Benzodiazepine withdrawal delirium with catatonic features. Occurrence in patients with partial seizure disorders

We report the cases of 3 patients with medically intractable seizures in whom withdrawal of treatment with a long-acting benzodiazepine (clorazepate dipotassium, 2 patients; clonazepam, 1 patient) was followed by delirium with catatoniclike features. While an increase in seizure frequency occurred during withdrawal and prior to the onset of behavioral changes, electroencephalograms did not show epileptiform activity during the delirium. We compared these 3 patients with 10 others with intractable seizures in whom antiepileptic therapy was withdrawn without subsequent behavior changes. High-dose benzodiazepine therapy and a history of viral encephalitis may be risk factors for withdrawal delirium.     

Antiepileptic effect and serum levels of clorazepate on children with refractory seizures

Clorazepate dipotassium is rapidly decarboxylated to yield desmethyl diazepam. The antiepileptic effect of clorazepate was studied in 29 epileptic children with refractory seizures. Their ages were ranged from one year 9 months to 20 years (mean 11 years 6 months). Serum clorazepate levels were also determined in 16 patients. The mean initial dose was 0.91 mg/kg/day, and the dose was increased up to 3 mg/kg/day. Within several days after initiation of clorazepate therapy, a decrease in seizure frequency was seen in patients in whom clorazepate was effective. Excellent results (decrease in seizure frequency by more than 80%) were obtained in 7 patients (24.1%), a moderate improvement with a 50 to 80% decrease was seen in 7 patients (24.1%), and a partial improvement with less than 50% decrease was seen in 7 patients (24.1%). No benefit was seen in 8 patients (27.7%). Serum clorazepate levels in patients with excellent results were 31 to 77 ng/ml (mean 55 ng/ml), those in patients with a moderate improvement were 130 to 225 ng/ml (mean 163 ng/ml), and those in patients with a partial improvement were 142 to 518 ng/ml (mean 273 ng/ml). Serum clorazepate levels in patients with no benefit were 34 to 97 ng/ml (mean 56 ng/ml). There was no direct relationship between serum clorazepate levels and clinical response. The results of this study indicate the efficacy of clorazepate for epileptic children with refractory seizures.     

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.     

Anticonvulsant effects of dipotassium clorazepate on hippocampal kindled seizures in rats

We examined the anticonvulsant properties of dipotassium clorazepate (DC) against hippocampal kindled seizures in rats. Adult male Wistar rats were subjected to kindling 1 week after the implantation of electrodes. After five stage 5 seizures were induced, the generalized convulsion triggering threshold (GST) was determined. Dipotassium clorazepate was administered intraperitoneally in rats that showed two stable stage 5 seizures induced at the GST current intensity. Dipotassium clorazepate at doses of 1 mg/kg or more produced an anticonvulsant effect, but did not readily suppress limbic seizures. Dipotassium clorazepate did not completely suppress after-discharges (AD) even at the highest dose, which was 5 mg/kg. Moreover, raised stimulus intensity failed to affect its efficacy as an anticonvulsant. The results of the present study suggest that DC has a modest anticonvulsant potency. It is reasonable to assume that its anticonvulsant efficacy is primarily due to attenuation of AD propagation rather than the raising of the seizure triggering threshold at the kindling focus.     

The efficacy of the combination of sertraline with buspirone for smoking cessation

In a double-blind placebo-controlled trial, we evaluated the efficacy of the combination of sertraline and buspirone plus cognitive-behavioral treatment to promote tobacco abstinence in individuals referred to a chemical dependency clinic. Ninety eight individuals 18-65 years of age were randomized to placebo or sertraline 25 mg/day for 2 days, followed by 50 mg from day 3 to 90, and buspirone 5 mg three times a day for 7 days, and 10 mg from day 8 to 90. The rate of continuous abstinence at the 26th week of follow-up, informed by the patient, was 43.5% in the active treatment group and 17.3% in the control group (p = 0.01). The odds ratio for continuous abstinence for the intervention group was 4.74 (95% CI 1.50-14.55) (adjusted for smoker households and number of cognitive sessions). Nicotine withdrawal symptoms were common in both groups (98.7% vs. 95.5% p = 0.37). The combination of sertraline and buspirone with cognitive-behavioral therapy was more effective than placebo and cognitive-behavioral therapy to promote smoking cessation.     

