BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed 'anxioselective'. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a 'lagtime' of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence. Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important.

RATIONALE: Natural strain differences exist in mice for behavioural traits such as emotional reactivity. OBJECTIVE: The present experiments compared the behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the benzodiazepine diazepam. METHODS: The tests used were the light/dark choice task and the elevated plus-maze, two well-validated anxiolytic screening tests. RESULTS: In vehicle-treated animals, differences on variables designed to measure anxiety-related behaviours were observed in both tests. In the light/dark test, the strains could be divided into three distinct groups: two non-reactive strains (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL, NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6, DBA/2 and NZB. The strain distribution between the light/dark and the elevated plus-maze tests shows similarities and differences, suggesting that each of these experimental procedures represents a different set of behaviours. Marked differences between a number of strains of mice in their sensitivity to the anxiolytic-like action of diazepam were observed in both the light/dark and the elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA and C3H strains were responsive to diazepam in both tests, although in the case of CBA mice, effects may have been contaminated by behavioural suppression. SJL mice were largely unresponsive to the action of the benzodiazepine in both tests, whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only in the elevated plus-maze. CONCLUSION: The finding of differential strain distributions both with and without diazepam treatment in the light/dark and the elevated plus-maze tests, indicates that not all strains of mice are suitable for investigating the effects of GABA/BZ receptor ligands. This study may thus provide a useful guide for choosing the best strain of mice for studying the pharmacology of fear-related behaviours.

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.

PURPOSE: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures. METHODS: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizure-prevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel-Haenszel analyses; random effects model used if heterogeneity was significant. RESULTS: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Effective: Phenobarbital for recurrence of febrile seizures [relative risk (RR), 0.51; 95% confidence interval (CI), 0.32-0.82) and cerebral malaria (RR, 0.36; CI, 0.23-0.56). Diazepam for contrast media-associated seizures (RR, 0.10; CI, 0.01-0.79). Phenytoin for provoked seizures after craniotomy or traumatic brain injury (craniotomy: RR, 0.42; CI, 0.25-0.71; TBI: RR, 0.33; CI, 0.19-0.59). Carbamazepine for provoked seizures after traumatic brain injury (RR, 0.39; CI, 0.17-0.92). Lorazepam for alcohol-related seizures (RR, 0.12; CI, 0.04-0.40). More than 25% reduction ruled out valproate for unprovoked seizures after traumatic brain injury (RR, 1.28; CI, 0.76-2.16), and carbamazepine for unprovoked seizures after craniotomy (RR, 1.30; CI, 0.75-2.25). CONCLUSIONS: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out.

Stiff-man syndrome, a rare disorder characterized by intermittent spasms and stiffness of the axial muscles, is associated with an electromyographic pattern of continuous motor unit activity in affected muscles. Since the initial description in 1956, the stiff-man syndrome has been reported to occur in various clinical and neurologic settings. In this study, we reviewed the current state of knowledge about this syndrome, defined diagnostic criteria, provided a long-term follow-up of the disorder, and assessed rehabilitative attempts in affected patients. Use of rigorous criteria that identify patients who have the stiff-man syndrome is important because the initial clinical manifestations are similar to those of other neuromuscular diseases. Analysis of 13 patients with stiff-man syndrome examined at the Mayo Clinic during the past 30 years revealed that treatment with diazepam decreased the muscle spasms. Because some muscle spasms usually persist, rehabilitation is an important adjunct that may further improve function when it is centered on the treatment of low-back pain and hyperlordosis, mobility problems, gait abnormalities, and muscular stiffness.

The present series of experiments compared the behavioral effects of the novel non-peptide CRF antagonist CP-154,526 with those of diazepam and the 5-HT1A receptor partial agonist buspirone in classical animal models of anxiety including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that diazepam (2.5-10 mg/kg, i.p.) produced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, i.p.) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6-20 mg/kg) was devoid of significant activity in both procedures. In the elevated plus-maze, diazepam (2 mg/kg, i.p.) produced significant effects on traditional (i.e. spatio-temporal) and ethologically derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1-4 mg/kg, i.p.) reduced risk assessment activities only, and CP-154,526 (0.6-20 mg/kg, i.p.) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5-5 mg/kg, i.p.) and CP-154,526 (10-40 mg/kg, i.p.) affected all behavioral indices of anxiety, while buspirone reduced risk assessment activities at the highest doses only (10 and 15 mg/kg, i.p.). In the free-exploration test, diazepam (1 mg/kg, i.p.) reduced avoidance responses towards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 failed to affect the former behavior and weakly reduced the latter (5 and 20 mg/kg, i.p.). Buspirone (1.25-5 mg/kg, i.p.) was inactive in this test. Finally, in the MDTB, diazepam (0.5-3 mg/kg, i.p.) attenuated all defensive reactions of mice confronted with a rat stimulus (i.e. flight, risk assessment and defensive attack) or with a situation associated with this threat (i.e. contextual defense). Buspirone (1.25-5 mg/kg, i.p.) reduced defensive attack and contextual defense, while CP-154,526 (5-20 mg/kg, i.p.) affected all defensive behaviors, with the exception of one risk assessment measure. The finding that CP-154,526 displayed positive effects in mice but not in rats may be due to increased sensitivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact that animals were exposed to unavoidable stress stimuli which may lead to a significant activation of the CRF system. Although in mice the anxiety-reducing potential of CP-154,526 is superior to that of the atypical anxiolytic buspirone, it is smaller in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam.