Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule

RATIONALE: Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. OBJECTIVE: Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. METHOD: Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). RESULTS: Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. CONCLUSIONS: These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.     

Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia. A[123I]-IDEX SPECT study

RATIONALE: In vitro data have shown anticholinergic properties of the atypical antipsychotic drug olanzapine. Substantial occupancy of muscarinic receptors may be an explanation for the low incidence of extrapyramidal side effects induced by olanzapine. OBJECTIVES: To obtain an in vivo measurement of muscarinic receptor occupancy by olanzapine compared with risperidone in patients with schizophrenia stabilised on medication. METHODS: Five patients with schizophrenia treated with olanzapine and five patients treated with risperidone were studied. Muscarinic receptor occupancy in the striatum and cortex was studied in vivo with SPECT using [123I]-IDEX as a radioligand. SPECT data were compared with those of six healthy subjects. RESULTS: Patients stabilised on olanzapine showed significantly lower mean (+/-SD) striatal and cortical (1.50+/-0.21 and 1.51+/-0.22, respectively) muscarinic receptor binding ratios of [123I]-IDEX (reflecting higher levels of muscarinic receptor occupancy) than controls (3.91+/-0.61 and 3.65+/-0.70, respectively). Furthermore, [123I]-IDEX binding ratios in patients treated with risperidone were slightly lower than controls, reaching significance only in the striatum (2.99+/-0.27 versus 3.91+/-0.61, for risperidone and controls). CONCLUSIONS: The substantial occupancy of muscarinic receptors in the striatum and cortex by olanzapine may be an explanation for the low incidence and severity of extrapyramidal side effects of this antipsychotic drug. Furthermore, it may also explain the anticholinergic side effects of olanzapine.     

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.     

Inhibitory effects of clozapine and other antipsychotic drugs on noradrenaline transporter in cultured bovine adrenal medullary cells

The effects of clozapine and other antipsychotic drugs on noradrenaline (NA) transport were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NA transporter. Incubation of adrenal medullary cells with clozapine (30–1000 ng/ml) inhibited desipramine (DMI)-sensitive uptake of [³H]NA in a concentration-dependent manner (IC₅₀=110 ng/ml or 336 nM). Other antipsychotic drugs such as haloperidol, chlorpromazine, and risperidone also decreased [³H]NA uptake (IC₅₀= 144, 220, and 210 ng/ml or 383, 690, and 512 nM, respectively). Eadie-Hofstee analysis showed that clozapine reduced V_max of uptake of [³H]NA and increased K_m. Furthermore, clozapine inhibited specific binding of [³H]DMI to plasma membranes isolated from bovine adrenal medulla (IC₅₀=48 ng/ml or 146 nM). Scatchard plot analysis of [³H]DMI binding revealed that clozapine decreased both B_max and K_d. Other antipsychotic drugs, including haloperidol, chlorpromazine, and risperidone, also reduced [³H]DMI binding to the membranes. In transfected Xenopus oocytes expressing the bovine NA transporter, clozapine inhibited [³H]NA uptake in a concentration-dependent manner similar to that observed in adrenal medullary cells. These results suggest that clozapine and haloperidol directly inhibit transport of NA by acting on the site of an NA transporter that influences both substrate transport and binding of tricyclic antidepressants. Received: 13 April 1999 / Final version: 2 November 1999     

抗精神病药致静坐不能的临床研究

目的　探讨抗精神病药 (APD)致静坐不能的临床特征及相关因素。方法　采用临床标准化评定工具对 2 60例精神分裂症住院病人进行 3个月的观察研究。结果　静坐不能发生率为 2 3 5 % ,不伴焦虑症状者为 3 6 1%。发生时间在治疗后 4周内及下午、晚上较多 (P <0 0 1) ;静坐不能组的APD治疗剂量、治疗前BPRS评分较高 (P <0 0 5或P <0 0 1) ;静坐不能评分与各临床变量无显著相关性。单发组与伴发组临床资料有一定差异 ;心得安治疗静坐不能效果良好 ,单发组疗效优于伴发组 (P <0 0 1) ,而对其他锥体外系症状疗效差。结论　静坐不能发生受生物时间、精神症状、药物及个体素质等因素的影响。静坐不能多数应归属于急性锥体外系反应 ,部分可能为药源性精神副反应的运动不宁状态。作者提出了静坐不能不同类别与处理措施。     

