Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine

Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT₃ antagonist ondansetron or non-selective 5-HT_2A/2C antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0-6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10 mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction “circuit” by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT₃ or 5-HT₂ antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.     

Efficacy and withdrawal of clobazam, lorazepam and buspirone in the treatment of anxiety disorders

This multicentre study was conducted to evaluate the efficacy and consequences of progressive or abrupt withdrawal of clobazam in the treatment of Generalized Anxiety Disorder in a double blind study in comparison to lorazepam and buspirone. 128 outpatients suffering from Generalized Anxiety Disorder according to DMS III criteria were included in the study and treated for three weeks. They were randomly divided into 4 groups: group 1: 32 patients receiving clobazam, abruptly withdrawn and replaced by a placebo; group 2: 29 patients receiving clobazam with progressive withdrawal over 3 weeks, clobazam being replaced by a placebo; group 3: 33 patients receiving lorazepam with progressive withdrawal over 3 weeks, lorazepam being replaced by a placebo; group 4: 34 patients receiving buspirone, abruptly withdrawn and replaced by a placebo. The dosages were increased progressively during the first week of treatment. At the end of this time, the patients received either 30 mg clobazam or 30 mg buspirone or 3 mg lorazepam daily. After the first week, the Hamilton Anxiety Rating Scale (HARS) showed a significant improvement in clobazam and lorazepam groups but not in buspirone group. All the drugs were equally effective after three weeks of treatment. The anti-anxiety activity persisted after withdrawal of the studied drug in the 4 groups, without any signs of rebound anxiety or withdrawal syndrome. No clinically relevant differences were found between the 4 groups regarding safety. The side-effects reported were mainly drowsiness in clobazam and lorazepam groups, nausea and headache in buspirone group. In conclusion, clobazam like lorazepam improved anxiety more quickly than buspirone; after 3 weeks of therapy, efficacy was comparable with the 3 drugs and persisted after treatment discontinuation.     

Interactions between anxiety, social support, health status and buspirone efficacy in elderly patients

Psychosocial factors are among the etiological factors of anxiety, and have been shown to affect the anxiolytic efficacy of buspirone in laboratory rodents. Disparate human studies suggest that a similar interaction may be valid for anxious patients. However, this interaction is poorly known at present. It was hypothesized that social support and health status are especially relevant psychosocial problems in elderly, and as such, have a large impact on both anxiety and the efficacy of anxiolytic treatment with buspirone. The hypothesis was assessed by three independent studies performed in a total number of 384 elderly in-patients (109 males, 275 females, age approximately 80 years). A low number of social contacts associated with a large number of diseases proved to be a strong risk factor for anxiety, whereas the reverse condition (many contacts/few diseases) was associated with considerably lower Hamilton Rating Scale for Anxiety (HAM-A) scores. Buspirone ameliorated anxiety significantly in general, but the "many contacts/many diseases" condition was associated with twice as much improvement as the "few contacts/few diseases" condition. The patient's self-evaluation of health status was predicted strongly by the disease score used in the above two studies. Taken conjointly, data suggest that the major Axis-IV problems faced by the age class studied (social support and health status) have a strong effect on both anxiety and buspirone responsiveness in elderly patients. Thus, drug responses appear to be modulated by nonpharmacological factors, and research directed towards identifying such factors would provide information important to a more appropriate patient targeting of certain medications.     

丁螺环酮治疗老年焦虑症临床对照研究

目的探讨丁螺环酮治疗老年焦虑症的疗效及安全性。方法68例老年焦虑症患者随机分为两组,分别给予丁螺环酮和阿普唑仑治疗,疗程6周。使用汉密尔顿焦虑量表（HAMA）评定疗效,利用治疗中出现的症状量表（TESS）和实验室检查评价不良反应。结果丁螺环酮与阿普唑仑疗效相当,不良反应丁螺环酮较阿普唑仑少而轻。结论丁螺环酮治疗老年焦虑症疗效好,不良反应少,值得临床推广。     

丁螺环酮治疗广泛性焦虑症对照研究

目的：探讨国产丁螺环酮对广泛性焦虑症的治疗效果及不良反应。方法：对105例诊断为广泛性焦虑症的患者，随机分为丁螺环酮组(52例)和多虑平组(53例)，治疗6周。在入组前、治疗第1、2、4、6周末分别予汉密尔顿焦虑量表(HAMA)和副反应量表(TESS)评定疗效和不良反应。结果：丁螺环酮与多虑平抗焦虑作用相近，起效时间稍慢，无明显镇静作用，对焦虑症状有疗效。不良反应有口于、便秘、恶心等，不影响治疗。结论：国产丁螺环酮治疗广泛性焦虑症疗效确切，不良反应轻微。     

普萘洛尔对焦虑症的辅助治疗作用

目的：观察帕罗西汀联合普萘洛尔治疗焦虑症的临床疗效和不良反应。方法：205例广泛性焦虑患者随机分为研究组105例（帕罗西汀联合普萘洛尔治疗）,对照组100例（单用帕罗西汀治疗）,疗程6周。采用汉密尔顿焦虑量表（HAMA）、临床疗效总评量表（CGI）评定临床疗效;采用治疗中出现的症状量表（TESS）评定安全性。结果：研究组和对照组治疗总有效率分别为87.8%和75.5%,两组比较差异有统计学意义（P〈0.05）。研究组治疗2、4、6周时的HAMA减分率均高于对照组（P均〈0.01）。研究组头痛、心动过速、震颤等不良反应均较对照组少而轻。结论：帕罗西汀联合普萘洛尔治疗广泛性焦虑症具有良好的疗效和安全性,且优于单用帕罗西汀。     

The comparative efficacy of buspirone and diazepam in the treatment of anxiety.

In this double-blind study, 56 adult psychoneurotic outpatients with a primary diagnosis of anxiety neurosis were randomly assigned to receive buspirone (N = 18), diazepam (N = 20), or placebo (N = 18) over a four-week period. A battery of tests administered weekly indicated that buspirone, a new agent not chemically related to any currently marketed drugs, was as effective an antianxiety agent as diazepam and produced no more and perhaps fewer side effects. Buspirone showed excellent antidepressant effects as well. If further studies confirm the authors' findings and determine that buspirone does not result in tolerance and addiction, it would be more advantageous than the benzodiazepines in the treatment of anxiety.     

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder.

BACKGROUND: The objective of this randomized, double-blind study was to compare the efficacy and safety of venlafaxine extended release (XR) and buspirone in outpatients with generalized anxiety disorder (GAD) but without concomitant major depressive disorder. METHOD: Male and female outpatients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with either venlafaxine XR (75 or 150 mg/day), buspirone (30 mg/day in 3 divided doses), or placebo for 8 weeks. The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale (CGI) scores. Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale (HAD). RESULTS: The efficacy analysis included 365 patients and the safety analysis, 405. At week 8, adjusted mean HAM-A psychic anxiety, anxious mood, and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients. On the HAD anxiety subscale, venlafaxine XR, 75 or 150 mg/day, was significantly more efficacious than placebo at all time points except weeks 1 (both dosages) and 2 (150-mg/day dosage only) and significantly more efficacious than buspirone at all time points except week 1. On the CGI-Improvement scale, scores for venlafaxine XR (both dosages) and buspirone were numerically superior to those for placebo at all time points, and statistical significance was observed at weeks 3, 4, 6, and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone. The adverse events were not essentially different between treatment groups. CONCLUSION: Venlafaxine XR is an effective, safe, and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder. This agent was significantly superior to buspirone on the HAD anxiety subscale. Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response.     

A trial of buspirone for anxiety in Parkinson's disease: Safety and tolerability

IntroductionIn Parkinson's disease (PD), anxiety is common, associated with lower health-related quality of life, and undertreated. The primary objective of this study was to determine the tolerability of buspirone for the treatment of anxiety in PD.MethodsIndividuals with PD and clinically significant anxiety were randomized 4:1 to flexible dosage buspirone or placebo for 12 weeks. Treatment was initiated at 7.5 mg twice daily and titrated based on response and tolerability to an optimal dosage (maximum 30 mg twice daily). The primary outcome was the proportion of participants who failed to complete the study on study drug. Secondary outcomes included adverse events, dosage reductions, motor function, dyskinesias, and anxiety.ResultsA total of 21 participants enrolled, 4 were randomized to placebo and 17 to buspirone (mean (SD) age 65.5 (9.8), 76.5% male, 88% on concomitant antidepressant or anxiolytic). In the buspirone group, 7 (41%) failed to complete the study on drug, 5 due to intolerability. The median buspirone dosage was 7.5 mg twice daily. No serious adverse events occurred. A total of 9 (53%) buspirone participants experienced adverse events consistent with worsened motor function. In the buspirone group, mean (SD) improvement from baseline to week 12 in Hamilton Anxiety Rating Scale was −3.9 (3.8) and Parkinson Anxiety Scale −7.1 (6.4).ConclusionTolerability concerns do not support moving immediately forward with a large-scale efficacy trial. However, concomitant anxiolytics may have affected tolerability and a signal of efficacy was seen suggesting that future studies of buspirone monotherapy be considered.     

Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder

BACKGROUND: An earlier preliminary report suggested that prior treatment with benzodiazepines might predict a reduced response to buspirone in patients diagnosed with generalized anxiety disorder (GAD). To confirm or refute this hypothesis, the present data analysis was conducted. METHOD: One large data set (N = 735) of GAD patients (DSM-III) treated with buspirone, a benzodiazepine, and a placebo was analyzed by dividing all patients into 3 prior benzodiazepine (BZ) treatment groups: no prior BZ treatment, recent (< 1 month) BZ treatment, and remote (> or = 1 month) BZ treatment. Using an intent-to-treat last-observation-carried-forward (LOCF) data set, acute 4-week treatment response was assessed in terms of clinical improvement, attrition, and adverse events as a function of these 3 prior benzodiazepine treatment groups. RESULTS: Patient attrition was significantly higher (p < .05) in the recent BZ treatment group than in the remote and no prior BZ treatment groups with lack of efficacy given as the primary reason by patients receiving buspirone but not benzodiazepine or placebo. In the buspirone group, adverse events occurred more frequently in the recent BZ treatment group than in the remote BZ treatment and no prior BZ treatment groups. Finally, clinical improvement with buspirone was similar to benzodiazepine improvement in the no prior BZ treatment and remote BZ treatment groups, but less than benzodiazepine improvement in the recent BZ treatment group, leading to the smallest buspirone/placebo differences in improvement in the recent BZ treatment group. CONCLUSION: These data suggest that the initiation of buspirone therapy in GAD patients who have only recently terminated benzodiazepine treatment should be undertaken cautiously and combined with appropriate patient education.     

丁螺环酮治疗广泛性焦虑症临床分析

目的：探讨丁螺环酮治疗广泛性焦虑症的疗效和不良反应。方法：对50例临床诊断为广泛性焦虑症的病人用丁螺环酮治疗4周，采用Hamilton焦虑量表(HAMA)及副反应量表(TESS)进行评定。结果：丁螺环酮治疗广泛性焦虑症的有效率90．7％，显效率55．9％；主要不良反应是轻微的口干及头昏和头晕等，偶可致窦性心律不齐。结论：丁螺环酮治疗广泛性焦虑症有效，不良反应轻微。     

Effect of buspirone on sexual dysfunction in patients with generalized anxiety disorder

After 4 weeks' treatment with buspirone, sexual function was normalized in 8 of 10 patients with generalized anxiety disorder. Nine of the patients had reported decreased sexual function before treatment. Buspirone appears to offer a clinical advantage over existing anxiolytics, which are usually associated with impairment of sexual function.     

丁螺环酮与丙咪嗪治疗广泛性焦虑症的对照研究

目的　比较丁螺环酮与丙咪嗪治疗广泛性焦虑症的疗效与不良反应。方法　将 70例符合CCMD 3诊断标准的广泛性焦虑症患者 ,随机分为两组 ,分别应用丁螺环酮或丙咪嗪治疗 6周 ,采用焦虑自评量表(SAS)、Hamilton焦虑量表 (HAMA)和不良反应量表 (TESS)进行疗效及不良反应评定。结果　丁螺环酮与丙咪嗪对广泛性焦虑症的治疗均有显著疗效 ,但疗效差异无显著性 ,(χ2 =0 .12 9,P >0 .0 5 ) ,丁螺环酮的不良反应明显低于丙咪嗪 (t=4 .73,P <0 .0 1)。结论　丁螺环酮治疗广泛性焦虑症安全有效 ,副作用小     

Explorative single-blind study on the sedative and hypnotic effects of buspirone in anxiety patients

In this single-blind study the sedative and hypnotic properties of buspirone, a nonbenzodiazepine anxiolytic, were investigated in 8 anxious outpatients. Polysomnographic recordings were gathered during baseline, at the start of active medication, after 3 weeks of treatment and one night after discontinuing treatment. Daytime alertness was measured using the Multiple Sleep Latency Test and performance tests. The effects of buspirone on sleep structure were minimal and of no clinical consequence. Subjectively, the patients reported improved sleep quality. There were no effects on daytime alertness at the beginning, after 3 weeks or at sudden discontinuation of the medication. It is concluded that buspirone does not have a sedative or hypnotic effect in anxiety patients.     

A clinical trial of buspirone and diazepam in the treatment of generalized anxiety disorder

In double-blind trials with hundreds of patients, buspirone has proven to be as effective an anxiolytic as the benzodiazepines. It causes less sedation and motor impairment than diazepam, and may be particularly useful in geriatric patients. We conducted a 4 week double-blind, randomized trial of buspirone versus diazepam and placebo in thirty adult outpatients with generalized anxiety disorder. Maximum doses were 40 mg of diazepam or buspirone or eight placebo tablets a day. There were no significant differences in outcome between the three groups on any physician or subject measures. Some implications of this finding are discussed.