丁螺环酮对难治性精神分裂症治疗的增效作用

目的:探讨丁螺环酮对难治性精神分裂症(TRS)治疗的增效作用与安全性。方法:80例TRS患者随机分入合用组(氯氮平+丁螺环酮)和氯氮平组,每组40例,观察治疗12周。采用阳性和阴性症状量表(PANSS)和治疗中出现的症状量表(TESS)分别评定临床疗效和不良反应。结果:在治疗2、4、12周,合用组临床疗效优于对照组(P均<0.05);两组干预后各因子积分和总分均较入组前显著下降(P均<0.001);阳性因子积分和总分,干预与时间存在交互效应(P<0.01);总分存在组间差别(P<0.05);同期对照比较,除入组后8周阴性因子积分和12周阴性因子和一般精神病理因子积分外,其余各时点各因子积分和总分,合用组减分幅度大于对照组(P<0.05)。不良反应总发生率两组间差异无显著性(P>0.05)。结论:丁螺环酮对氯氮平治疗难治性精神分裂症有一定的增效作用,且不增加不良反应。     

Outcomes on the pharmacopsychometric triangle in bupropion-SR vs. buspirone augmentation of citalopram in the STAR*D trial

Bech P, Fava M, Trivedi MH, Wisniewski SR, Rush AJ. Outcomes on the pharmacopsychometric triangle in bupropion‐SR vs. buspirone augmentation of citalopram in the STAR*D trial. Objective: To compare within the framework of a novel pharmacopsychometric triangle, augmentation treatment with bupropion vs. buspirone in the acute therapy of major depression in the STAR*D study. The triangle provides a composite view in three domains of antidepressive activity, side effects, and quality of life. Method: Within the pharmacopsychometric triangle, the short six‐item subscales of the Hamilton Depression Scale (HAM‐D₁₇) and of the Inventory of Depressive Symptomatology (IDS‐C₃₀), referred to as HAM‐D₆ and IDS‐C₆, were focussed on pure antidepressive effect. Side‐effects (tolerable vs. intolerable) and quality of life were measured using patient‐administered questionnaires. A modified intention to treat sample was used. Results: Within the pharmacopsychometric triangle, bupropion‐SR (sustained release) was superior to buspirone when augmented to the current citalopram treatment. Thus, in the domain of pure antidepressive effect, bupropion‐SR was superior (P = 0.05) on the HAM‐D₆, IDS‐C₆, and IDS‐C₃₀, but not on the HAM‐D₁₇. In the domain of side effects, the total scores on the Patient Rated Inventory of Side Effects (PRISE) were reduced significantly more by bupropion‐SR than by buspirone (P = 0.03). In the domain of quality of life, the total scores on the Quality of Life Enjoyment and Satisfaction Questionnaire (QLES‐Q) showed a trend (P = 0.10) from baseline to endpoint of a superiority for bupropion‐SR compared with buspirone. Conclusion: In all domains of the pharmacopsychometric triangle, bupropion‐SR was superior to buspirone as augmentation therapy in depressed outpatients not responding to citalopram.     

丁螺环酮治疗焦虑性障碍的Ⅲ期临床研究

目的 :对丁螺环酮治疗焦虑性障碍的疗效及不良反应进行评价。方法 :对符合中国精神疾病分类方案与诊断标准第二版修订版 (CCMD 2 R)的广泛性焦虑症及符合广泛性焦虑症症状学诊断标准的伴有其他疾病的 1 496例病人 ,口服丁螺环酮治疗 4wk ,剂量 5～ 60mg·d-1。疗效及不良反应评定使用HAMA ,TESS及有关实验室检查。结果 :治疗后HAMA减分率为 (62±3 1 ) % ,显效率在 5 0 %以上 ,不良反应发生率为 2 5 .87% ,主要为头昏、恶心、口干、失眠等。结论 :丁螺环酮治疗焦虑性障碍疗效确切 ,不良反应较少     

Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.     

