The effect of glucocorticoids on the anxiolytic efficacy of buspirone

RATIONALE: The serotonergic system and the hypothalamus-hypophysis-adrenocortical axis reciprocally influence each other. Therefore, the interaction between stress and serotonergic anxiolytics should be of major concern for both laboratory investigations and clinical treatment. OBJECTIVES: We have studied the effects of the serotonergic anxiolytic buspirone in rats in which basal levels of glucocorticoids were low and stable, while acute stress reactions were inhibited or exogenously induced. METHODS: Rats were adrenalectomised. Subcutaneous corticosterone pellets maintained basal glucocorticoid concentrations while acute changes were mimicked by corticosterone injections. Anxiety was assessed by the social interaction test. Temporal changes were evaluated by submitting rats to the same manipulations three times at two-day intervals. RESULTS: Buspirone applied to animals with stable and low plasma glucocorticoid concentrations induced a dramatic increase in social interactions. A slight locomotor suppressive effect was also noticed. The effects of buspirone proved to be stable over time in these animals. Acute treatment with corticosterone doubled the locomotor suppressive effects of buspirone and reversed its anxiolytic effects: the buspirone-corticosterone combination was anxiogenic after the first application. During the second and third treatment, the impact of corticosterone on buspirone efficacy gradually decreased, but the combined treatment remained about half as effective in reducing anxiety as buspirone alone.     

Anti-conflict efficacy of buspirone following acute versus chronic treatment

In many animal studies, acute treatment with the novel anxiolytic agent buspirone exhibits only minimal anxiolytic efficacy (i.e., increases in punished responding) when compared to benzodiazepines and barbiturates. The present studies examined the effects of acute pre-test challenges with buspirone in subjects receiving chronic post-test buspirone or saline treatments. Chronic post-test treatment with buspirone (4 mg/kg/day for 4 weeks, followed by 8 mg/kg/day for 12 weeks) did not significantly affect CSD behavior. Consistent with previous reports, acute pre-test administration of buspirone (0.125–2 mg/kg, IP) to subjects receiving chronic post-test saline treatment resulted in only a modest anti-conflict effect in the CSD paradigm (approximately ten shocks over control). In contrast, subjects chronically treated with buspirone exhibited a dramatically greater anti-conflict effect following acute challenge with buspirone (up to 40 shocks over control). These data are consistent with the hypothesis that the full anxiolytic efficacy of buspirone requires repeated administration.     

Pharmacological and clinical effects of buspirone

Clinical trials have demonstrated that buspirone (BuSpar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or chlorazepate. Buspirone has a unique structure and a pharmacologic profile which distinguishes it from the benzodiazepines. Because it lacks the anticonvulsant, sedative, and muscle-relaxant properties associated with other anxiolytics, buspirone has been termed "anxioselective." Animal studies suggest that it lacks potential for abuse, and this finding is supported by clinical investigations. Further preclinical work supports the contention that buspirone lacks liability to produce physical dependence or to significantly interact with central nervous system depressants such as ethanol. Moreover, biochemical investigations have not identified any direct interaction of buspirone with the benzodiazepine-gamma-aminobutyric acid-chloride ionophore complex. Pharmacologic studies on the molecular level indicate that buspirone interacts with dopamine and serotonin receptors. Recent behavioral, electrophysiological, and biochemical studies have clearly demonstrated that early hypotheses that buspirone might be considered a neuroleptic are no longer tenable. Recent evidence indicates that other neurotransmitter systems (serotonin, norepinephrine, acetylcholine) mediate buspirone's effects. It is hoped that future studies can define the mechanism by which buspirone alleviates the clinical manifestations of anxiety.     

