Comparison of hippocampal G protein activation by 5-HT<Subscript>1A</Subscript> receptor agonists and the atypical antipsychotics clozapine and S16924

This study employed [³⁵S]guanosine 5-O-(3-thiotriphosphate) ([³⁵S]GTPS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT_1A receptors with those of reference agonists at postsynaptic 5-HT_1A receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, E_max, values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC₅₀) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT_1A receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT_1A receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [³⁵S]GTPS binding, consistent with partial agonist properties. In [³⁵S]GTPS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT_1A receptors, was more potent in the septum (pEC₅₀~6.5) than in the dentate gyrus of the hippocampus (pEC₅₀~5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 µM) did not enhance [³⁵S]GTPS labelling in any structure, S16924 (10 µM) modestly increased [³⁵S]GTPS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 µM)-stimulated [³⁵S]GTPS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT_1A receptors in the hippocampus. These data support a role of postsynaptic 5-HT_1A receptors in the functional profiles of certain antipsychotic agents.     

Effects of sub-chronic antipsychotic drug treatment on body weight and reproductive function in juvenile female rats

Rationale Weight gain caused by some antipsychotics is not only confined to adults but can also adversely affect both children and adolescents. Indeed, olanzapine and risperidone have been associated with extreme weight gain in adolescents even greater than that reported in adults. We have recently shown substantial weight gain in adult female rats following treatment with olanzapine and risperidone but not ziprasidone. Objectives The aim of the present study was to compare the effects of several antipsychotics on weight gain and reproductive function in juvenile (aged 7 weeks) female hooded Lister rats. Methods Olanzapine (4 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), sulpiride (10 mg/kg), haloperidol (0.5 mg/kg) or vehicle was administered i.p. once per day for 21 days. Body weight, food and water intake were measured daily, in addition to the determination of stage of the oestrous cycle. Results Sub-chronic administration of olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone, significantly increased body weight compared to vehicle-treated animals during weeks 1–3. Sulpiride significantly increased food and water intake. Significantly increased percentage intra-abdominal fat weight was observed in olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone-treated animals. Marked disruption of the oestrous cycle was observed in all but the ziprasidone-treated group, which continued to have regular 4-day oestrous cycles. Conclusions Weight gain observed in these juvenile animals was 1.5–2 times greater than that previously observed in adult rats. These findings have important implications for the use of antipsychotics in children and adolescent patients.     

Randomized,controlled, double-blind,multicenter comparison of the cognitive effects of ziprasidone versus olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder

Background Newer antipsychotic medications have been reported to enhance cognitive functioning in schizophrenia. Head to head studies with double-blind methods are still relatively few in number.Objectives To compare the relative cognitive enhancing effects of ziprasidone and olanzapine in the treatment of acutely ill inpatients with schizophrenia or schizoaffective disorder.Procedures In this 6-week, multicenter, double-blind, parallel-designed trial, patients were randomized to ziprasidone or olanzapine. No patient who had ever received a complete treatment trial with either of these medications previously was entered into the study. Cognitive testing measuring attention, motor speed, memory, executive functioning, and verbal skills were performed on all patients at baseline and endpoint.Results Treatment with either ziprasidone or olanzapine was associated with statistically significant improvements from baseline in attention, memory, working memory, motor speed, and executive functions. Treatment with olanzapine was also associated with a statistically significant improvement in verbal fluency. No statistically significant differences between these medications were found in the magnitude of improvement from baseline on any of the cognitive measures (other than verbal fluency in an exploratory analysis). Observed changes were not associated with changes in clinical symptoms measured using the PANSS or changes in movement disorders.Conclusions During 6 weeks of treatment, ziprasidone and olanzapine demonstrated substantial and comparable cognitive-enhancing effects relative to previous treatment. These effects were noted in all aspects of cognitive functioning previously proven to predict functional outcome in schizophrenia. No overall differences were detected between the medications in terms of the extent of cognitive enhancement.     

