Discriminative stimulus effects of alprazolam and diazepam: generalization to benzodiazepines, antidepressants and buspirone

Rats in one group were trained to discriminate alprazolam (1.0mg/kg, i.p.) and in another group diazepam (3.0mg/kg, i.p.) from saline in a two-lever drug discrimination procedure. Food presentation occurred after 10 consecutive responses on the lever associated either with the training drug or with saline. Alprazolam, diazepam, lorazepam and chlor diazepoxide increased responding on the drug-associated lever in a comparable dose-related manner in both groups of rats: the relative order of potency was lorazepam >/= alprazolam > diazepam >/= chlordiazepoxide. Flumazenil (10.0mg/kg, i.p.) attenuated the effects of the training drugs. A range of doses of buspirone and four drugs having antidepressant properties (amitriptyline, fluoxetine, cericlamine, imipramine) then were studied in both groups of rats. All five drugs caused approximately 40% increases (group mean) in drug-appropriate responding in alprazolam-trained rats whereas only amitriptyline partially substituted for diazepam. The results indicate that alprazolam has interoceptive stimulus effects that overlap with the stimulus effects of diazepam, yet the effects of alprazolam may not be identical to those of diazepam because the antidepressant drugs and buspirone substituted partially for alprazolam but generally not for diazepam.     

The effects of alprazolam and buspirone in light and moderate female social drinkers

Individuals who are moderate/heavy drinkers are at increased risk to abuse benzodiazepines and this risk is increased in women compared to men. However, no studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of benzodiazepines compared to female light drinkers (LD). Fourteen female MD who consumed an average of 36 drinks/month were compared to 14 female LD who consumed an average of 4.2 drinks/month. None of the participants had either a first- or second-degree family history of alcoholism. The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg) and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures and subjective-effects questionnaires. Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. There were few differences between LD and MD with respect to subjective response or performance impairment following either alprazolam or buspirone. Although MD reported greater ratings of Good Drug Effect and Drug Liking than LD, this was neither dose-related, nor specific to alprazolam. The results of the present study suggest that female MD without a family history of alcoholism experience the same level of performance impairment as female LD, although they tend to report greater positive subjective effects from alprazolam.     

A comparison of the single-dose effects of alprazolam, buspirone, and placebo upon memory function.

The effects of alprazolam and buspirone at varying dosages were compared with placebo in a battery of memory and cognitive tests in a sample of 125 young, healthy medical students by utilizing a single-dose, double-blind design. Although the dosages in this study did not impair visuomotor reaction time in any of the experimental groups, 1.0 mg of alprazolam did result in significantly impaired performance on selective aspects of memory function as assessed by the memory battery.     

Metergoline abolishes the prolactin response to buspirone

Pretreatment of nine healthy subjects with the non-selective 5-HT receptor antagonist, metergoline (4 mg), abolished the increase in plasma prolactin produced by the anxiolytic drug, buspirone (15 mg). While these findings are consistent with a role for 5-HT receptors in the stimulatory effect of buspirone on plasma prolactin, a dopaminergic mechanism cannot be excluded by the present data.     

The relationship of alprazolam dose to steady-state plasma concentrations

Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM-III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and alpha-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as responders within the 60 ng/ml and above group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral response to buspirone in cocaine and phencyclidine withdrawal

The effects of buspirone in treating cocaine and phencyclidine (PCP) withdrawal were studied. Withdrawal symptoms of these two street-drugs are thought to be due to norepinephrine, dopamine and possibly serotonin depletion. Buspirone acts by enhancing dopaminergic and noradrenergic firing as well by suppressing serotonergic activity. Thirty-two cocaine abusers and 24 PCP abusers were withdrawn over a 30-day period. Half of each group received buspirone 10 mg t.i.d. and the other half 10 mg placebo t.i.d. In the cocaine group, buspirone was significantly more effective from the fifth day onward. In the PCP group, significant improvement was seen on the thirtieth day. Delayed effectiveness in PCP is thought due to its actions at other neurotransmitter sites.     

