Plasma Concentrations Of Antipsychotics Research Articles

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Plasma concentrations of antipsychotics and QTc prolongation: a pilot study

Background: Certain antipsychotics are known to cause QTc interval prolongation, which has been associated with increased risk of arrhythmia and sudden death. Previous studies have investigated whether there is an association between oral antipsychotic dose and QTc interval prolongation, however only few have examined the association between antipsychotic plasma concentrations and QTc interval.Material and methods: We performed a cross-sectional study with 22 forensic psychiatric in-patients. We measured the plasma concentration of the prescribed antipsychotics and performed an ECG simultaneously. We used Bazett's formula to calculate QTc and defined QTc as prolonged when: >460 ms for women and >450 ms for men.Results: Seventy-seven percent (n = 17) of the subjects were men (mean age = 40 years) and 91% (n = 20) were diagnosed with schizophrenia. QTc’s ranged from 369 to 437 ms. Patients receiving QTc prolonging drugs had significantly greater QTc interval compared to patients receiving non-prolonging drugs. Weak to moderate negative correlations were found between QTc interval and both defined daily dose (DDD) and antipsychotic plasma concentration. There was no statistical difference between the correlations for DDD and plasma concentration versus QTc interval.Conclusion: We did not find a stronger association between antipsychotic plasma concentration and QTc than between antipsychotic dose and QTc. We suggest close monitoring with regular electroencephalogram’s until the development of a better marker for predicting the risk of cardiac arrhythmia.

The development and use of population reference ranges as a tool to interpret antipsychotic plasma concentrations

The development and use of population reference ranges as a tool to interpret antipsychotic plasma concentrations

Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study.

Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM(®), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.

P.3.d.048 Expected and effective plasma concentrations of antipsychotics and changes in psychopathology

Cognitive impairment is present in euthymic patients with bipolar disorder and correlates with impairments in everyday functioning. We aimed to examine the efficacy of lurasidone adjunctive therapy compared with treatment as usual (TAU) in improving cognition.For this randomised, open-label, pilot study, we recruited patients aged 19–65 years with euthymic bipolar I disorder from the Mood Disorder Centre in UBC Hospital (Vancouver, Canada). We included patients who were taking lithium, or valproate, or an atypical antipsychotic, or a combination of these for mood stabilisation and who showed reduced cognitive functioning (SD≤ −0·25 relative to demographics-corrected norms) on either the Trail Making Test-B or the California Verbal Learning Test-II. Patients were randomly assigned using a randomised block design with a block size of four to TAU or lurasidone adjunctive therapy (20–80 mg/day) for 6 weeks. A research coordinator masked to group allocation administered the International Society for Bipolar Disorders Battery for Assessment of Neurocognition (ISBD-BANC) at baseline and at endpoint. The primary outcome was change in global cognition score, which consisted of the mean demographics-corrected t-score value of the several ISBD-BANC measures, analysed in all patients who completed both tests. This trial is registered on ClinicalTrials.gov, number NCT02147379.Between July 2, 2014, and Oct 19, 2015, 34 patients were randomly allocated to lurasidone adjunctive therapy (17 patients) or TAU (17 patients). Two patients from each group did not complete the study. The mean lurasidone dose was 48·24 (SD 15·90) mg/day. Lurasidone adjunctive therapy was more effective than TAU in improving the primary efficacy measure of ISBD-BANC global cognition score (mean difference 2·92 [95% CI 0·27–5·57]; time × treatment interaction F=5·09; p=0·032). The between-group effect size (0·82) on baseline versus study-end difference scores in the ISBD global cognition score was of moderate to large magnitude. The magnitude of benefit with lurasidone adjunctive therapy in improving global cognition (effect size 0·46) was greater compared with the improvement observed in the TAU group (0·04). Adverse events were reported by nine (60%) patients in the luradisone group and two (13%) in the TAU group.Our results provide some preliminary evidence for the efficacy of lurasidone in improving cognition in euthymic patients with bipolar I disorder. The strengths of this study were the characterisation of the sample and use of tests sensitive to cognitive impairment in bipolar disorder. Its limitations were the sample size and inability to completely control for other medication use. Larger double-blind trials are warranted to investigate this further.Sumitomo Dainippon Pharma.

Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.

Management of antipsychotic treatment discontinuation and interruptions using model-based simulations.

BackgroundMedication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.MethodsStarting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.ResultsFollowing complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.ConclusionDue to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.

Predicting Plasma Concentration of Risperidone Associated With Dosage Change

Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.

Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents

This study investigated prolactin levels in two groups of children and adolescents receiving risperidone ( N = 29) or olanzapine ( N = 13). It focused not only on significant differences but also on effect sizes; took into account dose effects and gender differences; used a longitudinal design (months 1, 3, 6 and 12) that helped control for individual differences; and took into account response differences due to the duration of antipsychotic treatment. Additionally, this study investigated tolerance development using statistical tests, and explored the effect of antipsychotic plasma concentrations at months 1 and 3. After adjusting for gender, treatment duration and individual effects, mean prolactin levels on risperidone were 4.9 ng/mL higher than on olanzapine (10.3 times higher after controlling for dosing potency). On risperidone treatment, the adjusted mean prolactin level at the 3rd month of treatment was significantly higher than at the 1st month; at the 12th month it was significantly lower than at the 1st month; the 1st and 6th months were not significantly different. On olanzapine treatment, adjusted mean prolactin levels at the 3rd and 6th months of treatment were significantly higher than at the 1st month; at the 12th month it was lower than at the 1st month, but the difference was not significant. In males, at the 3rd month, an increase of 1 ng/mL in plasma 9-hydroxyrisperidone concentrations raised prolactin levels significantly by 0.44 ng/mL. In females, independently of duration (1 or 3 months), an increase of 1 ng/mL in plasma olanzapine concentrations raised prolactin levels significantly by 2.1 ng/mL. After adjusting for dose and the greater potency of risperidone, the increase in prolactin levels during risperidone treatment appeared to be 10.3 times higher than that during olanzapine treatment. Our study showed a pattern consistent with the development of prolactin tolerance over time. Future prolactin studies in children and adolescents taking antipsychotics need to include larger samples with more frequent prolactin measures and long-term plasma concentrations.

The impact of Cytochrome P450‐2D6 genotype on the use and interpretation of therapeutic drug monitoring in long‐stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice

This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.

Pharmacokinetic optimisation of the treatment of psychosis.

Psychosis is a generic term covering (for the purposes of the present article)) schizophrenia, brief reactive psychoses and manic episodes. Traditionally, research has focused on the effect of antipsychotic agents on positive or productive symptoms such as hallucinations or delusions. More recently, attention has been focused on negative symptoms such as emotional withdrawal or impairment of social participation. Typical antipsychotic medications such as phenothiazines have little effect on these clinical manifestations. This has raised interest in atypical antipsychotics such as clozapine. Acute psychotic episodes are less difficult to treat than long term schizophrenic manifestations. Current research indicates that antipsychotics are effective only if a threshold concentration is reached, but that above a certain level, dose escalation is of no benefit to the patient. This implies the existence of an optimal therapeutic concentration range. Due to interindividual variability caused by age, genetic and interethnic factors or drug-drug interactions, antipsychotic plasma concentrations show a wide range of values for the same dosage regimen. This is why clinical pharmacokinetic principles and therapeutic drug monitoring are essential tools for dosage individualization. Clinical pharmacokinetics in therapeutics implies that the pharmacokinetic parameters of the medication under scrutiny are known. This is, however, not always the case with antipsychotics since, due to the difficulties encountered in conducting phase I studies in healthy volunteers with these substances, published data are not always complete.

Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation

Plasma antipsychotic concentrations were measured in five patients when their anticonvulsant medications were discontinued. Plasma antipsychotic concentrations increased by two- to five-fold at 4 weeks after cessation. All patients demonstrated either moderate or marked improvement as antipsychotic plasma concentrations increased. Four patients experienced extrapyramidal side effects within 30 days of anticonvulsant discontinuation. Careful monitoring of clinical symptoms, adverse effects, and plasma antipsychotic concentrations is recommended.