Medication Appropriateness for Older Nursing Home Patients With a Limited Life Expectancy: From STOPP/START Version 2 to the ReNeWAL Criteria.

OBJECTIVES: To adapt the 2015 Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) criteria to older nursing home patients with a limited life expectancy of 1.5 to 2 years. DESIGN: A modified Delphi consensus study. SETTING AND PARTICIPANTS: The study was established in The Netherlands and conducted online. The international panel consisted of 23 experts with experience in medicine for older people. METHODS: The expert panel was presented with the 2015 STOPP/START criteria using an online survey program (Survey Monkey). The panelists were asked for their opinion on the appropriateness of the STOPP and START criteria, and adaptations to these criteria for older nursing home patients with a limited life expectancy on 4-point Likert scales. Consensus was defined as ≥70% of the panelists answering (very) inappropriate or (very) appropriate, and (completely) disagree or (completely) agree. RESULTS: Twenty-one panelists completed all 3 Delphi rounds. The final list of "Represcribing for Nursing home residents With A Limited life expectancy (ReNeWAL)" criteria comprises 132 criteria: 98 criteria to stop (70 original STOPP criteria and 28 adapted) and 34 criteria to start (16 original START criteria and 18 adapted) for older nursing home patients with a limited life expectancy. Considerations that panelists mentioned for adapting criteria were mainly prevention and treatment of discomfort. CONCLUSION AND IMPLICATIONS: It is clear that represcribing for older nursing home patients is highly complex and requires the consideration of various elements. The ReNeWAL criteria may be useful in enhancing represcribing for older nursing home patients with a limited life expectancy.

[A prescription for yourself or acquaintances, a good idea?] / Een recept voor jezelf of een bekende, een goed idee?

Many doctors regularly write a prescription for themselves or for family members or friends. In this article, we discuss the legal and ethical considerations surrounding these prescriptions. We also discuss the role of the pharmacist who receives the prescription. Although there is no legal obstacle, codes of conduct and guidelines state that prescribing to acquaintances or yourself is undesirable, especially because it is often not possible to maintain sufficient professional distance, necessary to provide proper treatment. If the GP or other care providers have no knowledge of the prescription and no medical file is kept, undesirable situations may arise for the patient. A prescription for yourself or acquaintances can be made occasionally and under special circumstances (acute situation, no serious problem, short-term), but then requires a quick transfer of treatment to regular practitioners.

Impact of Drug Recalls on Patients in The Netherlands: A 5-Year Retrospective Data Analysis.

Drug recalls occur frequently and have the potential to impact considerable numbers of patients and healthcare providers. However, in the absence of a comprehensive overview the extent of conducted recalls and their impact on patients remains unknown. To address this, we developed a comprehensive overview of drug recalls affecting patients. We compiled this overview based on the drug recall registrations from the Jeroen Bosch Hospital (JBZ), the University Medical Center Utrecht (UMCU), and the Royal Dutch Pharmacists Association (KNMP). A retrospective data analysis was conducted to identify drug recalls that affected patients. Specifically, we defined these as drug recalls that required patients to actively switch their drug to a different batch or brand of the same drug or to switch to a drug within the same or a different class of drugs. To quantify the impact, we used real-world drug dispensing data. Between January 1, 2017, and December 31, 2021, we identified 48 drug recalls that necessitated patients to make active changes to their medications an estimated 855,000 times. Most of the affected patients (292,000) were required to switch to a different brand of the same drug, whereas in 95,000 cases patients had to switch to a drug from another drug class. Our study suggests that a significant number of patients are affected by drug recalls. Future efforts are needed to elucidate patients' experiences and preferences regarding drug recalls, which could provide valuable insights to aid decision-making by relevant (national) authorities concerning drug recalls.

Effect of conventional hemodialysis on the apixaban plasma concentration.

PURPOSE: Apixaban is a factor Xa inhibitor used in patients undergoing hemodialysis treatment. The objective of this study is to investigate the effect of hemodialysis on apixaban plasma concentrations. METHODS: This observational study is on patients treated with apixaban 2.5 mg twice daily on conventional hemodialysis with standard low-molecular-weight heparin (LMWH) anticoagulation (nadroparin 3800-7600 IU). Plasma blood samples were collected before starting dialysis (t1), 2 h after starting dialysis (t2), and directly after dialysis (t3). Apixaban concentration was measured before and after dialysis. Anti-Xa activity was measured for all three samples. RESULTS: A significant difference was observed between the apixaban concentration before and after dialysis (mean before dialysis 141.03 ng/mL; mean after dialysis 102.71 ng/mL; p = 0.003). Nonetheless, both apixaban plasma concentrations and anti-Xa levels remained within the reference range. Anti-Xa levels had a strong correlation with the apixaban concentrations (r = 0.935, p = 0.000). Thus, anti-Xa activity might be used as a surrogate for apixaban plasma concentration. CONCLUSION: There seems to be no need for dose adjustments of apixaban; co-administration of LMWH next to apixaban might also be unnecessary.