从58例住院精神病人意外死亡看安全用药

目的调查住院精神病人意外死亡情况,以指导临床治疗。方法回顾性调查我院精神科36年间出院病案,对符合意外死亡的病案进行详细统计分析。结果我院36年(1966～2001)来住院精神病人意外死亡58例,占出院病人总数的1.75‰。意外死亡主要为药物治疗中原因不明的猝死17例(29.31%)、自杀12例(20.69%)、意外窒息9例(15.52%)、过度镇静7例(12.07%)、恶性综合征(NMS)6例(10.35%)。意外死亡主要由抗精神病药毒副作用所致,与联合用药、高剂量有关,而氯氮平单一较低剂量治疗中也发生较多猝死。结论单一用药,中小剂量,慎用氯氮平,选用新型抗精神病药,做好心血管监护,加强责任心,提高应急处理能力是避免意外死亡发生的良策。     

精神分裂症老年患者服药依从性和血药浓度检测的意义

目的　探索精神分裂症老年患者服用抗精神病药的依从性与血药浓度的关系及其临床意义。方法　观察 180例门诊中精神分裂症老年患者 ,其中单一服用氯丙嗪 5 8例、奋乃静 6 5例、氯氮平 4 0例、氟哌啶醇 17例。患者于入组后 2周和 3个月末分别检测血药浓度 ,评定其服药依从性、疗效和副反应。结果　应用氯丙嗪、奋乃静或氯氮平者在剂量相仿时 ,其血药浓度为完全依从者高于部分依从者 ,部分依从者高于不依从者 (F检验 ,P <0 0 1)。完全依从者的血药浓度与剂量呈显著性正相关 (Pearson检验 ,r=0 4 3～ 0 6 2 ,P <0 0 5或 <0 0 1)。血药浓度过低者的痊愈 +显著进步率为 5 1 2 % ,远低于血药浓度中 (72 2 % )高 (70 8% )者。血药浓度过高者的副反应发生率达 4 4 6 % ,明显高于血药浓度中 (2 5 0 % )低 (2 3 3% )者。结论　服药依从性与疗效密切相关 ,精神分裂症老年患者的服药依从性评估和血药浓度检测非常重要。     

PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride

Tracer doses of ¹¹C-SCH 23390 and ¹¹C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with ¹¹C-SCH 23390, but not ¹¹C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of ¹¹C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. ¹¹C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.     

Neurocognition in bipolar disorders—A closer look at comorbidities and medications

The last decade has witnessed a growing interest in the neuropsychological study of bipolar disorder (BD). This chronic mood disorder is associated with persistent neurocognitive impairments even during periods of euthymia, particularly in the broad domains of attention, verbal memory and executive functions. More interestingly, cognitive dysfunction seems to predict a poorer functional outcome among BD patients and thus represents an important target for future therapies. The aetiology of cognitive dysfunction is probably multifactorial, including gene-environment interactions with potentially confounding variables as well. Drug-induced cognitive adverse effects represent an important and difficult to examine confounder. This review provides an overview of selected aspects of neurocognition in bipolar disorder with a focus on the relative contributions of medications as well as medical and psychiatric comorbid conditions to cognitive dysfunction. Finally, recommendations for future research in the field are provided including collaborative studies with larger samples, observational follow-up studies, as well as randomized clinical trials comparing head-to-head the neurocognitive impact of different medications.     

住院精神病人精神药物使用情况调查

目的 :了解精神病人用药现状 ,为临床用药提供一定依据。方法 :对某精神病医院 373例住院精神病人用药情况进行时点调查。结果 :使用频率最高的抗精神病药物依次为氯氮平、舒必利、利培酮、氟哌啶醇等 ,单用抗精神病药物 2 5 7例 (6 8 90 % ) ,合并用抗精神病药物 85例(2 2 8% )。结论 :住院精神病人以精神分裂症为主 ,最常用为非典型抗精神病药物 ,单一使用为主 ,其它典型抗精神病药物使用频率已下降