Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5 mg/kg, i.p.), sertindole (0.63, 1.3, 2.5 mg/kg, s.c.) or clozapine (0.5 and 1 mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics — olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.     

Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats

Rationale: Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. Objectives: The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. Methods: Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. Results: Generalization testing revealed full substitution with the atypical antipsychotics olanzapine (90.3% maximum generalization), sertindole (99.8%), and risperidone (87.1%) and partial substitution for quetiapine (seroquel, 66.4%) and the typical antipsychotics haloperidol (56.8%) and thioridazine (74.3%). Remoxipride (23.1%) and the typical antipsychotics chlorpromazine (27.9%) and fluphenazine (29.5%) did not reliably substitute for clozapine. Conclusions: In contrast to previous clozapine drug discrimination studies with higher training doses, the atypical antipsychotics olanzapine, sertindole, and risperidone reliably substituted for clozapine while typical antipsychotics did not. These results suggest that low-dose clozapine drug discrimination may be a more sensitive assay for distinguishing atypical from typical antipsychotic drugs. Received: 3 August 1999 / Final version: 9 December 1999     

Glucose intolerance with atypical antipsychotics.

BACKGROUND: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance. OBJECTIVE: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs. METHODS: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed. RESULTS: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77). CONCLUSION: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.     

Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management

Since chlorpromazine was introduced to the market in the early 1950s, the use of antipsychotic drugs has been associated with venous thromboembolism (VTE) in a number of reports. During the last decade the evidence has been strengthened with large epidemiological studies. Whether all antipsychotics increase the risk for VTE or the risk is confined to certain drugs is still unclear. The aim of this article is to present an updated critical review focusing on the incidence, mechanisms and management of VTE in users of antipsychotics. After searching the databases PubMed and Scopus for relevant articles we identified 12 observational studies, all of which were published after the year 2000. In most of these studies an elevated risk of VTE was observed for antipsychotic drugs, with the highest risk for clozapine, olanzapine and low-potency first-generation antipsychotics. The risk seems to be correlated with dose. The elderly, who mainly use lower doses, do not show an increased risk of VTE to the same extent as younger subjects. The underlying biological mechanisms explaining the association between antipsychotic medication and VTE are to a large extent unknown. Several hypotheses have been proposed, such as body weight gain, sedation, enhanced platelet aggregation, increased levels of antiphospholipid antibodies, hyperprolactinaemia and hyperhomocysteinaemia. The risk of VTE in schizophrenia and other psychotic disorders may also be related to the underlying disease rather than the medication. Very limited evidence exists to guide how cases of VTE in subjects using antipsychotics should be handled. An attempt to compile an algorithm where the patients' individual risk of VTE is assessed and preventive clinical measures are suggested has been published recently. Strong consideration should be given to discontinuation of the offending antipsychotic drug in patients experiencing a VTE, and another antipsychotic drug with a presumably lower risk should be chosen if antipsychotic drug treatment is still indicated. It is essential that physicians and patients are aware that VTE may be an adverse drug reaction to the antipsychotic treatment so the condition is identified early and treated appropriately.     

Different effects of antipsychotic drugs on insulin release in vitro.

The aim of this study was to examine the influence of antipsychotic drugs on insulin release from pancreatic beta cells in vitro. The effect of seven antipsychotics (i.e. chlorpromazine, haloperidol, perphenazine, zuclopenthixol, clozapine, olanzapine and risperidone) in a concentration of 10(-6) M was investigated on basal and glucose-stimulated insulin release. Clozapine increased basal insulin release, whereas haloperidol inhibited glucose-stimulated release and the other five antipsychotics had no significant effects. A possible stimulatory effect of clozapine on insulin release may explain its ability to increase appetite and induce weight gain.     