Hospital registration of adverse drug reactions in electronic health records: importance and contribution to pharmacovigilance.

BACKGROUND: Information on registered adverse drug reactions (ADRs) in hospitals may provide a large real-world data source that can be used to ensure patients' safety. This study aimed to assess the potential contribution of hospital registration of ADRs in electronic health records (EHR) to pharmacovigilance. RESEARCH DESIGN AND METHODS: An observational retrospective descriptive study using data from the Jeroen Bosch Hospital in the Netherlands in 2019. 'Serious and/or severe' and 'previously unknown' ADRs registered systematically in the corresponding field of EHRs were assessed. RESULTS: ADR data concerning 1010 patients were included. In total, 1630 ADRs were registered in EHRs. Fifty-eight serious and/or severe ADRs (5.2%) were registered. Tubulointerstitial nephritis was the most frequently registered severe ADR and was mainly associated with antibacterials for systemic use. A total of 82 previously unknown ADRs (5%) were registered. 'Migraine' and 'chest pain' were the most frequently registered unknown ADRs. Additionally, 25 ADRs (1.5%) were registered that may be attributable to 10 drugs 'under additional monitoring.' CONCLUSIONS: Hospital registrations of ADRs in EHRs provide information on ADRs, which are challenging to assess during clinical trials. However, improvements are required to optimize this registration before it can serve as a valuable data source for pharmacovigilance purposes.

Personal Continuity and Appropriate Prescribing in Primary Care.

PURPOSE: Personal continuity between patient and physician is a core value of primary care. Although previous studies suggest that personal continuity is associated with fewer potentially inappropriate prescriptions, evidence on continuity and prescribing in primary care is scarce. We aimed to determine the association between personal continuity and potentially inappropriate prescriptions, which encompasses potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), by family physicians among older patients. METHODS: We conducted an observational cohort study using routine care data from patients enlisted in 48 Dutch family practices from 2013 to 2018. All 25,854 patients aged 65 years and older having at least 5 contacts with their practice in 6 years were included. We calculated personal continuity using 3 established measures: the usual provider of care measure, the Bice-Boxerman Index, and the Herfindahl Index. We used the Screening Tool of Older Person's Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) specific to the Netherlands version 2 criteria to calculate the prevalence of potentially inappropriate prescriptions. To assess associations, we conducted multilevel negative binomial regression analyses, with and without adjustment for number of chronic conditions, age, and sex. RESULTS: The patients' mean (SD) values for the usual provider of care measure, the Bice-Boxerman Continuity of Care Index, and the Herfindahl Index were 0.70 (0.19), 0.55 (0.24), and 0.59 (0.22), respectively. In our population, 72.2% and 74.3% of patients had at least 1 PIM and PPO, respectively; 30.9% and 34.2% had at least 3 PIMs and PPOs, respectively. All 3 measures of personal continuity were positively and significantly associated with fewer potentially inappropriate prescriptions. CONCLUSIONS: A higher level of personal continuity is associated with more appropriate prescribing. Increasing personal continuity may improve the quality of prescriptions and reduce harmful consequences.

Deprescribing practices, habits and attitudes of geriatricians and geriatricians-in-training across Europe: a large web-based survey.

PURPOSE: To provide an overview of the current deprescribing attitudes, practices, and approaches of geriatricians and geriatricians-in-training across Europe. METHODS: An online survey was disseminated among European geriatricians and geriatricians-in-training. The survey comprised Likert scale and multiple-choice questions on deprescribing approaches and practices, deprescribing education and knowledge, and facilitators/barriers of deprescribing. Responses to the survey questions and participant characteristics were quantified and differences evaluated between geriatricians and geriatricians-in-training and between European regions. RESULTS: The 964 respondents (median age 42 years old; 64% female; 21% geriatricians-in-training) were generally willing to deprescribe (98%) and felt confident about deprescribing (85%). Despite differences across European regions, the most commonly reported reasons for deprescribing were functional impairment and occurrence of adverse drug reactions. The most important barriers for deprescribing were patients' unwillingness, fear of negative consequences, lack of time, and poor communication between multiple prescribers. Perceived risk of adverse drug reactions was highest for psychotropic drugs, nonsteroidal anti-inflammatory drugs, cardiovascular drugs, and opioid analgesics. Only one in four respondents (23% of geriatricians and 37% of geriatricians-in-training) think education in medical school had sufficiently prepared them for deprescribing in clinical practice. They reported that their future deprescribing activities would probably increase with improved information sharing between various prescribers, deprescribing recommendations in guidelines, and increased education and training. Approximately 90% think that a paradigm shift is required for prescribers and patients, increasing focus on the possible benefits of deprescribing (potentially) inappropriate medications. CONCLUSIONS: Based on the outcomes of this survey, we recommend investing in improved inter-professional communication, better education and evidence-based recommendations to improve future patient-centered deprescribing practices.

