Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients.

AIMS: To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). METHODS: Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. RESULTS: The average age of the included population (n = 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P < .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P < .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P < .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P < .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P = .012) and poor (+17%, P = .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. CONCLUSION: This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo.

BACKGROUND: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear. OBJECTIVE: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients' serum after adjusting for sex, age, and smoking habits. METHODS: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway. From the same patients, the following UGT variants were genotyped using Real-Time PCR: UGT2B:GA haplotype (defined as UGT2B:GA; rs1513559A>G and rs416593T>A) and UGT1A4*3 (rs2011425T>G). Serum concentrations of CLZ 5N- and N+-glucuronide were measured by UPLC high-resolution mass spectrometry. RESULTS: None of the genotypes had significant impact on CLZ exposure (p>0.05). However, compared to UGT2B:AT/AT and UGT1A4*1/*1, the 5N-glucuronide exposure was reduced in UGT2B:GA/GA carriers (-75 %, p=0.03) while the exposure was non-significantly increased in UGT1A4*3 carriers (+100 %, p=0.14), respectively. The N+-glucuronide exposure was unchanged in UGT1A4*3 vs. noncarriers (p=0.28), but significantly reduced in heterozygous (-50 %, p=0.016) and homozygous carriers (-70 %, p=0.021) of UGT2B:GA compared to UGT2B:AT/AT carriers, respectively. CONCLUSION: The UGT2B:GA and UGT1A4*3 variants had no impact on CLZ exposure but were associated with differences and preferences in CLZ glucuronidation. The latter might be of potential relevance for CLZ tolerability since levels of the N+-glucuronide metabolite may reflect the generation and trapping of reactive metabolites involved in CLZ-induced toxicity.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

The specialist health service for geriatric psychiatry during the COVID-19 pandemic. / Alderspsykiatriske helsetjenester under covid-19-pandemien.

BACKGROUND: Older patients with mental disorders are particularly likely to be affected by negative consequences of the infection control measures that have been implemented as a result of the COVID-19 pandemic. MATERIAL AND METHOD: A questionnaire survey was sent to 18 departments of geriatric psychiatry from all four health regions in Norway. RESULTS: Altogether 83 therapists from various occupational groups responded, with representatives from all the health regions. Almost one-half (45.8 %) reported an exacerbation of patients' mental condition to a large or very large degree due to social isolation, and an equal proportion (48.2 %) reported that normal follow-up was limited. The contact between the specialist and primary health services was reduced, and 15.6 % reported that patients had failed to receive the necessary somatic medical assistance to a large or very large degree. INTERPRETATION: The service for older patients with mental disorders in the specialist health service was reduced as a result of the COVID-19 pandemic, while coordination with the primary health service was also curtailed, and many patients deteriorated mentally as a result of the infection control measures. Collaboration between the specialist and primary health services may be an important focus area for this patient group.

Impact of age and gender on paliperidone exposure in patients after administration of long-acting injectable formulations-an observational study using blood samples from 1223 patients.

PURPOSE: Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. METHODS: Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15-49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. RESULTS: In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21-30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001). CONCLUSION: The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.

Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation-an observational study including 2044 patients.

PURPOSE: Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype. METHODS: Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005-2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18-64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used. RESULTS: Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25-33%, p < 0.001) and oral formulation (+ 25-29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: - 30%; LAI: - 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001). CONCLUSION: The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.

Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders.

BACKGROUND: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. METHODS: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. RESULTS: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4-4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5-2.8), followed by aripiprazole (2.3%; 1.7-2.8), risperidone (2.4%; 1.6-3.0), quetiapine (2.8%; 2.3-3.2) and olanzapine (4.9%; 4.1-5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6-2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. CONCLUSIONS: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.

Impact of antipsychotic polypharmacy on nonadherence of oral antipsychotic drugs - A study based on blood sample analyses from 24,239 patients.