8种不同非典型抗精神病药严重不良反应对比研究

目的研究8种不同非典型抗精神病药不良反应规律和特点,为临床安全合理用药提供参考。方法收集2015年1月至2019年4月浙江省上报的氯氮平、利培酮、奥氮平、喹硫平、氨磺必利、齐拉西酮、阿立哌唑和帕利哌酮导致的严重不良反应报告1497例,利用Excel软件进行统计并分析。结果非典型抗精神病药不良反应累及系统以肝胆系统损害和神经系统损害为主;不同药物呈现特有的不良反应,如帕利哌酮导致生殖系统损害、氯氮平导致胃肠系统损害、奥氮平导致血液系统损害、氨磺必利导致内分泌系统损害、阿立哌唑导致泌尿系统损害。结论各种非典型抗精神病药不良反应发生广泛,要加强不良反应监测,如定期随访肝功能和B超等。另外,应关注不同药物特有的不良反应,结合患者的基础疾病进行临床合理用药。     

Effects of antipsychotic drugs on operant responding after acute and repeated administration

RATIONALE: The current generation of atypical antipsychotic drugs represents an improvement over traditional ("typical") antipsychotics in many respects. However, a theoretical framework and adequate preclinical models have not yet been developed to predict or explain differences among the atypical antipsychotics, a necessary component of future development. OBJECTIVES: The purpose of the present set of experiments was to identify differences between the acute and subchronic effects of several atypical antipsychotic drugs and the typical antipsychotic haloperidol on operant responding in rats. METHODS: The effects of haloperidol and the atypical antipsychotics clozapine, olanzapine, risperidone, sertindole, quetiapine, remoxipride, and thioridazine were determined in rats trained to respond for food reward under a multiple fixed ratio 30/fixed interval 60 s schedule. A profile of the acute effects of each drug on response rates, response durations, and within-session effects were determined. Next, the dose of each drug that produced 75% suppression of response rates was administered for 16 consecutive days to determine whether or not tolerance would develop to the rate-suppressing effects of that dose. RESULTS: All drugs produced dose-related decreases in response rates. Only haloperidol and risperidone produced significant increases in response duration, while only haloperidol and remoxipride displayed within-session response decrements. Tolerance was evident for clozapine and to a lesser extent thioridazine. CONCLUSIONS: These results illustrate that the current generation of atypical antipsychotics are a heterogeneous group and that operant procedures may be useful for identifying differences preclinically. Specifically, clozapine appears to possess properties that distinguish it from other atypical antipsychotics, particularly after repeated dosing.     

Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice

We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test.Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5 mg/kg; s.c.) or clozapine (0.5 and 1 mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia.     

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit

The aim of this study was to investigate the use of psychotropic medication and therapeutic drug monitoring in a high-security psychiatric unit and to compare the doses and serum concentrations both with the recommended intervals and with the doses and serum concentrations in a control group. One hundred thirty-two patients were admitted in the period from January 2000 to December 2005. All available samples were used when comparing serum concentrations and doses with the recommended ranges. For the comparison of doses and serum concentration-to-dose (C:D) ratios with the control group only 1 sample from each patient was used. A total of 459 analyses of 27 different drugs in samples from 8 women and 73 men were included. The median number of therapeutic drug monitoring analyses per patient was 4 (range 1-29). Thirty-seven of the 81 patients (46%) used 2 or more antipsychotics at the same time. Clozapine, lamotrigine, olanzapine, quetiapine, ziprasidone, and zuclopenthixol were often given in doses above the recommended. The serum levels were frequently above those recommended for clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zuclopenthixol. The serum levels were significantly higher in the study group than in the control group for clozapine, lamotrigine, quetiapine, and zuclopenthixol. The given dose was significantly higher in the study group than in the control group for clozapine, lamotrigine and zuclopenthixol. The C:D ratio was significantly lower in the study group than in the control group for olanzapine but higher for quetiapine. The non-evidence based practice of high-dose polypharmacy with several antipsychotics is widely used in this unit. The use of higher doses in the study group than in the control group was not due to differences in metabolism or adherence to treatment between the 2 groups. The frequent use of therapeutic drug monitoring did not seem to have a great impact on the prescribed doses.     

Clozapine and olanzapine, but not conventional antipsychotics, increase insulin release in vitro.

