Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study.

BACKGROUND: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. METHODS: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. RESULTS: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. CONCLUSIONS: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Applicability of somatic monitoring instructions in clinical practice guidelines on antipsychotic drug use.

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.

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial).

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.

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 ).

Cross-national comparison of medication use in Australian and Dutch nursing homes.

Background: cross-national comparisons can be used to explore therapeutic areas and identify potential medication issues. Methods: we used cross-sectional pharmacy supply data to explore medication use for nursing home residents in Australia (AU n = 26 homes, 1,560 residents) and the Netherlands (NL n = 6 homes, 2,037 residents). Binary logistic regression analysis was used to calculate the sex and aged adjusted odds ratios (OR) and associated 95% confidence intervals with a flexible Bonferroni-Holm procedure used to adjust for multiple hypothesis testing. Results: total use of antipsychotics (AU: 37.7%, NL: 40.3%; OR 0.91 (0.79-1.04, P = 0.16) and antibacterials (66.8% AU, 62.4% NL, OR 1.08 (0.93-1.24, P = 0.31) was similar, but choice of individual agents differed between the two countries. Differences were observed in the use of antithrombotics (46.7% AU, 64.7% NL, OR 0.48 (0.42-0.56, P > 0.01), ophthalmologicals (44.3% AU, 22.1% NL, OR 2.80 (2.42-3.24, P < 0.001), laxatives (77.1% AU, 65.8% NL, OR 1.65 (1.41-1.92, P < 0.001). Conclusion: while the general prevalence of medication use in nursing home residents was similar across the two countries, distinct differences existed in the choice of agent among therapeutic groups. Comparing use between countries identified a number of potential medication related problem areas that need further exploration.

ASSESSING PARENTING IN THE CONTEXT OF REUNIFICATION OF INFANTS/TODDLERS AND THEIR FAMILIES: HOW TO FACE THE CHALLENGES?

Since a substantial portion of infants and toddlers reenter care after reunification, the question of whether family reunification is feasible needs to be answered very cautiously. How parenting is assessed is of major importance in answering this question, but the quality of these assessments is often poor. With an eye to improving current practice, we conducted an integrative review, in which we analyzed the challenges related to the assessment of parenting vis-à-vis reunification and linked relevant knowledge from research with significant know-how from practice. The challenges appear to be embedded in the struggle to define (especially good enough) parenting and the complex context of child protection. As an answer to the challenges, the integrative review resulted in a framework of four key components required for sufficient parenting-assessment practice: (a) the use and development of expertise; and (b) providing families aiming for reunification with an intervention that is intensive, (c) flexible, and (d) organized as teamwork. Providing families with such an intervention gives them the opportunity to make substantial changes in their parenting and helps professionals assess the capacity of parents to grow to an acceptable level of caretaking for their child. Further implications for research and practice are discussed.

Speech understanding in noise with the Roger Pen, Naida CI Q70 processor, and integrated Roger 17 receiver in a multi-talker network.

Roger is a digital adaptive multi-channel remote microphone technology that wirelessly transmits a speaker's voice directly to a hearing instrument or cochlear implant sound processor. Frequency hopping between channels, in combination with repeated broadcast, avoids interference issues that have limited earlier generation FM systems. This study evaluated the benefit of the Roger Pen transmitter microphone in a multiple talker network (MTN) for cochlear implant users in a simulated noisy conversation setting. Twelve post-lingually deafened adult Advanced Bionics CII/HiRes 90K recipients were recruited. Subjects used a Naida CI Q70 processor with integrated Roger 17 receiver. The test environment simulated four people having a meal in a noisy restaurant, one the CI user (listener), and three companions (talkers) talking non-simultaneously in a diffuse field of multi-talker babble. Speech reception thresholds (SRTs) were determined without the Roger Pen, with one Roger Pen, and with three Roger Pens in an MTN. Using three Roger Pens in an MTN improved the SRT by 14.8 dB over using no Roger Pen, and by 13.1 dB over using a single Roger Pen (p < 0.0001). The Roger Pen in an MTN provided statistically and clinically significant improvement in speech perception in noise for Advanced Bionics cochlear implant recipients. The integrated Roger 17 receiver made it easy for users of the Naida CI Q70 processor to take advantage of the Roger system. The listening advantage and ease of use should encourage more clinicians to recommend and fit Roger in adult cochlear implant patients.

High persistence and low treatment rates of metabolic syndrome in patients with mood and anxiety disorders: A naturalistic follow-up study.

BACKGROUND: Patients with affective and anxiety disorders are at risk of metabolic syndrome (MetS) and, consequently, cardiovascular disease and premature death. In this study, the course and treatment of MetS was investigated using longitudinal data from a naturalistic sample of affective- and anxiety-disordered outpatients (Monitoring Outcome of psychiatric PHARmacotherapy [MOPHAR]). METHODS: Demographics, clinical characteristics, medication use, and MetS components were obtained for n = 2098 patients at baseline and, in a FU-subsample of n = 507 patients, after a median follow-up (FU) of 11 months. Furthermore, pharmacological treatment rates of MetS were investigated at baseline and FU. Finally, demographic and clinical determinants of change in MetS (component) scores were investigated. RESULTS: At baseline, 34.6 % of n = 2098 patients had MetS, 41.4 % of whom received treatment. Of patients with persisting MetS, 46.1 % received treatment for one (or more) MetS component(s) at baseline, and 56.6 % received treatment at FU. Treatment rates of solely elevated blood pressure and reduced HDL-cholesterol did significantly, but modestly, improve. Higher age, male sex, smoking behavior, low education, diabetes, and depressive versus anxiety disorder were predictors of worse outcome at FU on at least one MetS component. LIMITATIONS: We did not have data on lifestyle interventions as a form of treatment, which might partly have explained the observed low pharmacotherapeutic treatment rates. CONCLUSION: MetS (components) show high persistence rates in affective- and anxiety-disordered patients, and are, despite adequate monitoring, undertreated over time. This indicates that adherence and implementation of monitoring protocols should be crucially improved in psychiatric outpatients in secondary care.

Effects of controlled discontinuation of long-term used antipsychotics on weight and metabolic parameters in individuals with intellectual disability.

Antipsychotics are frequently prescribed agents in individuals with intellectual disability, often for behavioral symptoms. Efficacy of antipsychotics for this is ambiguous, so discontinuation should be considered. Weight gain and metabolic dysregulation are well-known adverse effects of antipsychotics which increase the risk of the metabolic syndrome. We performed a discontinuation study in 99 adults with intellectual disability, living in residential facilities who used antipsychotics for behavioral symptoms for more than 1 year. The aim of the present study was to investigate the effects of discontinuation of long-term used antipsychotics on weight, body mass index (BMI), and parameters of the metabolic syndrome and to investigate the influence of genetic polymorphisms and medication factors on these outcomes. Discontinuation of antipsychotics led to a mean decrease of 4 cm waist circumference, of 3.5 kg weight, 1.4 kg/m2 BMI, and 7.1 mm Hg systolic blood pressure. In those participants who had not completely discontinued use of antipsychotics we found a decrease in weight and BMI and an increase in fasting glucose. The presence of the C-allele of serotonin 5-hydroxytryptamine receptor polymorphism rs141334 was associated with higher waist circumference and higher plasma levels of triglycerides and lower levels of high-density lipoprotein. Achievement of complete discontinuation predicted a larger decrease in waist circumference and BMI. In conclusion, results of the study show the beneficial effects of discontinuation of long-term used antipsychotics on metabolic outcomes.

Evaluation of speech recognition of cochlear implant recipients using a personal digital adaptive radio frequency system.

BACKGROUND: Previous research supports the use of frequency modulation (FM) systems for improving speech recognition in noise of individuals with cochlear implants (CIs). However, at this time, there is no published research on the potential speech recognition benefit of new digital adaptive wireless radio transmission systems. PURPOSE: The goal of this study was to compare speech recognition in quiet and in noise of CI recipients while using traditional, fixed-gain analog FM systems, adaptive analog FM systems, and adaptive digital wireless radio frequency transmission systems. RESEARCH DESIGN: A three-way repeated-measures design was used to examine performance differences among devices, among speech recognition conditions in quiet and in increasing levels of background noise, and between users of Advanced Bionics and Cochlear CIs. STUDY SAMPLE: Seventeen users of Advanced Bionics Harmony CI sound processors and 20 users of Cochlear Nucleus 5 sound processors were included in the study. DATA COLLECTION AND ANALYSIS: Participants were tested in a total of 32 speech-recognition-in noise-test conditions, which included one no-FM and three device conditions (fixed-gain FM, adaptive FM, and adaptive digital) at the following signal levels: 64 dBA speech (at the location of the participant) in quiet and 64 dBA speech with competing noise at 50, 55, 60, 65, 70, 75, and 80 dBA noise levels. RESULTS: No significant differences were detected between the users of Advanced Bionics and Cochlear CIs. All of the radio frequency system conditions (i.e., fixed-gain FM, adaptive FM, and adaptive digital) outperformed the no-FM conditions in test situations with competing noise. Specifically, in conditions with 70, 75, and 80 dBA of competing noise, the adaptive digital system provided better performance than the fixed-gain and adaptive FM systems. The adaptive FM system did provide better performance than the fixed-gain FM system at 70 and 75 dBA of competing noise. At the lower noise levels of 50, 55, 60, and 65 dBA, no significant differences were detected across the three systems, and no significant differences were found across the quiet conditions. In all conditions, performance became poorer as the competing noise level increased. CONCLUSIONS: In high levels of noise, the adaptive digital system provides superior performance when compared to adaptive analog FM and fixed-gain FM systems.

Lithium surveillance by community pharmacists and physicians in ambulatory patients: a retrospective cohort study.

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.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone).

The current Dutch Pharmacogenetics Working Group (DPWG) guideline, describes the gene-drug interaction between CYP2D6 and the opioids codeine, tramadol and oxycodone. CYP2D6 genotype is translated into normal metaboliser (NM), intermediate metaboliser (IM), poor metaboliser (PM) or ultra-rapid metaboliser (UM). Codeine is contraindicated in UM adults if doses >20 mg every 6 h (q6h), in children ≥12 years if doses >10 mg q6h, or with additional risk factors. In PMs, an alternative analgesic should be given which is not or to a lesser extent metabolised by CYP2D6 (not tramadol). In IMs with insufficient analgesia, a higher dose or alternative analgesic should be given. For tramadol, the recommendations for IMs and PMs are the same as the recommendation for codeine and IMs. UMs should receive an alternative drug not or to a lesser extent metabolised by CYP2D6 or the dose should be decreased to 40% of the commonly prescribed dose. Due to the absence of effect on clinical outcomes of oxycodone in PMs, IMs and UMs no action is required. DPWG classifies CYP2D6 genotyping for codeine "beneficial" and recommends testing prior to, or shortly after initiation of treatment in case of higher doses or additional risk factors. CYP2D6 genotyping is classified as "potentially beneficial" for tramadol and can be considered on an individual patient basis.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs.

The Dutch Pharmacogenetics Working Group (DPWG) guideline presented here, presents the gene-drug interaction between the genes CYP2C19 and CYP2D6 and antidepressants of the selective serotonin reuptake inhibitor type (SSRIs). Both genes' genotypes are translated into predicted normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), or ultra-rapid metabolizer (UM). Evidence-based dose recommendations were obtained, based on a structured analysis of published literature. In CYP2C19 PM patients, escitalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 75% of the normal maximum dose. Escitalopram should be avoided in UM patients. In CYP2C19 PM patients, citalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 70% (65-75%) of the normal maximum dose. In contrast to escitalopram, no action is needed for CYP2C19 UM patients. In CYP2C19 PM patients, sertraline dose should not exceed 37.5% of the normal maximum dose. No action is needed for CYP2C19 IM and UM patients. In CYP2D6 UM patients, paroxetine should be avoided. No action is needed for CYP2D6 PM and IM patients. In addition, no action is needed for the other gene-drug combinations. Clinical effects (increase in adverse events or decrease in efficacy) were lacking for these other gene-drug combinations. DPWG classifies CYP2C19 genotyping before the start of escitalopram, citalopram, and sertraline, and CYP2D6 genotyping before the start of paroxetine as "potentially beneficial" for toxicity/effectivity predictions. This indicates that genotyping prior to treatment can be considered on an individual patient basis.

[Anxiety and mood disorders are independent risk factors for cardiovascular diseases]. / Stemmings- en angststoornissen als risicofactor voor cardiovasculaire ziekten.

OBJECTIVE: Psychiatric conditions are insufficiently highlighted as cardiovascular risk factors in the CVRM guideline. Objectives of this review are 1) to determine if anxiety and mood symptoms/disorders are independent cardiovascular risk factors; 2) to compare this risk to a population without these psychiatric conditions and 3) to ascertain the influence of psychiatric disease severity. DESIGN: Narrative systematic review METHOD: We searched for meta-analyses and systematic reviews in PubMed. Quality assessment by AMSTAR criteria. RESULTS: 10 reviews were included from 172 hits. (Sub)clinical depression and mood disorders are associated with an increased independent risk to develop cardiovascular diseases, coronary artery disease, myocardial infarction and cerebrovascular disease. Bipolar disorders increase the cerebrovascular risk, but not myocardial infarction. Anxiety disorders/symptoms heighten the cardiovascular, myocardial and cerebrovascular risk. CONCLUSION: Anxiety and mood symptoms/disorders are independent cardiovascular risk factors. Severe anxiety and mood disorders should be included as separate risk factors in the CVRM guideline.

Association between the 1291-C/G polymorphism in the adrenergic α-2a receptor and the metabolic syndrome.

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic α-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the α-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.

Combined HTR2C-LEP genotype as a determinant of obesity in patients using antipsychotic medication.

Obesity is one of the most serious common somatic adverse effects of atypical antipsychotic agents. Genetic factors partly determine the individual patients risk of developing obesity during treatment. As weight-regulating mechanisms, such as the leptinergic and serotonergic system, may be interdependent, genetic polymorphisms in these systems also may show interactions. To determine whether combined HTR2CLEP genotype or HTR2C-LEPR genotype are associated with obesity in patients using atypical antipsychotic drugs, a cross-sectional study design was used. The study population included 200 patients aged between 18 and 65 years of age, diagnosed with a psychotic disorder, all of whom had been using an atypical antipsychotic for at least 3 months. Primary outcome measure was presence of obesity (body mass index, >30). Determinants were the combined (HTR2C -759C/T-LEPR Q223R), (HTR2C -759C/T-LEP -2548G/A, (HTR2C rs1414334-LEPR Q223R) and (HTR2C rs1414334-LEP -2548G/A) genotypes. Of the 200 included patients, 61 (31%) were obese. In patients without the HTR2C -759T allele, presence of the LEP -2548G allele was associated with obesity (odds ratio, 2.88; 95% confidence interval, 1.05-7.95). The results of the other analyses showed some nonsignificant trends. The combined (HTR2C -759C/TYLEP -2548G/A) genotype may be a determinant of obesity in patients during treatment with atypical antipsychotic drugs.

[Discontinuation of SSRIs and SNRIs]. / Het afbouwen van SSRI's en SNRI's.

Interruption or abrupt discontinuation of the use of antidepressants may lead to withdrawal symptoms. These are most common with selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs).There is insufficient scientific evidence about the prevalence of antidepressant withdrawal symptoms and how to optimally discontinue antidepressants. The multidisciplinary document 'Discontinuation of SSRIs & SNRIs' offers a rationale and suggestions for the gradual tapering of these antidepressants. The following factors are consistently named as risk factors for the occurrence of withdrawal symptoms: (a) the patient experiences withdrawal symptoms in case of non-compliance or skipped doses; (b) a previous attempt to stop was unsuccessful; and (c) the patient is being treated with higher doses than the smallest effective dose of SSRIs or SNRIs. In patients with one or more risk factors, a tapering schedule with non-linear dose-reduction steps should be considered. The speed at which these steps are taken, should be adjusted depending on occurrence of withdrawal symptoms. Shared decision-making by patient and physician is the best way to select a tapering schedule.

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.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. 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 three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.