoring at four outpatient departments for mood and anxiety disorders in The Netherlands. We consecutively recruited adult patients visiting a participating outpatient department between March and November 2014. The primary outcome was percentage of patients without monitoring measurements. Secondary outcomes were number of measurements per parameter per patient per year and time from start of treatment to first measurement. RESULTS: We included 324 outpatients, of whom 60.2% were female. Most patients were treated for depressive disorders (39.8%), anxiety disorders (16.7%) or bipolar or related disorders (11.7%) and 198 patients (61.1%) used at least one psychotropic drug. For 186 patients (57.4%), no monitoring records were recorded (median treatment period 7.3 months, range 0-55.6). The median number of measurements per parameter per year since the start of outpatient treatment for patients with monitoring measurements was 0.31 (range 0.0-12.9). The median time to first monitoring measurement per parameter for patients with monitoring measurements was 3.8 months (range 0.0-50.7). DISCUSSION: Somatic monitoring in outpatients with mood and anxiety disorders is not routine clinical practice. Monitoring practices need to be improved to prevent psychiatric outpatients from undetected somatic complications.

Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring.

Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high-risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances).

Availability of CYP2D6 genotyping results in general practitioner and community pharmacy medical records.

AIM: To investigate the availability of CYP450-2D6 (CYP2D6) genotyping results in general practitioner (GP) and/or community pharmacy records, and the influence thereof on psychotropic CYP2D6 substrate dosing. MATERIALS & METHODS: Primary outcome was the percentage of patients genotyped for CYP2D6 with their genotype/phenotype registered in GP and/or pharmacy records. Secondary outcome was the number of defined daily doses of psychotropic CYP2D6 substrates prescribed after genotyping. RESULTS: For 216 out of 1307 eligible patients, medication overviews could be obtained. Genotyping results were available at GPs for 3.1% and at pharmacies for 5.9%. The average psychotropic CYP2D6 substrate dose was not different between any non-extensive metabolizer group and extensive metabolizer group (all p ≥ 0.486). CONCLUSION: Valuable information for individualizing psychiatric pharmacotherapy is lost on a large scale.

Medication Discrepancies at Outpatient Departments for Mood and Anxiety Disorders in the Netherlands: Risks and Clinical Relevance.

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.

Rosiglitazone is a superior bronchodilator compared to chloroquine and ß-adrenoceptor agonists in mouse lung slices.

BACKGROUND: Current therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where ß-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices. METHODS: Relaxation to RGZ and CQ was assessed following submaximal methacholine (MCh) pre-contraction, in slices treated overnight with either RGZ, CQ or albuterol (ALB) (to induce ß-adrenoceptor desensitization), and in slices treated with caffeine/ryanodine in which contraction is associated with increases in Ca2+ sensitivity in the absence of contractile agonist-induced Ca2+ oscillations. Furthermore, the effects of RGZ, CQ, ALB and isoproterenol (ISO) on the initiation and development of methacholine-induced contraction were also compared. RESULTS: RGZ and CQ, but not ALB or ISO, elicited complete relaxation with increasing MCh pre-contraction and maintained their potency and efficacy following ß-adrenoceptor desensitization. RGZ, CQ and ALB maintained efficacy following overnight incubation with RGZ or CQ. Relaxation responses to all dilators were generally maintained but delayed after caffeine/ryanodine. Pre-treatment with RGZ, but not CQ, ALB or ISO, reduced MCh potency. CONCLUSIONS: This study demonstrates the superior effectiveness of RGZ in comparison to CQ and ß-adrenoceptor agonists as a dilator of mouse small airways. Further investigation of the mechanisms underlying the relatively greater efficacy of RGZ under these conditions are warranted and should be extended to include studies in human asthmatic airways.

Noncanonical WNT-5A signaling regulates TGF-ß-induced extracellular matrix production by airway smooth muscle cells.

Transforming growth factor ß (TGF-ß), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF-ß-induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF-ß and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT-5A being the most profoundly expressed. Interestingly, WNT-5A shows ∼2-fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT-5A is markedly induced in response to TGF-ß (4-16-fold; EC50 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT-5A engages noncanonical WNT signaling pathways, as inhibition of Ca(2+) and c-Jun N-terminal kinase (JNK) signaling attenuated this TGF-ß response, whereas the canonical WNT antagonist Dickkopf 1 (DKK-1) did not. Accordingly, WNT-5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT-5A receptors Frizzled 8 (FZD8) and RYK attenuated TGF-ß-induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT-5A signaling is activated by and necessary for TGF-ß-induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.