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors

The atypical antipsychotic olanzapine was compared to other atypical as well as typical antipsychotic agents for in vivo occupancy of D₁, D₂, D₃, 5HT₂, and muscarinic receptors in rat brain. Blockade of D₂ receptors was determined by measuring the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). To assess the interaction with phosphoinositide (PI)-coupled 5HT_2A and muscarinic receptors in vivo, we used a novel radiometric technique to measure in vivo PI hydrolysis. The antagonism of olanzapine and other antipsychotic agents on 5HT_2A and muscarinic receptors was determined by in vivo blockade of PI hydrolysis, stimulated by the 5HT₂ agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or the muscarinic agonist pilocarpine. Olanzapine inhibited 5HT₂, D₂, and D₃ in vivo binding with high potency (ID₅₀ = 0.15, 0.6 and 1.2 mg/kg, IP, respectively), while inhibiting D₁ and muscarinic in vivo binding with much less potency (ID₅₀ > 10 mg/kg, IP). The binding of olanzapine to D₂ receptors in neostriatum was well correlated with the increase of DOPAC (ED₂₀₀ = 0.8 mg/kg, IP) in vivo, indicating dopamine D₂ antagonism. In vivo PI hydrolysis was increased by DOI in frontal cortex and by pilocarpine in hippocampus up to 2- and 7-fold above the basal level, respectively. The agonist-induced increases in PI hydrolysis were fully blocked by the 5HT_2A antagonist MDL100907 and the muscarinic antagonist scopolamine, indicating the mediation by 5HT_2A receptors in frontal cortex and PI-coupled muscarinic receptors (m1, m3, and m5) in hippocampus, respectively. Olanzapine was about 8-fold more potent in vivo in blocking DOI-induced stimulation of PI hydrolysis (ID₅₀ = 0.1 mg/kg, IP) than pilocarpine-induced stimulation of PI hydrolysis (ID₅₀ = 0.8 mg/kg, IP). In conclusion, olanzapine is more potent in blocking the 5HT_2A receptor than D₁, D₂, D₃ and muscarinic receptors in vivo, consistent with its favorable clinical profiles. In addition, the novel in vivo PI hydrolysis assay proved to be a useful and reliable in vivo method to assess the functional efficacy of compounds that interact with the 5HT₂ and muscarinic receptors. Received: 10 February 1998/Final version: 22 April 1998     

齐拉西酮联合心境稳定剂治疗双相障碍躁狂发作和混合发作

目的：研究和探讨齐拉西酮合并碳酸锂或丙戊酸钠治疗躁狂发作和混合发作的疗效和安全性。方法：对符合CCMD-3躁狂发作和混合发作诊断标准的68例研究对象随机分成两组,试验组应用齐拉西酮合并碳酸锂或丙戊酸钠,对照组单一使用碳酸锂或丙戊酸钠,治疗观察6周。采用杨氏躁狂量表（YMRS）评定疗效,以副反应量表（TESS）及实验室有关辅助检查评价安全性。 结果：两组在治疗前后症状均有显著降低（F＝9.05,P＜0.01;F＝6.10,P＜0.01）。齐拉西酮组在治疗第1周末的减分率比对照组显著,这种差异在1~6周持续存在,而且第6周结束后的临床痊愈率也显著高于对照组。研究组1周末、治疗2周末、治疗4周末、治疗6周末YMRS分别是21.4±8.4,14.6±5.5,8.9±3.3,6.5±3.4,对照组分别是23.9±7.2,20.9±8.1,17.8±7.8,12.8±8.9,组间差异有统计学意义（P＜120.01）,试验组的相对变化分别是6.1±3.5,12.9±4.8,20.1±5.3,21.4±5.5,对照组分别是2.1±3.0,6.8±4.5,11.5±5.6,14.4±5.3,组间比较差异有统计学意义（P＜0.01）。两组间有效率差异有统计学差异（68.5%,48.5%, X2=4.47,P＜0.05）。两组间痊愈率也有统计学意义（54.3%, 18.2%, X2=9.52,P＜0.01）。但是两组间均没有严重的药物副作用,因无疗效和副作用导致的脱落率两组差异无显著性。结论：齐拉西酮合并碳酸锂或丙戊酸钠治疗躁狂发作和混合发作双相障碍的疗效比较理想,比单一使用心境稳定剂更好。     