Clorazepate in dogs: tolerance to the anticonvulsant effect and signs of physical dependence

Dogs were treated with clorazepate, which is known to be completely metabolized to desmethyldiazepam. 2 mg/kg t.i.d. were given orally for 5-6 weeks, a dose regimen providing plasma concentrations of desmethyldiazepam in the range known to be therapeutic in man. The rate of development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold for pentetrazole before, during and after cessation of treatment. The development of tolerance was not as clear and pronounced as that found after treatment with diazepam and clonazepam in earlier studies with dogs. The seizure threshold was elevated by a factor of 1.2-3.5 during the first 2 weeks of treatment; during the following weeks, tolerance developed in only 2 out of 6 dogs (decline of the pentetrazole threshold in spite of rising or unchanged plasma concentrations). 36 h after withdrawal of clorazepate, the convulsive threshold had fallen below the control values in all dogs, but 1 week later it had returned to the control level. One day after cessation of treatment, 2 out of 6 dogs showed withdrawal seizures, which, in 1 case, were lethal. This shows that severe withdrawal symptoms, even lethal seizures, may appear after abrupt discontinuation of chronic clorazepate treatment, in spite of the relatively low tolerance liability of clorazepate.     

Clorazepate therapy for intractable epilepsy

Thirty-one epileptic patients with seizures refractory to conventional anticonvulsants were treated by adding clorazepate dipotassium to their regimen. Twelve cases showed improvement in seizure frequency, three of whom attained a seizure free state. Response to clorazepate was not related to the type of epilepsy, but patients with secondary generalized epilepsy tended to be less responsive than those with partial epilepsy. Among the various seizure types, generalized tonic-clonic seizures and simple partial seizures showed, although not significant, a tendency to be more responsive to clorazepate therapy than other seizure types, including complex partial seizures, atypical absence, atonic seizures, and tonic seizures. Drowsiness was the main adverse effect, of which 14 patients complained. Six patients were withdrawn from clorazepate because of drowsiness, but in the remaining 8 patients, this side effect disappeared within a week. The appearance of adverse effect was not related to the dose of clorazepate given. Clorazepate may be an effective secondary anticonvulsant in the treatment of intractable epilepsy.     

The efficacy of combined estrogen and buspirone treatment in olivopontocerebellar atrophy

BACKGROUND: Olivopontocerebellar atrophy (OPCA) is a chronic neurodegenerative disease with symptoms of cerebellar ataxia, parkinsonism, autonomic disturbances and ophthalmoplegia. Buspirone, a 5-HT1(A) agonist could constitute a symptomatic improvement in cerebellar dysfunction whereas estrogen has been investigated for neuroprotection. We conducted an open-labeled pilot trial to assess the efficacy of estrogen with buspirone treatment. PATIENTS AND METHODS: Eighteen patients (7 male and 11 female) with OPCA were randomized into the buspirone (15 mg/day, n=9), or the combined treatment group (estrogen, 0.625 mg/d plus buspirone, n=9). For the clinical rating, International Cooperative Ataxia Rating Scale (ICARS) was used and dysarthria, gaze evoked nystagmus, finger to nose, pronation-supination alternating movement, knee-tibia test, and gait speed were evaluated for 12 months. RESULTS: Buspirone-treated group showed improvements in finger to nose and pronation-supination alternating movement test (p=0.046 and p=0.025, respectively). The combination group (Estrogen+buspirone), however, showed no improvement in cerebellar sub-scales compared to the baseline. CONCLUSIONS: Buspirone treatment showed feasible efficacies for OPCA, while the combined treatment of estrogen and buspirone failed to improve, suggesting estrogen may not have further benefit in cerebellar dysfunction.     