This study was undertaken to examine the influence of conventional and atypical antipsychotics on insulin release in vitro, using isolated pancreatic islets and insulin-secreting INS-1 cells. The effect of the conventional antipsychotics haloperidol and zuclopenthixol, and the atypical agents clozapine and olanzapine in the concentration of 10(-6) M was investigated on basal and glucose-stimulated insulin release. Both clozapine and olanzapine increased basal insulin release, whereas zuclopenthixol inhibited glucose-stimulated release and haloperidol had no significant effect. In summary, clozapine and olanzapine, in contrast to conventional antipsychotics, increase basal insulin release. Interestingly, this stimulatory effect on insulin release in vitro may be supported by recent clinical findings, showing elevated insulin levels in patients being treated with clozapine or olanzapine.     

Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia

This review focuses on the comparative safety and efficacy profile of nine atypical antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine), which may ultimately affect the therapeutic options available for patients with schizophrenia. These antipsychotic compounds differ markedly in their potential to impact a number of quality-of-life measures. Furthermore, their differential effects on anxiety disorders, treatment-resistant depressive illness, cognitive functions and manic disorders may influence the selection of atypical antipsychotics for conditions associated with schizophrenia. The possible relevance of these parameters in evaluating the risk/benefit equation and probable involvement of varying receptor mechanisms is also discussed.     

Tolerability of atypical antipsychotics.

Atypical antipsychotics are expected to be better tolerated than older antipsychotics because of their lower propensity to cause certain adverse effects. All atypical drugs have been shown to cause fewer acute extrapyramidal symptoms (EPS) than a standard typical agent (usually haloperidol) and some (clozapine, sertindole and quetiapine) appear to cause these effects no more often than placebo. In the longer term, clozapine, olanzapine and (less robustly) other atypical antipsychotics are thought to cause less tardive dyskinesia than typical antipsychotics. Problems caused by hyperprolactinaemia occur less often with some atypical antipsychotics than with typical drugs although risperidone and amisulpride appear to have no advantages in this respect. Other adverse effects may occur as frequently with some atypical antipsychotics as with some typical drugs. Clozapine, risperidone and quetiapine are known to cause postural hypotension; clozapine, olanzapine and quetiapine are clearly sedative; and anticholinergic effects are commonly seen with clozapine, and, much less frequently, with olanzapine. Some adverse effects are more frequent with atypical drugs. Idiosyncratic effects seem particularly troublesome with clozapine and, to a lesser extent, sertindole, olanzapine and zotepine. Bodyweight gain is probably more problematic with atypical antipsychotics than with typical drugs. Overall tolerability, as judged by withdrawals from therapy, is not clearly proven to be better with atypical drugs, although some individual trials do indicate an advantage with atypical agents. Differences in tolerability between individual atypical antipsychotics have not been clearly shown. The tolerability profile of atypical drugs certainly benefits from a lower incidence of acute EPS effects, along with less certain or less uniform benefits in symptomatic hyperprolactinaemia or tardive dyskinesia. Other, perhaps more trivial, adverse effects militate against their good tolerability, and effects such as bodyweight gain may severely reduce tolerability. Without clear advantages in tolerability in patient groups used in trials, drug choice in regard to adverse effects should continue to be on a patient to patient basis.     

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

Clozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.     

Antipsychotics lack alpha 1A/B adrenoceptor subtype selectivity in the rat.

The alpha1A- and alpha1B-adrenoceptor affinity of the typical (chlorpromazine, haloperidol, pimozide, thioridazine and trifluoperazine) and atypical (clozapine, olanzapine, quetiapine, risperidone and sertindole) antipsychotics was determined by competition binding at alpha1A- and alpha1B-adrenoceptors in rat submaxillary gland and liver. Although all antipsychotics bound to both subtypes with relatively high affinity (K(i)s<74 nM), none were selective (>10-fold). Comparison with published dopamine D2 receptor affinities suggests that antipsychotic blockade of alpha1A- and/or alpha1B-adrenoceptors may contribute to the antipsychotic activity of all the atypical and several of the typical antipsychotics examined.     

Effects of typical and atypical antipsychotics on glucose–insulin homeostasis and lipid metabolism in first-episode schizophrenia

Rationale Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.Objectives The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.Materials and methods One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.Results After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.Conclusions This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.     