Nonadherence to oral antipsychotic drugs is a major issue in clinical psychiatry giving rise to treatment failure. Further, polypharmacy is common in the treatment of psychotic disorders due to insufficient treatment effect during monotherapy. As a potential circuit problem, we hypothesized that antipsychotic polypharmacy is associated with increased risk of nonadherence. To investigate this, in terms of 'complete' nonadherence, the rates of undetectable serum drug concentrations during prescribing of doses used in psychotic disorders were compared during antipsychotic 'monotherapy' vs 'polypharmacy' treatment using therapeutic drug monitoring (TDM) data of 24,239 patients. A complete nonadherence patient was objectively defined as the detection of at least one event of undetectable serum concentration of a prescribed antipsychotic drug. The rate of complete nonadherence patients was compared between antipsychotic monotherapy and polypharmacy by multivariate logistic regression analyses. The overall rate of complete nonadherence in the population was 6.8% (n = 1,644; 95%CI: 6.5-7.1). Compared to monotherapy patients, the rate of nonadherence increased significantly with the number of co-prescribed antipsychotic drugs. After adjusting for sex (p = 0.091) and age (p < 0.001) as covariates, the rates of nonadherence vs monotherapy were 1.69-fold (95% CI: 1.48-1.92; p < 0.001) for two, 2.60-fold (95% CI: 1.88-3.59; p < 0.001) for three, and 3.54-fold (95% CI: 1.46-8.58; p = 0.005) for four or more co-prescribed antipsychotics, respectively. The present naturalistic study shows that antipsychotic polypharmacy significantly increases the rate of complete nonadherence, which is positively correlated with increasing number of concurrently used antipsychotic drugs. Thus, the intended clinical benefit of combining oral antipsychotic drugs may probably be reduced by increased nonadherence.

Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status.

PURPOSE: Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole. METHODS: Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation. RESULTS: We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups. CONCLUSIONS: In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.

Prescribing of antipsychotic drugs to older patients living at home 2006­18. / Forskrivning av antipsykotika til hjemmeboende eldre 2006­18.

BACKGROUND: It is generally agreed that prescribing of antipsychotic drugs to older patients should be reduced, but figures for the prescribing of these drugs to older patients living at home in Norway are not available. The study aimed to investigate developments in prescribing of antipsychotic drugs among older patients living at home from 2006 to 2018, and whether there were differences in prescribing rates between the age groups 65-74 years, 75-84 years and 85 years or older. MATERIAL AND METHOD: Data were retrieved from the Norwegian Prescription Database. All persons aged 65 years or older who were dispensed at least one antipsychotic drug in 2006, 2010, 2014 and 2018 were included, and gender-specific prevalence for the ten most widely used antipsychotic drugs was calculated. RESULTS: The proportion of patients aged 65 or older who were prescribed antipsychotic drugs in the period decreased for both sexes. For the age group 65-74 years, an increase was found from 2014 to 2018. There was a clear decrease in the prescribing rate for prochlorperazine and levomepromazine, whereas prescriptions for quetiapine increased. INTERPRETATION: Attention should be paid to the increase in prescribing of antipsychotic drugs for the youngest age group of older patients (65-74 years) in the last four years, along with the increase in prescribing of quetiapine for older patients.

The Effect of Valproic Acid on Olanzapine Serum Concentration: A Study Including 2791 Patients Treated With Olanzapine Tablets or Long-Acting Injections.

BACKGROUND: The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. METHODS: From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. RESULTS: The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). IMPLICATIONS: These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.

Age Impacts Olanzapine Exposure Differently During Use of Oral Versus Long-Acting Injectable Formulations: An Observational Study Including 8,288 Patients.

PURPOSE: Olanzapine is a commonly prescribed antipsychotic available as oral and long-acting injectable (LAI) formulations. Data are lacking on the use and safety of olanzapine-LAI in older patients. The aim of this study was to investigate the effect of increasing age on olanzapine exposure during oral versus LAI administration in a real-life setting. METHODS: This observational study was based on routine therapeutic drug monitoring data collected during 2005-2017. As a measure of exposure, absolute concentrations and concentration/dose ratios of olanzapine were defined as outcome variables. Linear mixed-model analyzes were used to allow for inclusion of multiple samples per patient and adjustment for covariate effects. RESULTS: Olanzapine concentrations and doses from 8,288 patients (21,378 measurements) were included. The number of patients on oral treatment was 7,893 (42%, 50 years or older), while 395 were using olanzapine-LAI (27%, 50 years or older). In contrast to oral use, where the dose-adjusted concentration of olanzapine increased significantly for patients 50 years or older (P < 0.001), increasing age had no effect on olanzapine concentration following LAI administration (P = 0.550). The effects of smoking habits and gender were equal in oral and olanzapine-LAI users. CONCLUSION: While the dose-adjusted systemic exposure of olanzapine increases by age after oral administration, these novel findings from a large patient population show that systemic exposure of olanzapine-LAI is unaffected by age, probably due to the lacking influence of age-related changes in gastrointestinal absorption and/or presystemic metabolism. From a pharmacokinetic point of view, it is therefore no reason to restrict the use of olanzapine-LAI in older patients requiring long-term treatment.