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

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

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

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

Hypothermia following antipsychotic drug use

Objective: Hypothermia is an adverse drug reaction (ADR) of antipsychotic drug (APD) use. Risk factors for hypothermia in ADP users are unknown. We studied which risk factors for hypothermia can be identified based on case reports. Method: Case reports of hypothermia in APD-users found in PUBMED or EMBASE were searched for risk factors. The WHO international database for Adverse Drug Reactions was searched for reports of hypothermia and APD use. Results: The literature search resulted in 32 articles containing 43 case reports. In the WHO database, 480 reports were registered of patients developing hypothermia during the use of APDs which almost equals the number of reports for hyperthermia associated with APD use (n=524). Hypothermia risk seems to be increased in the first days following start or dose increase of APs. APs with strong 5-HT2 antagonism seem to be more involved in hypothermia; 55% of hypothermia reports are for atypical antipsychotics. Schizophrenia was the most prevalent diagnosis in the case reports. Conclusion: Especially in admitted patients who are not able to control their own environment or physical status, frequent measurements of body temperature (with a thermometer that can measure low body temperatures) must be performed in order to detect developing hypothermia

Clinically relevant potential drug-drug interactions in intensive care patients:A large retrospective observational multicenter study

Purpose: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. Materials & methods: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. Results: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. Conclusions: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients

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