A Systematic Review of the Current Evidence from Randomised Controlled Trials on the Impact of Medication Optimisation or Pharmacological Interventions on Quantitative Measures of Cognitive Function in Geriatric Patients.

BACKGROUND: Cognitive decline is common in older people. Numerous studies point to the detrimental impact of polypharmacy and inappropriate medication on older people's cognitive function. Here we aim to systematically review evidence on the impact of medication optimisation and drug interventions on cognitive function in older adults. METHODS: A systematic review was performed using MEDLINE and Web of Science on May 2021. Only randomised controlled trials (RCTs) addressing the impact of medication optimisation or pharmacological interventions on quantitative measures of cognitive function in older adults (aged > 65 years) were included. Single-drug interventions (e.g., on drugs for dementia) were excluded. The quality of the studies was assessed by using the Jadad score. RESULTS: Thirteen studies met the inclusion criteria. In five studies a positive impact of the intervention on metric measures of cognitive function was observed. Only one study showed a significant improvement of cognitive function by medication optimisation. The remaining four positive studies tested methylphenidate, selective oestrogen receptor modulators, folic acid and antipsychotics. The mean Jadad score was low (2.7). CONCLUSION: This systematic review identified a small number of heterogenous RCTs investigating the impact of medication optimisation or pharmacological interventions on cognitive function. Five trials showed a positive impact on at least one aspect of cognitive function, with comprehensive medication optimisation not being more successful than focused drug interventions. More prospective trials are needed to specifically assess ways of limiting the negative impact of certain medication in particular and polypharmacy in general on cognitive function in older patients.

General practice and patient characteristics associated with personal continuity: a mixed-methods study.

BACKGROUND: Personal continuity of care is a core value of general practice. It is increasingly threatened by societal and healthcare changes. AIM: To investigate the association between personal continuity and both practice and patient characteristics; and to incorporate GPs' views to enrich and validate the quantitative findings. DESIGN AND SETTING: A mixed-methods study based on observational, routinely collected healthcare data from 269 478 patients from 48 Dutch general practices (2013-2018) and interviews with selected GPs. METHOD: First, four different personal continuity outcome measures were calculated relating to eight practice and 12 patient characteristics using multilevel linear regression analyses. Second, a thematic analysis was performed of semi-structured interviews with 10 GPs to include their views on factors contributing to personal (dis) continuity. These GPs worked at the 10 practices with the largest difference between calculated and model-estimated personal continuity. RESULTS: Both a larger number of usual GPs working in a practice and a larger percentage of patient contacts with locum GPs were dose-dependently associated with lower personal continuity (highest versus lowest quartile -0.094 and -0.092, respectively, P<0.001), whereas days since registration with the general practice was dose-dependently associated with higher personal continuity (highest versus lowest quartile +0.017, P<0.001). Older age, number of chronic conditions, and contacts were also associated with higher personal continuity. The in-depth interviews identified three key themes affecting personal continuity: team composition, practice organisation, and the personal views of the GPs. CONCLUSION: Personal continuity is associated with practice and patient characteristics. The dose-dependent associations suggest a causal relationship and, complemented by GPs' views, may provide practical targets to improve personal continuity directly.

Psychotropic drug treatment for agitated behaviour in dementia: what if the guideline prescribing recommendations are not sufficient? A qualitative study.