齐拉西酮治疗32例女性精神分裂症患者不良反应观察

目的 探讨齐拉西酮对女性精神分裂症患者的安全性.方法 收集32例女性精神分裂症患者,给予齐拉西酮治疗观察6周,分别于治疗前及治疗后第2、4、6周末进行实验室及心电图检查,探讨该药对女性精神分裂症患者血脂、血糖、体重及心电图的影响.结果 治疗后精神分裂症患者甘油三酯、胆固醇及体重均较治疗前有明显升高,差异具有统计学意义（P＜0.05）;治疗4周后精神分裂症患者QT及QTC间期均较治疗前有显著延长,差异具有统计学意义（P＜0.05）.结论 齐拉西酮对女性精神分裂症患者血脂、体重及QT间期影响较大,对血糖影响较小.     

齐拉西酮对精神分裂症患者生活质量的影响

目的比较齐拉西酮与氟哌啶醇对精神分裂症患者生活质量的影响。方法对门诊74例服用氟哌啶醇及72例服用齐拉西酮的精神分裂症患者用生活质量综合评定问卷(GQOLI),阳性症状及阴性症状量表(PANSS),副反应量表(TESS)进行调查、分析。结果齐拉西酮组患者的生活质量优于氟哌啶醇组。结论齐拉西酮治疗精神分裂症更有利于患者提高生活质量和适应社会。     

齐拉西酮合并阿米替林治疗难治性抑郁症的临床研究

目的观察齐拉西酮合并阿米替林治疗难治性抑郁症的疗效和毒副作用。方法根据入院顺序分层随机法,将60例难治性抑郁症患者平均分为研究组（齐拉西酮＋阿米替林）和对照组（阿米特林＋安慰剂）,在治疗前、治疗后4、8、12周末分别用汉密尔顿抑郁量表（HAMD）、总体疗效量表（CGI）和副反应量表（TESS）评定疗效和毒副作用。结果治疗4周后研究组HAMD总分及各因子分比治疗前明显降低,且治疗因子分显著低于对照组,治疗后4、8、12周末TESS评分,4周末研究组高于对照组,8、12周末两组无显著差异。结论齐拉西酮合并阿米替林治疗难治性抑郁症疗效确切。     

齐拉西酮门诊治疗精神分裂症疗效观察

目的了解齐拉西酮门诊治疗精神分裂症的疗效和不良反应。方法选取用齐拉西酮治疗的门诊精神分裂症患者70例,分别在治疗前及用药后4、8、12周末用PANSS量表和TESS量表评价疗效和不良反应。结果治疗12周后PANSS总分及各因子评分均显著下降（P〈0．005）;有效率为81．4％,主要不良反应为失眠,无一例QTc期≥500ms。结论齐拉西酮门诊治疗精神分裂症安全有效,可明显改善患者阳性和阴性症状,有利于预防复发和恢复患者的社会功能;并且可以持续改善代谢功能,对患者体重无影响,可降低心脑血管发生和死亡风险。     

齐拉西酮与奋乃静治疗急性精神分裂症对照研究

目的观察齐拉西酮治疗急性精神分裂症的临床疗效及安全性。方法将64例急性精神分裂症患者随机分为2组,各32例,研究组口服齐拉西酮,对照组口服奋乃静治疗,观察6周。于治疗前及治疗后第2周、4周、6周末采用阳性与阴性症状量表（positive and negative syndrome scale,PANSS）评定临床疗效,以副反应量表（TESS）评定不良反应。结果在第2周末评分研究组比对照组有显著下降,在第6周末2组评分均显著下降,差异无显著性;研究组不良反应发生率低于对照组,且程度较轻。结论齐拉西酮治疗急性精神分裂症起效快,疗效好,不良反应轻,安全性高。