Figure 1 - uploaded by Matcheri Keshavan
Content may be subject to copyright.
Percent D2 receptor occupancy as a function of plasma olanzapine concentrations at 4 Weeks after Injection of 300 mg OP Depot (N=14). The regression line has been fit to the rectangular hyperbole equation: occupancy=Emax (plasma concentration/(plasma concentration+EC50)), where Emax is the maximum receptor occupancy with an estimated EC50 (SD)=11.01.3 ng/ml.

Percent D2 receptor occupancy as a function of plasma olanzapine concentrations at 4 Weeks after Injection of 300 mg OP Depot (N=14). The regression line has been fit to the rectangular hyperbole equation: occupancy=Emax (plasma concentration/(plasma concentration+EC50)), where Emax is the maximum receptor occupancy with an estimated EC50 (SD)=11.01.3 ng/ml.

Source publication
Article
Full-text available
A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D(2) receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizo...

Context in source publication

Context 1
... ¼ 14), reflecting the occupancy of the oral olanzapine dose of the study group (15.274.8 mg/day). Over the entire study period, an expected curvilinear asymptotic significant relationship was found between plasma olanzapine con- centrations and D 2 receptor occupancy (r ¼ 0.76, Pp0.001) (Figure 1). These data were fitted to the equation described in the Patients and Methods section to yield a concentration associated with 50% of maximal occupancy (EC 50 ) of 11.071.3 ...

Similar publications

Article
Full-text available
Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in he...