温胆安神汤联合丁螺环酮治疗抑郁症的临床效果及对患者认知功能的影响

目的探讨温胆安神汤联合丁螺环酮治疗抑郁症的临床效果及对患者认知功能的影响。方法选取我院2018年1月至2019年1月收治的500例抑郁症患者作为研究对象,按电脑随机数字表法分为对照组(250例,丁螺环酮治疗)和试验组(250例,温胆安神汤+丁螺环酮治疗)。比较两组患者的症状评分、情绪改善情况及认知功能。结果治疗后,两组患者的各项症状评分均降低,且试验组明显低于对照组,差异具有统计学意义(P<0.05)。治疗后,两组患者的汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)评分均降低,且试验组明显低于对照组,差异具有统计学意义(P<0.05)。治疗后,两组患者的蒙特利尔认知评估量表(MoCA)各项评分及总分均升高,且试验组明显高于对照组,差异有统计学意义(P<0.05)。结论温胆安神汤联合丁螺环酮治疗抑郁症的临床效果显著,可有效改善患者症状及情绪状况,并提升患者认知功能。     

Differential regulation of intestinal and hepatic CYP3A by 1α,25-dihydroxyvitamin D3: Effects on in vivo oral absorption and disposition of buspirone in rats

1α,25-Dihydroxyvitamin D₃ (also called 1,25(OH)₂D₃ or calcitriol) is the biologically active form of vitamin D, which functions as a ligand to the vitamin D receptor (VDR). It was previously reported that intestinal cytochrome P450 3A (CYP3A) expression was altered by 1,25(OH)₂D₃-mediated VDR activation. However, to clarify whether the change in CYP3A subfamily expression by VDR activation can affect metabolic function, further evidence is needed to prove the effect of 1,25(OH)₂D₃ treatment on CYP3A-mediated drug metabolism and pharmacokinetics. Here, we report the effects of 1,25(OH)₂D₃ on CYP3A activity and in vivo pharmacokinetics of buspirone in Sprague–Dawley rats. CYP3A mRNA expression and CYP3A-mediated testosterone metabolism were enhanced in the intestine but were unaffected in the livers of rats treated with 1,25(OH)₂D₃. Notably, the oral pharmacokinetic profile of buspirone (CYP3A substrate drug) and 6′-hydroxybuspirone (major active metabolite of buspirone formed via CYP3A-mediated metabolism) was significantly altered, while its intravenous pharmacokinetic profile was not affected by 1,25(OH)₂D₃ treatment. To the best of our knowledge, this study provides the first reported data regarding the effects of 1,25(OH)₂D₃ treatment on the in vivo pharmacokinetics of intravenous and oral buspirone in rats, by the differential modulation of hepatic and intestinal CYP3A activity. Our present results could lead to further studies in clinically significant CYP3A-mediated drug–nutrient interactions with 1,25(OH)₂D₃, including 1,25(OH)₂D₃–buspirone interaction.

Buspirone improves the anti-cataleptic effect of levodopa in 6-hydroxydopamine-lesioned rats

In Parkinson's disease (PD), prolonged exposure to L-3,4-dihydroxyphenylalanine (L-DOPA) results in motor fluctuations, such as the on-off phenomenon, and L-DOPA-induced dyskinesia. Previously, we found that activation of 5-HT(1A) in the substantia nigra pars compacta (SNc) decreased catalepsy in parkinsonian rats. In the current investigation, we attempted to evaluate the effect of buspirone on the anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned male Wistar rats. Catalepsy was induced by the unilateral infusion of 6-OHDA (8 μg/2 μl/rat) into the central region of the SNc. After a 3-week recovery period, rats received L-DOPA intraperitoneally (ip; 15 mg/kg) twice daily for 20 days, and the anti-cataleptic effect of L-DOPA was assessed by the bar test at days 5, 10, 15 and 20. The results showed that L-DOPA had an anti-cataleptic effect only until day 15, and its effect was abolished on day 20. On day 21, these rats were co-treated with three different doses of buspirone (0.1, 0.5 and 2.5 mg/kg, ip) and L-DOPA (15 mg/kg, ip). At a dose of 0.5 mg/kg, buspirone improved the anti-cataleptic effect of L-DOPA. Furthermore, the effect of buspirone (0.5 mg/kg, ip) on the anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was reversed by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine hydrobromide (NAN-190; 0.5 mg/kg, ip), a 5-HT(1A) receptor antagonist. From these results, it may be concluded that buspirone improves the anti-cataleptic effect of L-DOPA in a 6-OHDA-induced animal model of PD through the activation of 5-HT(1A) receptors. In this regard, further investigations should be undertaken to clarify the exact mechanism of the interaction between 5-HT(1A) and dopaminergic neurons.     

Randomized,single‐blind,trial of sertraline and buspirone for treatment of elderly patients with generalized anxiety disorder

Aim: Generalized anxiety disorder (GAD) in elderly people is common, but few systematic studies regarding the best treatments have been performed. The aim of the present study was to evaluate the efficacy and safety of sertraline and buspirone in the treatment of elderly patients with GAD. Methods: Based on selection criteria, 46 patients were recruited who met DSM‐IV criteria for GAD. Patients were randomly assigned to sertraline (50–100 mg/day) or buspirone (10–15 mg/day) for 8 weeks in a single‐blind trial. The primary outcome measure used in the present study was the Hamilton Rating Scale for Anxiety (HRSA). Results: Both sertraline and buspirone had significant anxiolytic efficacy. A steady decrease in the total HRSA scores for both groups was observed throughout the study period. After 2 and 4 weeks, buspirone was found to be significantly superior to sertraline (P < 0.001), but at the end of study period this difference did not reach statistical significance (P = 0.16). The mean HRSA score after 8 weeks significantly decreased in subjects treated with sertraline (P < 0.001), and buspirone (P < 0.001). No clinically adverse events or changes in laboratory test results were observed during the study period. Conclusion: Both sertraline and buspirone appear to be efficacious and well tolerated in the treatment of GAD in elderly patients. Further studies with larger sample size, evaluating the effect of medical illness, cognitive impairment, depression, and combined therapy with support and psychotherapy are needed.     

N-alkyl-substituted aryl-piperazine drugs: Relationship between affinity for serotonin receptors and inhibition of aggression

Buspirone is the first of several N-alkyl-substituted aryl-piperazine-containing drugs to be approved for use as an anxiolytic agent. These drugs do not interact with the benzodiazepine-GABA receptor complex and therefore do not share the sedating and anticonvulsant effects of benzodiazepines. Buspirone and its analogs, gepirone and ipsapirone, act as agonists both pre- and postsynaptically at 5HT_la receptor sites. A series of piperazine-containing drugs was tested for their affinity at the 5HT_la (postsynaptic) binding sites in hippocampus and compared with their ability to inhibit isolation-induced aggression by mice. The potent 5HT_la agonist, 8-OH-DPAT, was the most potent drug in both tests: IC₅₀ = 1 nM, and ED₅₀ = 2.4 μmol/kg for inhibition of [³H]-5HT binding and aggression, respectively. There was a good correlation between ability to inhibit aggression and ability to inhibit [³H]-5HT binding to hippocampal membranes. Fluprazine (DU 27716) was the major exception, but results with SKF 525-A pretreatment to inhibit drug oxidation suggest that both fluprazine and metabolites have antiaggressive activity. Like other aryl-piperazine drugs, fluprazine is potentiated by coadministration of a postsynaptic 5HT receptor antagonist, methysergide. Since antagonists of postsynaptic 5HT receptors potentiate gepirone and 8-OH-DPAT inhibition of aggression, these data suggest that affinity for 5HT_la receptors at presynaptic autoreceptor sites is critical for the antiaggressive activity of these drugs and possibly for their anxiolytic effects.     

Effect of 5-HT1A receptor agonists on amino acid- and dopaminergic responses of neurons

Department of General and Clinical Pharmacology, M. Gor'kii Donetsk Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR P. V. Sergeev.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 12, pp. 609–610, December, 1991.