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study

RATIONALE: Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. OBJECTIVES: To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. METHODS: Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). RESULTS: Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. CONCLUSIONS: The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.     

Antipsychotic-induced type 2 diabetes: evidence from a large health plan database

Case evidence suggests that some of the atypical antipsychotics may induce type 2 diabetes. The objective of this study was to evaluate the association of antipsychotic treatment with type 2 diabetes in a large health plan database. Claims data for patients with psychosis within a health plan of nearly 2 million members were analyzed using logistic regression. Frequencies of newly treated type 2 diabetes in patients untreated with antipsychotics and among patients treated with quetiapine, risperidone, olanzapine, and conventional antipsychotics were compared. Based on exposure measured in months of antipsychotic treatment, quetiapine and risperidone patients had estimated odds of receiving treatment for type 2 diabetes that were lower than those of patients untreated with antipsychotics (not statistically significant); patients treated with conventional antipsychotics had estimated odds that were virtually equivalent to those of patients untreated with antipsychotics; olanzapine alone had odds that were significantly greater than those of patients untreated with antipsychotics (P = 0.0247). Odds ratios based on 8 months of screening for pre-existing type 2 diabetes and assuming 12 months of antipsychotic treatment were: risperidone = 0.660 (95% CI 0.311-1.408); olanzapine = 1.426 (95% CI 1.046-1.955); quetiapine = 0.976 (95% CI 0.422-2.271); and conventional antipsychotics = 1.049 (95% CI 0.688-1.613). Case reports, prospective trials, and other retrospective studies have increasingly implicated olanzapine and clozapine as causing or exacerbating type 2 diabetes. Few have implicated risperidone while evidence on quetiapine has been limited. This study supports earlier findings on risperidone versus olanzapine and builds evidence on quetiapine. Additional studies are needed to evaluate the association of antipsychotic treatment with type 2 diabetes.     

非典型抗精神病药物血液系统不良事件信号挖掘和数据分析

目的 基于美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）挖掘6种非典型抗精神病药物氯氮平、奥氮平、阿立哌唑、喹硫平、利培酮、齐拉西酮血液系统不良事件（ADE）信号,为临床安全使用非典型抗精神病药物提供参考。方法 下载2017年第1季度—2021年第3季度共19个季度的FAERS数据,采用比值失衡法中的报告比值比（ROR）法和综合标准法（MHRA）检测数据库中非典型抗精神病药物的ADE信号,统计并分析血液系统ADE信号的相关信息。结果 从FAERS数据库得到以氯氮平、奥氮平、阿立哌唑、利培酮、喹硫平、齐拉西酮6种非典型抗精神病药物为首要怀疑药物的ADE共389431例次,涉及报告病例116706例。血液系统ADE报告共计47144例次,涉及报告病例9658例。氯氮平产生血液系统信号22个,涉及报告病例6808例;奥氮平产生血液系统信号19个,涉及报告病例736例;喹硫平产生血液系统信号18个,涉及报告病例560例;阿立哌唑产生血液系统信号8个,涉及报告病例60例;利培酮产生血液系统信号3个,涉及报告病例16例;齐拉西酮产生血液系统信号1个,涉及报告病例5例。结论 基于真实世界的非典型抗精神病药物血液系统ADE信号挖掘有助于开展安全性评价,为临床安全应用提供参考。     

Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics

In the rat, selective suppression of conditioned avoidance response has been widely reported as a test with high predictive validity for antipsychotic efficacy. Recent studies have shown that the relationship between dopamine D2 receptor occupancy and the suppression of conditioned avoidance response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity of the present conditioned avoidance response procedure, in vivo striatal dopamine D2 receptor occupancy was determined in parallel using 3H-raclopride as the radioligand. The PK/PD relationship was established by modelling the time-response and time-plasma concentration data. We found the order of dopamine D2 receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone>clozapine. Overall, a good agreement was observed between the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK/PD model may act as a guide for determining effective plasma concentrations of potential antipsychotics in the clinical setting and thereby accelerating the overall drug development process.