Citations

... It was found that oral supplementation was needed in half the patients for the first 4 months. 22 The authors concluded that this could indicate that oral supplementation of olanzapine or a higher dose or frequency of injections could be required. 22 It is notable that secondary care community mental health services refused to accept two patients (5%) prescribed OLAI at discharge from inpatient care, as they were not able to provide the required 3 h PIS monitoring, giving the clinician no option but to discontinue the otherwise effective OLAI. ...
... 22 The authors concluded that this could indicate that oral supplementation of olanzapine or a higher dose or frequency of injections could be required. 22 It is notable that secondary care community mental health services refused to accept two patients (5%) prescribed OLAI at discharge from inpatient care, as they were not able to provide the required 3 h PIS monitoring, giving the clinician no option but to discontinue the otherwise effective OLAI. As discussed, the incidence of PIS is reported as less than 0.1% in the Summary of Product Characteristics, supported by a study reporting a rate of 0.044%. ...
Article
Full-text available
Background Olanzapine pamoate has been shown to be an effective second-generation long-acting injection. Its popularity has possibly been adversely affected by the rare incidence of post-injection syndrome (PIS) and the associated requirement to monitor for 3 h after each injection. Objective This study aimed to collect and present data on the use of olanzapine long-acting injection (OLAI) over a 10-year period in a high-security forensic hospital in South East England. Design This was a non-interventional retrospective study collecting information from anonymised electronic patient and prescription records. As per hospital Trust guidelines, patient consent to access of hospital records was presumed unless explicitly withdrawn. Method All patients prescribed OLAI between the years 2009 and 2019 were identified. Data collected included date that OLAI was started, stopped, dose range, side effects and concomitant medication. Results Of 88 patients who were started OLAI, 45 (51%) continued at month 24. At 60 months, 22 of 70 (31%) patients for whom data were available continued with OLAI. Over 60% of continuers were on higher than recommended doses. Of almost 5000 injections administered, there was 1 episode of PIS. Conclusion OLAI is an effective treatment for schizophrenia and schizoaffective disorder, especially when used in patients have been able to tolerate the drug and were stabilised on it for 24 months. In over half the patients who continued OLAI, the doses were higher than that recommended by the manufacturer. The incidence of PIS in this study was very low in comparison with other studies. Registration code 2049
... 21,22 Furthermore, the TEAEs reported were in line with those observed in previous studies with Risperidone ISM 4,5 and the overall dropout rate was also in agreement with those reported in other studies with antipsychotics. [23][24][25] Most treatment-related TEAEs reported were mild or moderate in severity, leading to study drug discontinuation in only two subjects (2.5%), one due to sedation whilst receiving oral treatment and one due to akathisia following a Risperidone ISM dose. ...
Article
Full-text available
Introduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment. Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone. Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.
... Furthermore, the D2 receptors occupancy was found to correlate directly with the plasma concentrations of olanzapine [40]. ...
... It was demonstrated that patients affected by schizophrenia and treated with antipsychotics have a good clinical response when the D2 occupancy rate is between 65 and 80%, while over 80% patients show extrapyramidal side effects and hyperprolactinemia [44,45]. D2 receptor occupancy in relation to LAI SGA plasma concentrations was mainly investigated by PET in small-sample studies of patients treated with risperidone [34][35][36], with the exception of the study by Mamo and collaborators [40] who tested olanzapine and also performed the longest follow-up. All the studies found a positive association between receptor occupancy and LAI SGA plasma concentrations [40] or dose [35,36]. ...
... D2 receptor occupancy in relation to LAI SGA plasma concentrations was mainly investigated by PET in small-sample studies of patients treated with risperidone [34][35][36], with the exception of the study by Mamo and collaborators [40] who tested olanzapine and also performed the longest follow-up. All the studies found a positive association between receptor occupancy and LAI SGA plasma concentrations [40] or dose [35,36]. Of note, Uchida and coauthors proposed a non-linear association between D2 receptor occupancy and LAI risperidone plasma concentrations [34]. ...
Article
Atypical antipsychotic depot medications are currently recommended for patients with schizophrenia (SCZ) to prevent relapse and ameliorate the long-term prognosis of these patients. This review critically summarizes the available data about the association between the plasma concentrations of long-acting SecondGeneration Antipsychotics (SGAs) and the clinical effectiveness of these compounds in patients affected by SCZ or schizoaffective disorder. Our question is if the measurement of these concentrations can be helpful for clinicians in predicting treatment response and clinical stabilization of patients. Bibliographic research on the main databases was performed, and 13 studies were finally included in this review. Contrasting results were found between plasma concentrations of long-acting injectable (LAI) risperidone and clinical amelioration according to rating scale scores. Data are too scanty to draw conclusions for olanzapine and paliperidone. In contrast, despite small sample sizes, data are quite concordant in showing a relation between long-acting SGA plasma concentrations and D2 receptor occupancy. Despite the preliminary encouraging results, particularly for D2 receptor occupancy, future research with larger samples will have to confirm the clinical usefulness of measuring LAI SGA plasma concentrations to predict the clinical response of patients affected by severe mental conditions such as SCZ.
... Among SGAs, only PET studies including active drug concentrations in blood for olanzapine pamoate and risperidone microspheres were available. [79][80][81][82] For LAIs of novel compounds such as paliperidone and aripiprazole, researchers often extrapolated TDM findings supported by PET evidence from oral to LAI. 46,83 However, studies available for risperidone and olanzapine clearly illustrate a relationship between plasma concentrations and D 2 /D 3 receptor occupancy, which can ...
... Evidence from molecular imaging studies suggested that some patients could be adequately treated with 10-15 ng/mL, which would be slightly lower than recommended. 62,73 For olanzapine pamoate, only one trial was available, 80 which was conceptualized as a dosefinding study by the manufacturer; in this study, 14 patients stabilized on oral olanzapine were ...
Article
Purpose: The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, as well as in maintenance treatment. Methods: The authors critically reviewed three types of data: 1) positron emission tomography (PET) data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, 2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and 3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. Results: Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations, as these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including co-medications and comorbidities. Reported data combined with PET evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. Conclusions: Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.
... mg/d in those whose PL are ,20 ng/mL and have not achieved a favorable response. Notably, there were studies [6][7][8][9] included in this review that were also separately cited by the AGNP guidelines. ...
... Some patients on the LAI required oral supplementation, but that need diminished when occupancy 60% was attained. 6 In the other study, 25 patients were studied to determine clinical efficacy and tolerability of OLZ LAI in relation to PL and clinical outcome in the maintenance phase of schizophrenia. Over 9 months, all patients received either 210, 300, or 405 mg every 4 weeks. ...
Article
Full-text available
Introduction: In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States. Methods: The Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine-4 antipsychotics commonly used in the United States with a "strong recommendation" for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges. Results: Olanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges. Discussion: Several limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.
... Some patients who respond to first-line antipsychotic treatment experience diminished treatment efficacy over time (23), which can lead to treatment non-compliance and relapse (81). Diminished antipsychotic efficacy may also occur despite stable D 2 receptor occupancy (82). These dynamics are depicted in Figure 1. ...
... Some patients who respond to first-line antipsychotic treatment experience diminished treatment efficacy over time (23), which can lead to treatment non-compliance and relapse (81). Diminished antipsychotic efficacy may also occur despite stable D 2 receptor occupancy (82). These dynamics are depicted in Figure 1. ...
Article
Full-text available
Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.
... Olanzapine pamoate is a nearly insoluble salt designed for aqueous based injection, with multiple dosing options available. 38,39 The kinetic profile of various approaches to achieve a steady state on a dose of 300 mg/4 weeks is illustrated in Figure 8. 20 The expected steady state plasma level for 300 mg/4 weeks is approximately 30 ng/ ml, and for 205 mg/2 weeks or 410 mg/4 weeks is 45 ng/ ml. 40 Severe sedation often requiring hospitalization occurred in approximately 2% of patients in the clinical trials with onset 30-300 minutes after injection. ...
Article
There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.
... When adhered to, standard antipsychotic treatment regimens in the clinic produce continuously high levels of D 2 occupancy. This is the case both when medication is taken orally every day (Farde et al., 1989) and when long-acting injectable antipsychotics are injected intramuscularly (Mamo et al., 2008;Remington et al., 2006). In rats, striatal D 2 occupancy declines significantly 24 h following a single s.c. ...
Article
Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16–17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity.
... Olanzapine LAI was associated with D2 receptor occupancy of approximately 60%. 5 Other LAI antipsychotics including haloperidol decanoate and risperidone LAI 6,7 occupy a higher percentage of dopamine D2 receptors. There are currently no data for paliperidone and aripiprazole LAIs. ...
... The available evidence indicates that MPH administration may increase or decrease seizure frequency in patients with epilepsy. 5 In a previous case report, a child with severe attention-deficit/hyperactivity disorder and unidentified cortical malformation developed status epilepticus on the 10th day of osmotic release oral system MPH 36 mg/d use. 6 The authors proposed that the effects of MPH on sleep latency might be related with the development of status epilepticus. ...