Delayed maze-learning in rats after prenatal exposure to clorazepate

Five pregnant Long-Evans rats were given 32 mg/kg of body weight of clorazepate dipotassium (Tranxene) intramuscularly on gestational days 8.5, 9.5, and 10.5. Five control mothers received sterile water. The control group of offspring (n = 19) and the experimental group (n = 20) were compared by means of a timetable for neurologic development and for maze learning ability. Although the experimental group was significantly slower in stomach-lifting and walking, the neurologic battery as a whole did not disclose any consistent difference. At 21 days of age, the experimental rats weighed significantly more than the control rats. On trials 10 to 14, the control group ran the maze in less than half of the time of the experimental group. The study emphasizes the need to include tests of cerebral function in addition to developmental reflexes to screen for subtle effects of teratogens, which the simpler developmental tests may miss.     

Clorazepate and lorazepam: clinical improvement and rebound anxiety

Sixty-two anxious patients were treated under double-blind conditions for 4 weeks with either clorazepate or lorazepam. Two-thirds of each treatment group were then switched abruptly to placebo for 2 weeks, while one-third continued to receive active medication. Two major findings were obtained. About 70% of the patients maintained improvement during the 2-week placebo period. Some patients, however, experienced rebound anxiety, which appeared to be more intense and occurred earlier when placebo was substituted for a benzodiazepine with a short half-life (lorazepam) than for one with a long half-life (clorazepate). The clinical relevance of these findings is discussed.     

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.     

Reversal of cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol

Cocaine is used worldwide and considered a public health problem. Relapse from addiction is one of the difficulties faced by cocaine users, and in most cases according to the period of abstinence, users may present symptoms such as anxiety or depression. To evaluate the anxiety-like behavior induced by different periods, rats were treated for 7 days with cocaine 20 mg/kg, i.p., and 24 h, 7 and 21 days after drug withdrawal were submitted to the elevated plus maze (EPM) and the open field (OF) tests. In different protocol, propranolol (10 mg/kg, i.p.), ondansetron (4 mg/kg, i.p.) and buspirone (5 mg/kg, i.p.) were administered once after 24 h and 7 days of abstinence from cocaine to evaluate possible reversal or attenuation of the symptoms caused by cocaine withdrawal. EPM results showed a reduction in all parameters after 24 h and 7 days of the last exposure to cocaine, indicating anxiety-like behavior. In the OF test, 24 h and 7 days of abstinence showed increased locomotor activity, while in the withdrawal 21 days the animals not alter the locomotor activity. The administration of propranolol, ondansetron or buspirone after a 24 h abstinence period reduced the animals? anxiety in the EPM, and in the OF all drugs were able to reduce locomotor activity. After abstinence 7 d, the drugs reduced locomotor activity in the OF, in the EMP propranolol and ondansetron reversed the anxiogenic effect induced by cocaine. These results suggest that the treatment of anxyogenic effects of abstinence from cocaine is dependent on the period of the withdrawal.     

Buspirone: sedative or stimulant effect?

OBJECTIVE: The primary objectives of this study were to evaluate the effects of initial and continued administration of buspirone on sleep induction and maintenance and sleep stage parameters, to determine the presence or absence of any drug-induced side effects, and to ascertain the presence or absence of sleep disturbances following abrupt withdrawal of the drug. METHOD: Six insomniac subjects who had chronic complaints of difficulty falling asleep and/or staying asleep and who were in good physical health, were not suffering from any major mental disorders, and had not used any medication for at least the last month participated in a 16-night sleep laboratory protocol. The protocol consisted of 4 placebo-baseline nights, 7 nights on which buspirone, 10 mg at bedtime, was administered, and 5 placebo-withdrawal nights. RESULTS: Wake time after sleep onset increased moderately during the first 3 nights of drug administration (there was a marked and significant increase on the first night) and increased by lesser degrees with continued drug administration. Overall, reports of side effects were infrequent. Following drug termination, there was a delayed and mild increase in sleep difficulty above baseline. CONCLUSIONS: These data not only confirm that buspirone lacks sedative effects but also suggest that the drug may have stimulant properties. Further, these findings suggest that buspirone has limited usefulness in anxious patients with concomitant sleep difficulties.     

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。     

Failure of clorazepate to cause malformations or fetal wastage in the rat

Clorazepate dipotassium (Tranxene), an anticonvulsant benzodiazepine, was tested for teratogenicity by injecting ten pregnant Long-Evans rats with 32 mg/kg of body weight intramuscularly on days 8.5, 9.5, and 10.5 of gestation. Ten control rats similarly received sterile water injections. Sixty fetuses recovered after killing five of the mothers on day 20.5 of gestation were sectioned to ascertain external and visceral malformations. Comparison with 55 control fetuses showed no statistically significant differences in external, visceral, or skeletal malformations, nor in fetal mortality, fetal and placental weight, and crown-rump length. Five clorazepate-treated rat mothers were allowed to deliver their 45 offspring for a companion study of possible behavioral effects. None of these additional 45 clorazepate-treated rats showed external malformations. Thus clorazepate caused no gross malformations in the rat under the conditions of this study.     

Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination

A girl with cardio-facio-cutaneous (CFC) syndrome due to a BRAF gene mutation (c.1454T→C, p.L485S) experienced repetitive epileptic spasms at the corrected age of 4 months. Electroencephalograms revealed hypsarrhythmia, and magnetic resonance imaging identified delayed myelination and a hypoplastic corpus callosum. Various antiepileptic treatments, including adrenocorticotropic hormone therapy, were ineffective, although transient seizure control was achieved by a ketogenic diet and clorazepate dipotassium. However, seizures with epileptic foci at the bilateral posterior temporal areas re-aggravated and remained intractable; severe psychomotor delay persisted. This case indicated that infantile spasms in CFC syndrome can be difficult to control and may be accompanied by severe psychomotor retardation and abnormal myelination.     

Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome

Forty patients with a history of difficulty discontinuing long-term, daily benzodiazepine therapy were randomly assigned, under double-blind conditions, to treatment with carbamazepine (200 to 800 mg/d) or placebo. A gradual taper (25% per week reduction) off benzodiazepine therapy was then attempted. Five weeks after taper, significantly more patients who had received carbamazepine than placebo remained benzodiazepine free, this despite the fact that no statistically significant differences in withdrawal severity could be demonstrated. Patients receiving carbamazepine reported a larger reduction in withdrawal severity than patients receiving placebo, but only at a trend level, and only on the daily patient-rated withdrawal checklist. Eleven patients (28%) required antidepressant therapy for depression or panic when assessed at 12-weeks follow-up. The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.     

Depressive symptoms and intellectual functioning in anxiety patients treated with clorazepate

The combined data from two 1970s anxiety studies that used clorazepate and placebo as controls were reanalyzed statistically with a focus on intellectual functioning and depressive symptoms. For the 176 patients given either clorazepate or placebo, significant improvement was observed on the mean scores of the intellectual item and the depressive item of the Hamilton Rating Scale for Anxiety; the clorazepate group was significantly more improved than the placebo group. Similar results were observed in patients' self-ratings. The authors conclude that clorazepate is effective in treating depressive symptoms and improving intellectual functioning in patients with generalized anxiety disorder.     

Value of prazepam drops in the brief treatment of anxiety disorders

In order to assess the clinical usefulness of benzodiazepine brief therapy with planned tapering, prazepam as drops was administered to 40 psychiatric outpatients suffering from generalized anxiety disorder. After a one-week placebo period, the patients received prazepam 40 mg daily (i.e., 10 drops in the morning, 10 drops at noon and 20 drops in the evening) during 3 weeks, with the possibility to adjust the doses after one week. The doses were then tapered at 4 mg/d (i.e., 1 drop in the morning, 1 drop at noon and 2 drops in the evening) until complete suppression of the treatment. The assessments, performed before the placebo period, at inclusion, after 1 and 3 weeks of active treatment, and after 1 and 2 weeks of tapering, included the Hamilton anxiety scale, the Lader tranquillizer withdrawal rating scale, and the collection of side effects; moreover, the patients completed daily a visual analogue scale. Results showed a very marked anxiolytic effect of prazepam with an already very significant decrease in the scores on the various scales after 1 week of treatment when the daily dose was significantly reduced. Three quarters of the patients were able to take part in the tapering of prazepam doses without exhibiting any reappearance of anxious symptomatology, rebound anxiety, or withdrawal symptoms. The tolerance of the treatment was rated as good or very good in 91.9% of the patients. This study demonstrates the possibility of a brief anxiolytic treatment followed by tapering in a majority of patients with generalized anxiety disorders. For this strategy, the availability of a drop form represents an obvious advantage.