A critique of recent studies on placebo effects of antidepressants: importance of research on active placebos

RATIONALE: Limited published data show that drug efficacy can be influenced by stressors. Thus, drug testing in stressed animals may unravel important variables determining drug effects. OBJECTIVES: The experiments tested the anxiolytic efficacy of the benzodiazepine chlordiazepoxide under conditions of acute stress. METHODS: Previously group-housed rats were injected with 0, 3, and 10 mg/kg chlordiazepoxide, thereafter being exposed to two types of stress: novelty (transfer to an individual cage) and social defeat. Controls were group-housed animals. Anxiety was assessed on the plus maze. RESULTS: Speed of locomotion was increased by chlordiazepoxide in both stressed groups but not in controls. Chlordiazepoxide exerted a marked reduction in anxiety in controls and defeated rats but not in novelty exposed animals. The effects of novelty exposure were considerably weaker when drug testing was performed 24 h later. CONCLUSIONS: Stress exposure had an impact on the behavioral effects of chlordiazepoxide. Changes in locomotor activity induced by the drug appear to depend on the presence of a stressor, while anxiolytic efficacy appears to depend on the type of the stressor. Since it has been shown that drug efficacy changes in a variety of behavioral situations and drug classes, it is suggested that experimental background is an important variable in determining behavioral effects of drugs.     

Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone

Rationale Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P ₄₅₀ (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice.Objectives The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs.Methods Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration.Results Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC (P<0.001) and 20% increase in the elimination half-life (P=0.0012) of 1-PP. Deramciclane did not potentiate the buspirone-induced increase in prolactin secretion. No significant differences were found in the psychomotoric testing or the subjective maximum sedation between the deramciclane phase and the placebo phase, either before or after buspirone administration. Of 16 subjects, 5 experienced dizziness during both study phases.Conclusion Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramciclane and a single dose of buspirone.     

丁螺环酮与帕罗西汀联合治疗焦虑症患者的临床效果探讨

目的探讨焦虑症患者应用丁螺环酮联合帕罗西汀治疗的临床效果。方法 80例焦虑症患者,采用抽签法分为对照组和观察组,每组40例。对照组患者采用帕罗西汀治疗,观察组患者采用丁螺环酮联合帕罗西汀治疗。比较两组患者的治疗效果、治疗前后焦虑自评量表(SAS)评分以及治疗期间不良反应发生情况。结果观察组患者的治疗总有效率为95.00%,显著高于对照组的75.00%,差异具有统计学意义(P<0.05)。治疗前,两组患者SAS评分比较差异无统计学意义(P>0.05);治疗后,两组患者的SAS评分均显著低于本组治疗前,且观察组低于对照组,差异均具有统计学意义(P<0.05)。观察组患者治疗期间不良反应发生率为5.00%,显著低于对照组的20.00%,差异无统计学意义(P<0.05)。结论焦虑症患者采取丁螺环酮联合帕罗西汀治疗,能够提高治疗效果,改善焦虑状态,同时减少用药不良反应。     

Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats

Background

There are no approved pharmacotherapies for preventing psychomotor stimulant relapse. The operant reinstatement model has been suggested as a screen for identifying candidate medications. The present study examined if the anxiolytic buspirone could attenuate reinstatement of extinguished responding in Long–Evans rats that previously self-administered intravenous cocaine or methamphetamine.

Methods

Rats were trained in 2-h daily sessions to self-administer 0.5 mg/kg cocaine or 0.1 mg/kg methamphetamine infusions followed by 12 days of instrumental extinction. Reinstatement was evoked by 17 mg/kg i.p. cocaine primes or response-contingent cocaine-paired cues in cocaine-reinforced rats, and by 1 mg/kg i.p. methamphetamine primes or response-contingent methamphetamine-paired cues in methamphetamine-reinforced rats.

Results

Buspirone (1 and 3 mg/kg) significantly (p < 0.05) attenuated cocaine cue but not cocaine prime reinstatement. Buspirone (1 and 3 mg/kg) also significantly attenuated methamphetamine cue reinstatement. Buspirone (3 mg/kg) significantly attenuated methamphetamine prime reinstatement. During all reinstatement tests, 3 mg/kg buspirone reduced levels of inactive lever pressing relative to those of vehicle, significantly so during the cocaine cue-induced reinstatement tests.

Conclusions

Given the complexity of buspirone's neuropharmacology consisting of serotonin 5-HT_1A receptor partial agonist activity, and dopamine D2, D3 and D4 receptor antagonist effects, it is uncertain which of these activities or their combination is responsible for the present results. Overall, these results suggest that buspirone may reduce the likelihood of relapse to cocaine and methamphetamine use under some conditions, although this speculation must be interpreted with caution given buspirone's similar potency to attenuate inactive-lever responding.     

文拉法辛缓释剂与丁螺环酮治疗广泛性焦虑症对照观察

目的 了解文拉法辛缓释剂与丁螺环酮治疗广泛性焦虑障碍的疗效和安全性.方法 将符合入组标准的患者随机分为研究组和对照组,研究组口服文拉法辛缓释剂,对照组口服丁螺环酮,疗程4周.临床疗效判定依据汉密尔顿焦虑量表(HAMA)减分率,不良反应采用不良反应量表(TESS)评定.结果 研究组有效率为78.38％,对照组有效率为74.36％,两组有效率比较,差异无统计学意义(x2=0.17,P＞0.05).但在第2周时研究组抗焦虑效果优于对照组,两组不良反应比较,差异无统计学意义.结论 文拉法辛缓释剂与丁螺环酮治疗广泛性焦虑症均有较好的疗效,不良反应少,但文拉法辛缓释剂抗焦虑效果在治疗第2周时优于丁螺环酮.     

Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety

Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT_1A receptor agonist) anxiolytic drug with some D₂ dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).     

Comparison of routes of administration and time course effects of zacopride and buspirone in mice using an automated light/dark test

The behavioral effects of zacopride and buspirone were assessed in mice in a fully automated 2-compartment light/dark test. A significant increase in time mice spent in the lit area was used as an indication of anxiolytic-like action. Doses of zacopride from 0.0001 to 17.8 mg/kg, IP, and buspirone from 3.16 to 17.8 mg/kg, IP, produced significant increases in time mice spent in the lit area of the chamber. In addition, zacopride and buspirone were compared for oral potency and for duration of action after IP and PO administration. Zacopride and buspirone produced anxiolytic-like activity between doses of 0.001 to 100.0 mg/kg, PO, and 10.0 to 56.2 mg/kg, PO, respectively. The duration of effect of buspirone was 2 to 4 h after IP or PO administration, while that for zacopride was ≥16 h by either route of administration. Thus, when compared for anxiolytic-like effects in this test, zacopride is a more potent and longer acting agent than buspirone.     

Ethological evaluation of the effects of acute and chronic buspirone treatment in the murine elevated plus-maze test: comparison with haloperidol

Buspirone is renowned for its highly inconsistent effects in animal models of anxiety. In the present study, the effects of acute (0.63–5.0 mg/kg) and chronic (1.25–5.0 mg/kg, daily, 15 days) buspirone treatment on the behaviour of mice in the elevated plus-maze test were assessed using a recently developed ethological scoring method. On acute administration, a selective reduction in risk assessment behaviours was observed at 1.25 mg/kg; these mild anxiolytic-like effects were maintained at higher doses (2.5–5.0 mg/kg) which also reduced measures of general activity. Similar, though more potent, effects were observed with chronic administration; the lowest dose tested (1.25 mg/kg) reduced open arm entries and total stretch attend postures while higher doses profoundly reduced all major indices of anxiety (traditional and novel) and, concomitantly, suppressed total entries and rearing. Acute administration of haloperidol (0.0125–0.1 mg/kg) appeared to mimic the behavioural suppressant effects of buspirone without selectively affecting anxiety-related measures at any dose. It is suggested that the anti-anxiety and behavioural suppressant profile of buspirone may reflect combined action at 5-HT_1A and D₂ receptors, respectively. Results are discussed in relation to the utility of risk assessment as a sensitive index of anxiety in models based upon unconditioned behaviour.     

Disinhibitory effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: Possible role of dopamine