Switching to amisulpride

The introduction of atypical antipsychotics represents an important advance in the treatment of schizophrenia. As their therapeutic efficacy, tolerability and safety profiles are clearly superior to classical neuroleptics, atypical antipsychotic agents are considered to be the treatment of choice in first episode patients. In addition, an increasing number of patients are being switched from classical to atypical antipsychotic agents. Switching is especially relevant in patients with a poor therapeutic response to classical neuroleptics and persistent symptoms (positive symptoms, negative symptoms, depressive syndromes, cognitive deficit); in patients with a psychotic relapse despite compliance; in patients with important side-effects (not only acute and tardive extrapyramidal symptoms [EPS] and general side-effects, but also dysphoria or neuroleptic-induced deficit syndrome [NIDS]); and in patients who are non-compliant due to side-effects. Switching to atypical antipsychotics should be performed with extreme care in stabilised patients; or in patients who present a danger to themselves or others at relapse; or in patients who are on depot neuroleptics who were non-compliant to previous oral treatment. Switching requires careful planning to reduce the risk of withdrawal effects (neuroleptic withdrawal syndrome, cholinergic rebound, exacerbation of symptoms or relapse, rebound of parkinsonism, dystonia, akathisia, dyskinesia), which may mask the beneficial effects and lead to early discontinuation of the new treatment. Patients, family and carers should be actively involved at all stages, and educated about the possible benefits and problems associated with switching therapy. Cross-tapering old and new treatment is the preferred method for switching and this involves tapering off the previous antipsychotic agent and any adjunctive treatment (sedatives, anticholinergic medication), while gradually titrating the new atypical antipsychotic agent to the established therapeutic dose. Switching patients to amisulpride treatment offers effective antipsychotic therapy, with a positive effect on negative and depressive symptoms. Amisulpride treatment also results in improved quality of life and social functioning in addition to fewer relapses and days of hospitalisation during long-term follow-up.     

抗焦虑新药—丁螺环酮的临床应用

在过去２０年中 ,对焦虑症状疾患的治疗中大量使用了三环类 (多虑平 )和苯二氮类药物 (ＢＺＤ) ,然而 ,随着这类药物应用的增加 ,人们对其副作用和安全性的认识亦越来越多。已知多虑平有较强的抗胆碱能及心血管方面的副作用 ,因而限制了它的临床应用 ;ＢＺＤ除可引起认知功能损害外 ,长期使用可产生药物依赖 ,停药时可产生严重的戒断症状。因此 ,临床医生普遍试图寻找一种安全性更大 ,副作用更小 ,即使长期使用也不会引起依赖的新抗焦虑药物。丁螺环酮于１９７２年由Ｗａ和Ｒａｙｂｕｒｍ首次合成 ,目前该药已由重庆西南制药总厂正式投产…     

Clinical notes on buspirone

The main aspects of the recent development of non-benzodiazepine anxiolytic drugs are the following: the possibility of giving drugs with peculiar anxioselective profile and with no benzodiazepine side-effects; the possibility of discriminating the anxiolytic from the hypnotic activity; the possibility of a nosographic delimitation: buspirone is used mainly in the treatment of generalized anxiety disorders. All these factors point to the possibility of a guided or planned anxiolysis with a more active participation from the patients.     

Effects of alprazolam, caffeine, and zolpidem in humans trained to discriminate triazolam from placebo

This study compared the discriminative stimulus effects of zolpidem, a nonbenzodiazepine hypnotic, to benzodiazepines. Eight participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. The discriminative stimulus effects, self-reported subjective effects, and performance effects of triazolam (0.05-0.35 mg/70 kg), alprazolam (0.25-1.75 mg/70 kg), zolpidem (2.5-35 mg/70 kg) and caffeine (75-525 mg/70 kg) were assessed under two-response and novel-response drug discrimination procedures. Under the two-response procedure, triazolam, alprazolam and zolpidem fully substituted for triazolam and caffeine did not. Under the novel-response procedure, triazolam and alprazolam substituted for triazolam and zolpidem partially substituted for triazolam. Zolpidem, but not triazolam or alprazolam, also produced some novel responding. Caffeine produced both placebo-appropriate and novel responding. The self-reported effects of triazolam, alprazolam and zolpidem were similar. Overall, zolpidem produced similar, but not identical, effects as the benzodiazepines.     

Switching from other agents to extended-release carbamazepine in acute mania

There is a dearth of available knowledge relating to the efficacy of switching from one psychotropic agent to another in treating patients with acute mania. Methods: This is a post hoc analysis of data from two randomized, placebo-controlled trials of carbamazepine extended-release capsules (CBZ-ERC) in the treatment of mania, to evaluate the efficacy of CBZ-ERC in patients previously nonresponsive to lithium (n 5 40), olanzapine (n 5 38), or valproate (VPA, n 5 77). Results: In patients previously on lithium, Young Mania Rating Scale (YMRS) scores improved significantly from baseline to end point (27.4 6 SD 3.5 vs. 15.8 6 11.1; P 5 .0002). In patients previously on VPA or olanzapine, YMRS scores significantly improved in both CBZ-ERC- and placebo-treated groups (VPA: CBZ-ERC, P , .0001; placebo, P 5 .0002; olanzapine: CBZ-ERC, P , .0001; placebo, P 5 .0054). Improvement in YMRS was significantly greater in CBZ-ERC-treated patients versus placebo in subjects previously nonresponsive to lithium (CBZ-ERC 11.6 6 10.3 vs. placebo 4.0 6 11.2, P 5 .03), or VPA (CBZ-ERC 10.8 6 11.9 vs. placebo 5.7 6 9.2; P 5 .04), and trending to be greater for those previously nonresponsive to olanzapine (olanzapine 13.2 6 9.3 vs. placebo 7.3 6 9.7, P 5 .06). Conclusions: CBZ-ERC is an effective therapy for bipolar patients previously nonresponsive to lithium or valproate. Medication switch is frequently associated with symptom improvement.     

A review of alprazolam withdrawal

A cumulative review of case reports in the literature describing withdrawal reactions secondary to alprazolam is presented. In four of eight reports, the primary withdrawal manifestations were grand mal seizures. One case was characterized by painful myoclonus. In the remaining three cases, the major complications consisted of rebound anxiety with psychotic features. Despite tapering of the daily dosage according to manufacturer guidelines, a withdrawal syndrome was precipitated in three of the cases. As a result of alprazolam's atypical pharmacodynamic profile, the issue is raised as to whether alprazolam is pharmacologically cross-tolerant with other benzodiazepines.     

Prolactin response to buspirone was reduced in violent compared to nonviolent parolees

A neuroendocrine challenge procedure was carried out in male and female parolees. The parolees were divided into violent and non-violent groups based upon their criminal history. Buspirone (0.4 mg/kg), a 5-HT_1a agonist, was used as the challenge agent and plasma prolactin levels were determined. The violent parolees had a blunted prolactin response compared to the non-violent parolees. While reduced serotonergic activity may account for this difference, the pharmacology of buspirone and control of prolactin release suggest a role for dopamine. A reduced serotonergic response would be consistent with a large body of data linking reduced serotonin function and aggressive behavior. While the mechanism is not definite, these data clearly provide evidence for an altered and blunted biological response in parolees with a history of violence. Received: 31 March 1998/Final version: 28 August 1998     

Discriminative stimulus properties of alprazolam

Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality. Received: 7 March 1999 / Final version: 22 June 1999     

Absence of effect of food on alprazolam absorption from sustained release tablets

This study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavailabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7.2 h while fasting and 7.0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.