BACKGROUND: Agitation is a common challenging behaviour in dementia with a negative influence on patient's quality of life and a high caregiver burden. Treatment is often difficult. Current guidelines recommend restrictive use of psychotropic drug treatment, but guideline recommendations do not always suffice. OBJECTIVE: To explore how physicians decide on psychotropic drug treatment for agitated behaviour in dementia when the guideline prescribing recommendations are not sufficient. METHODS: We conducted five online focus groups with a total of 22 elderly care physicians, five geriatricians and four old-age psychiatrists, in The Netherlands. The focus groups were thematically analysed. RESULTS: We identified five main themes. Transcending these themes, in each of the focus groups physicians stated that there is 'not one size that fits all'. The five themes reflect physicians' considerations when deciding on psychotropic drug treatment outside the guideline prescribing recommendations for agitated behaviour in dementia: (1) 'reanalysis of problem and cause', (2) 'hypothesis of underlying cause and treatment goal', (3) 'considerations regarding drug choice', (4) 'trial and error' and (5) 'last resort: sedation'. CONCLUSION: When guideline prescribing recommendations do not suffice, physicians start with reanalysing potential underlying causes. They try to substantiate and justify medication choices as best as they can with a hypothesis of underlying causes or treatment goal, using other guidelines, and applying personalised psychotropic drug treatment.

Dialysis or kidney transplantation in older adults? A systematic review summarizing functional, psychological, and quality of life-related outcomes after start of kidney replacement therapy.

BACKGROUND: In older patients, the choice between kidney transplantation (KT) and dialysis may be complicated because of a high prevalence of comorbidities and geriatric syndromes. Ideally, this decision-making process focusses on older patients' outcome priorities, which frequently include functional, psychological, and quality of life (QOL)-related outcomes. PURPOSE: This systematic review aims to summarize functional, psychological (including cognition), and QOL-related outcomes after start of kidney replacement therapy (KRT) in older adults. METHODS: We searched PubMed and Embase for research that investigated change in these variables after start of KRT in patients aged ≥ 60 years. Data were extracted using the summary measures reported in the individual studies. Risk of bias was assessed with the ROBINS-I tool. RESULTS: Sixteen observational studies (prospective n = 9, retrospective n = 7; KT-recipients n = 3, dialysis patients n = 13) were included. The results show that QOL improves in the majority of the older KT recipients. After start of dialysis, QOL improved or remained stable for most patients, but this seems less prevalent than after KT. Functional status decreases in a substantial part of the older dialysis patients. Furthermore, the incidence of serious fall injuries increases after start of dialysis. Nutritional status seems to improve after start of dialysis. CONCLUSION: The interpretability and comparability of the included studies are limited by the heterogeneity in study designs and significant risk of bias in most studies. Despite this, our overview of functional, psychological (including cognition), and QOL-related outcomes is useful for older adults and their clinicians facing the decision between KT and dialysis.

Kidney transplantation or dialysis in older adults-an interview study on the decision-making process.

BACKGROUND: In older patients with end-stage kidney disease (ESKD), the choice between kidney transplantation (KT) and dialysis may be more complex than in younger patients because of a higher prevalence of comorbidities and frailty. This study aims to provide greater insight into the current decision-making process by exploring the expectations, experiences and health outcome priorities of all stakeholders. METHODS: We performed semi-structured interviews with patients ≥65 years with ESKD (eGFR <15 ml/min/1.73m2, KT recipient or treated with dialysis), patients' relatives and healthcare professionals (nephrologists, nurses and medical social workers). Interviews were conducted until data saturation and thematically analysed. RESULTS: We performed 36 interviews (patients n = 18, relatives n = 5, healthcare professionals n = 13). Thematic analysis revealed five themes. Older patients' health outcome priorities were mostly related to quality of life (QOL). Individual older patients showed marked differences in the preferred level of engagement during the decision-making process (varying from 'wants to be in the lead' to 'follows the nephrologist') and in informational needs (varying from evidence-based to experience-based). On the contrary, healthcare professionals were quite unanimous on all aspects. They focused on determining eligibility for KT as start of the decision-making process, on clear and extensive information provision and on classical, medical outcomes. CONCLUSIONS: The decision-making process could benefit from early identification of older patients' values, needs and health outcome priorities, in parallel with assessment of KT eligibility and before discussing the treatment options, and the explicit use of this information in further steps of the decision-making process.

Body weight gain in clozapine-treated patients: Is norclozapine the culprit?

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

Clozapine Treatment During Pregnancy and the Postpartum Period: A Systematic Literature Review.