Low doses of buspirone, haloperidol and sulpiride were compared with diazepam in two experimental models of anxiety in rats. In a conflict test, 0.6 and 1.2 mg/kg buspirone, 0.05 and 0.10 mg/kg haloperidol and 0.5 mg/kg sulpiride significantly increased punished responding. Buspirone 1.2 and 2.5 mg/kg significantly reduced the number of unpunished responses while haloperidol and sulpiride at the doses tested had no effect. Effects on punished responding were seen in a narrow dose range and were less pronounced with these drugs than with diazepam. Similar results were obtained with rats', activity in the two-compartment exploratory test. At doses causing no change in the locomotion of rats in photocell activity cages, buspirone (0.1 mg/kg), haloperidol (0.025–0.100 mg/kg) and sulpiride (0.5–1.0 mg/kg) significantly increased the number of crossings between the two compartments. Again, the peak effects were small when compared with the effect of diazepam and the active dose range was very narrow. Apomorphine 0.2 mg/kg SC significantly counteracted the effect of 0.1 mg buspirone and 1.0 mg/kg sulpiride in the two-compartment exploratory test with no effect on 2.5 mg/kg diazepam.The data show that buspirone, in a narrow dose range, shows disinhibitory effects in experimental models of anxiety. Similar effects are shown by low doses of haloperidol and sulpiride. It is suggested that buspirone and sulpiride produce these disinhibitory effects by blocking particular dopamine receptors in the brain, possibly those located in the nerve terminals, but it is likely that other mechanisms, particularly serotonin, are involved in the effects of buspirone in anxious states.     

Discriminative stimulus properties of buspirone compared to central nervous system depressants in rats

Two groups of rats were trained to discriminate either IP buspirone from vehicle or IP oxazepam from vehicle using a two-lever FR-10 schedule of sweetened milk presentation. The discrimination in the buspirone group was difficult to establish due to potent response rate decreasing effects. Oxazepam was a very effective stimulus and the discrimination in the oxazepam group was readily established. Tests with oxazepam and pentobarbital in the buspirone group provided no evidence for generalization of the stimulus properties of buspirone to either drug. Tests with buspirone in the oxazepam group also provided no evidence of generalization to buspirone, although tests with pentobarbital indicated almost complete generalization. Finally buspirone and oxazepam were tested in a group of rats previously trained to discriminate pentobarbital from vehicle. The findings supported the data obtained in the buspirone and oxazepam groups, with no indication of generalization from pentobarbital to buspirone, but with complete generalization to oxazepam. These data suggest that buspirone does not share discriminative stimulus properties which are common to other CNS depressants.     

Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity

  Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to ”isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isolation deprives animals of mild daily stressors that are inherent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, repeated stressors may abolish the effects of isolation. Objectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abolish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the elevated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxiolytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk assessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of ”isolation stress”. However, isolation was anxiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation. Received: 23 May 1998 / Final version: 3 December 1998     

Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone

The present study evaluated the role of various neurotransmitter systems in mediating buspirone's blockade of the fear-potentiated startle effect, where acoustic startle amplitude is normally increased in the presence of a light previously paired with a shock. Large lesions of the dorsal and median raphe nuclei or IP injections of the serotonin antagonists cinanserin (10 mg/kg) or cyproheptadine (5 mg/kg) did not alter fear-potentiated startle, nor did these treatments prevent buspirone (5 or 10 mg/kg SC) from blocking fear-potentiated startle. The 5-HT_1A agonist 8-OH-DPAT (2.5–10.0) did not block fear-potentiated startle even at doses that produced a marked 5-HT syndrome. Another 5-HT_1A agonist, ipsapirone (10–20 mg/kg), blocked potentiated startle only at a very high dose (40 mg/kg).p-Chlorophenylalanine andp-chloroamphetamine did not alter fear-potentiated startle. Finally, pretreatment with the benzodiazepine receptor antagonist RO-15-1788 (1 mg/kg); the opiate antagonist naloxone (2 mg/kg) or the ₂-adrenergic antagonist yohimbine (5 mg/kg) did not reduce fear-potentiated startle, nor did they prevent buspirone from blocking fear-potentiated startle. Taken together, the data do not support the hypothesis that buspirone's anxiolytic effects are mediated by actions at 5-HT_1A receptors and more generally indicate that serotonergic neurons do not play an important role in fear-potentiated startle.     

艾司西酞普兰与丁螺环酮治疗广泛性焦虑症临床疗效观察

目的：探讨艾司西酞普兰治疗广泛性焦虑症（GAD）的临床疗效和安全性。方法：将符合入组标准的GAD患者随机分为研究组和对照组,研究组服用艾司西酞普兰,对照组服用丁螺环酮,疗程5周。采用汉密尔顿焦虑量表（HAMA）、临床疗效总评量表（CGI）、药物不良反应评定量表（TESS）分别在治疗前、治疗1、3、5周末进行评分。依据HAMA总分减分率判定疗效。结果：治疗5周末研究组总有效率79.41%,对照组总有效率80.56%,两组相比差异无统计学意义（χ2=0.01,P〉0.05）。治疗第一周末,两组HAMA评分,CGI评分与治疗前相比差异均有统计学意义（P〈0.05）,研究组HAMA、CGI评分与对照组相比差异有统计学意义（P〈0.05）。两组不良反应均较轻,不影响正常治疗。结论：艾司西酞普兰治疗GAD有效、安全,不良反应轻。     

120例女性精神病病人康复期焦虑、抑郁情绪及干预影响

目的 了解女性精神病病人康复期焦虑、抑郁情绪的影响及干预前后的变化。方法 对120例康复期女性精神病病人，采用（SAS、SDS）量表对其出现焦虑、抑郁情绪进行了评价分析，并使用多元回归分析找出影响因素并进行干预。结果 影响因素怕被歧视，担心出院后影响生活、影响婚姻、影响工作、住院次数等。干预前后的焦虑发生率为40．0％和23．3％，抑郁症状发生率为37．5％和18．3％，前后比较差异有显著意义。结论 有效的心理干预康复期女性精神病病人的焦虑、抑郁情绪有明显的改善作用。     

Intraventricular ACTH reduces social interaction in male rats

Intraventricular ACTH (1.25 microgram), ACTH (1.6 microgram) and ACTH:D-Phe (1.6 microgram) resulted in significant reductions in the time that pairs of male rats spent in active social interaction. This decrease in social behaviour was not accompanied by a decrease in motor activity. The results are similar to those previously found with peripheral administration of ACTH and suggest that these behavioural effects of ACTH are centrally mediated. None of the ACTH fragments had a significant effect on the latency with which thirsty rats started drinking in an unfamiliar environment. The results are discussed in relation to a possible anxiogenic action of ACTH.     

Differential effect of buspirone and diazepam on negative contrast in one-way avoidance learning

The main aim of the present work was to investigate the effect of buspirone, a 5-HT_1A receptor agonist, on successive negative contrast in one-way avoidance learning. Successive negative contrast was induced by shifting rats from a large reward (30 s spent in the safe compartment) to a small reward (1 s). Acute administration of buspirone (0.25, 0.5, 0.75 and 1.0 mg/kg i.p.) did not attenuate the contrast effect, as opposed to that observed for diazepam (1 mg/kg i.p.). The highest dose of buspirone used, however, did interfere with the learning of the avoidance response itself. Chronic buspirone (20 days, 0.5 and 0.75 mg/kg i.p.) did not have any effect on successive negative contrast either. Overall, these results could suggest that the 5-HT_1A receptor is not involved in the negative contrast effect studied, quite different to that observed for the γ-aminobutyric acid (GABA) system. The findings are compared to results obtained with animal models selectively sensitive to some anxiolytic drugs, as are the so-called ‘conflict models’.     

A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder

The efficacy of hydroxyzine and buspirone, controlled by placebo, was investigated in a double-blind, parallel group, multicentre study conducted in France and the UK. A total of 244 patients with generalised anxiety disorder in primary care was allocated randomly to treatments with hydroxyzine (12.5 mg morning and mid-day, 25 mg evening), buspirone (5 mg morning and mid-day, 10 mg evening) or placebo (three capsules/day) for 4 weeks, preceded by a 1-week single-blind placebo run-in and followed by 1-week single-blind placebo administration. Rating scales were applied on days -7,0,7,14,12,28 and 35. Seventy percent of the patients were female; the average age was 41 ± 11 years, and the mean Hamilton Anxiety Score at day 0 was 26.5 ± 4.2. Only 31 of the 244 patients dropped out, but equally in the three groups. Intention-to-treat LOCF analyses on the primary variable showed a significant difference only between hydroxyzine and placebo with respect to improvement on the Hamilton Anxiety Scale (10.75 versus 7.23 points, respectively). Secondary variables such as CGI and self-ratings (HAD scale) showed both hydroxyzine and buspirone to be more efficacious than placebo. Thus, hydroxyzine is a useful treatment for GAD. Received: 26 January 1998/Final version: 15 May 1998