Objective: The objective of this systematic review was to provide a critical appraisal of the evidence related to the safety of clozapine for schizophrenia during pregnancy and lactation.Data Sources: PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception through December 2020. Reference lists of included studies were hand-searched. The International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for unpublished trials, and PROSPERO was searched for unpublished reviews. The current marketing authorization holder of the originator brands Clozaril and Leponex was also contacted for pharmacovigilance data.Study Selection: Original reports published in English, German, French, or Dutch containing clinical and preclinical data were included if they provided data on maternal, fetal, and neonatal outcomes after clozapine exposure during pregnancy or lactation.Data Extraction: Two reviewers independently extracted relevant data.Results: A total of 860 records were identified, and the full texts of 117 articles were reviewed. Forty-two studies met the inclusion criteria. Data on perinatal clozapine exposure are of limited quality and quantity. Although clozapine demonstrates partial placental passage, data thus far do not support that clozapine is teratogenic; that it increases the risk of stillbirth, abortion, or fetal disorders; or that it increases the risk of delivery complications or premature birth. Information about clozapine exposure through breast milk is scarce, but based on its chemical properties, it is likely that clozapine enters the breast milk of nursing mothers taking clozapine.Conclusions: When weighing the risks and benefits of clozapine continuation during pregnancy and lactation versus switching to another antipsychotic, one should include severity of illness and treatment history but also be aware of the limitations of the available safety data regarding perinatal clozapine use, including the fact that there are few studies.

Older Patients' Perceptions of Medicines and Willingness to Deprescribe.

Introduction Major barriers in deprescribing are the ambivalence of patients, resistance to change, and poor acceptance of alternative treatments. Objective To investigate older patients' beliefs, understanding and knowledge, satisfaction with medicine use, health outcome priorities, their attitude toward deprescribing, and to identify associated patient factors. Methods This multi-center cross-sectional, semistructured survey study involved older outpatients (70 years of age and older) with polypharmacy. The survey comprised three validated questionnaires: Beliefs about Medicines Questionnaire, Patients' Attitudes Towards Deprescribing questionnaire, and the Health Outcome Prioritization tool, with additional questions about understanding and satisfaction. The association between questionnaire outcomes and patient characteristics was investigated. Results Fifty participants were included; they used an average of 9 (+/- SD 2.7) medicines. For most participants (82%), the necessity of using medicines outweighed their concerns. Participants could name 35% of their medicines and 43% of the indications. Overall, 76% were satisfied with the effect of their medicines, but 94% would be willing to stop their medication if advised by their doctor. Maintaining independence (46%) and reducing pain (31%) were the most important health outcome priorities reported by the patients; staying alive had the lowest priority (51%). Participants with higher levels of educational attainment had better knowledge and had more concerns about harmful effects. Conclusions Patients are open to deprescribing but would probably not initiate the conversation themselves because they are generally very satisfied with their medicines. Knowledge about their medicines and their indications is poor. If doctors initiate deprescribing, patients are probably willing to follow their advice. Patients' life priorities should be discussed in deprescribing conversations.

Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials.

BACKGROUND: Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty. METHODS: A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019. RESULTS: Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty. CONCLUSION: So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.

Psychotropic drug prescription rates in primary care for people with dementia from recorded diagnosis onwards.

BACKGROUND: Psychotropic drugs are frequently prescribed to people with dementia in nursing homes although severe adverse events and side effects are common. Less is known about the prevalence and types of psychotropic drug prescription in primary care for people with dementia. OBJECTIVE: This study examined the prevalence of psychotropic drug prescriptions in primary care among persons with dementia from the year of diagnosis onwards. METHODS: A longitudinal observational study using electronic health record (EHR) data was conducted. People with dementia were selected from EHR data of 451 general practices in the Netherlands. Age and gender-adjusted psychotropic drug prescription rates were calculated per 1000 person-years from the year the dementia diagnosis was first recorded in general practice up to 8 years after diagnosis. RESULTS: Data of 15,687 patients were analyzed. The prescription rate of psychotropic drugs (not including antidementia drugs) was 420 per 1000 person-years (95% CI 409; 431) in the first year after the recorded dementia diagnosis, which increased to 801 per 1000 person-years (95% CI 649; 989) in the eighth year. The most frequently prescribed drugs were antidepressants, antipsychotics, and antidementia drugs, followed by anxiolytics, hypnotics, and antiepileptics. CONCLUSIONS: After a dementia diagnosis is recorded in general practice, the prevalence of psychotropic drug prescriptions is substantial and increases steadily during the disease trajectory of persons with dementia. Although the (in)appropriateness of prescribing was not assessed, these insights may stimulate primary care clinicians to (re)consider their prescription policy of psychotropics for people with dementia more carefully.

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study.

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 µg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 µg/L). The shift in number of patients to therapeutic nortriptyline (50-150 µg/L) and safe hydroxynortriptyline (<200 µg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges.