Double-blind comparison of alprazolam and adinazolam for panic and phobic disorders

Subjects primarily suffering from DSM-III panic disorders (agoraphobia with panic attacks, 13 subjects; panic disorder, one subject) were tested with two drug treatments after a baseline was established using single-blind placebo capsules three times daily for 1 week. Double-blind, 4-week crossover treatments were given with alprazolam, 0.5-6.0 mg/day, and adinazolam mesylate, 10-120 mg/day. Mean final doses in mg/day were 3.1 for alprazolam and 95.5 for adinazolam mesylate. Both were broadly effective in comparison with the baseline condition. Measures included self-rated symptoms and global impressions, physician-rated global impressions, and two forms of challenges, agoraphobic and noradrenergic. The two active drugs were highly similar in overall efficacy across the sample, but alprazolam was favored globally in six subjects, and adinazolam was favored globally in another six subjects. Only two subjects obtained maximal improvement ratings without side effects with both drugs. No diagnostic or demographic factor correlated with the differential in responses to the two active treatments. No clinically significant laboratory abnormalities occurred with either drug.     

Alprazolam SR in the treatment of generalized anxiety: a multicentre controlled study with bromazepam

A multicentre, double‐blind, randomized trial compared the efficacy of a sustained‐release formulation of alprazolam with bromazepam in the treatment of generalized anxiety. One hundred and twenty‐one outpatients were randomly assigned to three weeks of active treatment with alprazolam SR (2 mg once daily) or bromazepam (3 mg three times daily), following a period of 3–7 days without medication. After treatment, doses were reduced by 50 per cent during a 1‐week dosage‐tapering period; patients were then followed for one additional week. There was no significant difference in the anxiolytic effects of alprazolam SR and bromazepam. The results in the two treatment groups were very similar and showed a rapid and statistically significant reduction in efficacy measures, including the total score on the Hamilton Anxiety Rating Scale and the Clinical Global Impression improvement and severity of illness scores. The mean changes from baseline scores were compared between treatments at each evaluation point and no statistically significant differences were observed. At week 3, more than 70 per cent of patients in the alprazolam SR and bromazepam groups were classified as responders. In conclusion, alprazolam SR, in a single daily dose, has a rapid onset of action and is effective in the treatment of generalized anxiety disorder. Its anxiolytic activity is similar to that of bromazepam taken in several daily doses and it has the advantage of enhancing patient compliance and reducing the potential for breakthrough anxiety. Copyright © 1999 John Wiley & Sons, Ltd.     

Setting New Standards for the Pharmacological Treatment of Panic Disorder

Three drugs are currently licensed for the treatment of panic disorder: the benzodiazepine, alprazolam; the tricyclic antidepressant, clomipramine; and, most recently, the selective serotonin reuptake inhibitor, paroxetine. Alprazolam and clomipramine are effective in the treatment of panic disorder, but are less than ideal agents due to their tolerability profiles. An extensive clinical trial programme has been undertaken to investigate the efficacy and tolerability of paroxetine treatment in panic disorder. This article reviews the clinical evidence for the short- and long-term efficacy and tolerability of paroxetine in panic disorder, and its effect on relapse prevention and on quality of life. The results from the short-term studies indicate that paroxetine is effective in treating panic disorder (with or without agoraphobia) either alone or in combination with cognitive-behavioural therapy. The minimum effective dose is 40 mg daily. Paroxetine was equally as effective as clomipramine in reducing the frequency of panic attacks but produced an earlier improvement in symptomatology. Continued treatment with paroxetine over periods of up to 9 months provided evidence that paroxetine maintained its anti-panic effect and prevented relapse. Paroxetine was well-tolerated during both the short- and long-term studies at doses of up to 60 mg per day. © 1997 John Wiley & Sons, Ltd.     

Drug Treatment of Panic Disorder

Abstract: Drug treatment of panic disorder is reviewed with focus on recent controlled studies. The efficacy of alprazolam, a triazolobenzodiazepine, and imipramine, a tricyclic antidepressant, has consistently been demonstrated, but there is reasonable evidence that other benzodiazepines or antidepressants might also be effective if equipotent doses are used. Most controlled studies demonstrate drug efficacy on several psychopathological symptoms, including the core symptom panic attacks. Limited evidence indicates that alprazolam may be more efficacious in treating panic attacks than avoidance behaviour, and the reverse when imipramine is concerned. Drug efficacy appears to be most consistently documented in moderately to severely ill panic patients. The benzodiazepines are better tolerated than antidepressants in terms of patient acceptance, and the improvement sets in faster with benzodiazepines. In the presence of depressive symptoms considered secondary to panic attacks and/or agoraphobia, both types of drugs appear efficacious. Difficulty discontinuing high-dose benzodiazepine treatment remains the most important side effect of the treatment but sedation can, like anticholinergic side effects of the tricyclic antidepressants, be troublesome, thereby diminishing patient compliance. The role of newly developed antidepressants with a more specific mode of action and milder side effects awaits evaluation in controlled trials.     

Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.     

The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard

In addition to possessing anti-anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4-benzodiazepines that have only anti-anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4-benzodiazepines. After acute administration, U-43,465 (16 mg kg-1) had a significant anxiolytic effect in the social interaction test. Neither adinazolam (1-3.5 mg kg-1) nor alprazolam (0.125-2 mg kg-1) had a significant effect. It is suggested that this is because, with adinazolam and alprazolam, doses at which anxiolytic effects can be observed are close to those at which sedative effects can be observed. U-43,465 (8-16 mg kg-1) and alprazolam (1-2 mg kg-1) had significant anxiolytic effects in the elevated plus-maze test of anxiety. U-43,465 (8-32 mg kg-1), adinazolam (0.5-5 mg kg-1) and alprazolam (0.2-2.0 mg kg-1) caused dose-related reductions in exploratory head-dipping, locomotor activity and rearing in the holeboard. In general the results seen in the three tests with the triazolobenzodiazepines alprazolam and adinazolam were similar to those seen with classical 1,4-benzodiazepines. With U-43,465, however, an anxiolytic effect was observed in the social interaction test after acute treatment; chronic treatment is required to see an effect with classical 1,4-benzodiazepines. In this U-43,465 resembles the effects of several novel non-benzodiazepine putative anxiolytic compounds that are believed to have less sedative potential than the benzodiazepines.     

A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam

Sustained-release (SR) alprazolam may facilitate compliance with oral benzodiazepine treatment of panic disorders that currently requires doses administered three or four times daily. To compare the pharmacokinetic, psychomotor performance, and subjective effects of alprazolam SR (1.5 mg), bromazepam (3 mg taken three times daily), and lorazepam (1 mg taken three times daily), 13 male volunteers (aged 20-45 years) randomly received on four separate occasions one of these medications or placebo. Once before and 11 times after drug administration, the subjects were tested using psychomotor performance tests (manual tracking and digit-symbol substitution test [DSST]) and computerized questionnaires (such as the Tufts University Benzodiazepine Scale [TUBS], the Addiction Research Center Inventory, and the visual analog scales) to determine the subjective effects of the drugs. Blood samples for the determination of the plasma levels of the drugs were collected before and 17 times after the drug was administered. A peak plateau of plasma alprazolam began approximately 6 hours after the dose, which was later than the initial peaks for lorazepam and bromazepam (1-2 hours after the dose). Once this plateau had begun, alprazolam SR sustained that concentration better than did the other two formulations. Of the 10 measures on which the response averaged for the first 14 hours differed among drugs (p < 0.05), bromazepam differed from placebo on two measures, lorazepam on four (including DSST Performance and TUBS Sedation), and alprazolam SR on nine (including all four affected by lorazepam). Lorazepam and alprazolam, but not bromazepam, produced significantly more sedation than placebo. The doses of the three drugs were not equipotent in sedation and mood effects. None of the drugs tested differed from placebo on measures relevant to abuse liability.     

Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects

The present reference drugs for the treatment of panic disorder and agoraphobia are imipramine and alprazolam. The latter decreases performance and cognitive functioning. No study of such functions in panic/agoraphobia is available. Fifty four out-patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia (PAG), taking part in a parallel groups controlled trial of imipramine (mean dose ±SEM 114±9 mg), clomipramine (50±4 mg) and propanteline (active placebo) over 8 weeks, were studied. A test battery of psychomotor and memory tests was administered at baseline, and after 1, 4 and 8 weeks of treatment. Their results were compared (at baseline and at the end of the trial) with those of a control group of 57 normal untreated subjects. There was no difference between treatments, and no drug effect on any test at any time. No consistent difference between patients and controls was detected. Given its apparently higher potency, and the absence of deleterious effects on cognitive measures known to be affected by benzodiazepines, we conclude that clomipramine is better than imipramine or alprazolam as a reference drug for panic/agoraphobia.     

Efficacy and safety of the 200–300 mg sustained release formulation of diltiazem administered once daily in patients with stable angina

The aim of this multicentre randomised double blind study was to compare the efficacy and safety of the 200–300 mg sustained release diltiazem formulation administered once daily (200–300 SR) with standard diltiazem (D) given three or four times daily to patients with stable angina. Patients aged 59 years, with a reproducible exercise test on placebo, were randomised to 4 weeks of treatment with 200–300 SR (n=70) or D (n=74). The initial dosage was 200 mg in the 200–300 SR group and 60 mg t.i.d. in the D group, increased to 300 mg once daily or 60 mg q.i.d., respectively, if ergometric parameters, which were always measured at the end of the dosing period, had not improved after two weeks. After 4 weeks of treatment, the antianginal efficacy at rest was comparable in the 200–300 SR and the D group; there was a prolongation of the total duration of exertion of 14% and 18% respectively (P<0.01 vs placebo for both groups with no intergroup difference). A dose-effect relation was found with both formulations.The 200–300 SR formulation gave full 24 hour anti-ischaemic protection when administered once daily. Its efficacy and safety were comparable to those of standard diltiazem t.i.d. or q.i.d. in patients with stable angina. The once daily administration should improve treatment compliance.     

Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial.

A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.     

Citalopram: new indication. No advantage

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.     

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P=0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P=0.031), and the difference in maximum category recall decrement was marginally significant (P=0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.     

Fluvoxamine in obsessive-compulsive disorder: similar efficacy but superior tolerability in comparison with clomipramine

Some meta-analyses have suggested that the selective serotonin reuptake inhibitors (SSRIs) are less effective than clomipramine in the treatment of obsessive-compulsive disorder (OCD). The aim of this double-blind, randomised, multicentre study was to directly compare the efficacy and safety of fluvoxamine and clomipramine in patients with OCD. A total of 227 patients were randomised to flexible doses of fluvoxamine or clomipramine (both 150-300 mg/day) for 10 weeks. Fluvoxamine and clomipramine were both clinically effective and there were no statistically significant differences between the two treatment groups, at any visit, on the National Institute of Mental Health Obsessive-Compulsive global rating scale, the Yale-Brown Obsessive-Compulsive scale (total score and obsession and compulsion subscores), the Clinical Global Impression severity of illness and global improvement subscales, the Clinical Anxiety Scale and the 17-item Hamilton Depression Rating Scale. However, there were differences in safety between the two treatments. Compared with fluvoxamine-treated patients, those treated with clomipramine had more anticholinergic side effects (dry mouth, constipation and tremor) and premature withdrawals due to adverse events (18 versus 9). The results from this controlled study indicate that fluvoxamine is as effective as clomipramine in the treatment of OCD but has a better tolerability profile. Copyright 2001 John Wiley & Sons, Ltd.     

The effects of repeated doses of clomipramine and alprazolam on physiological,psychomotor and cognitive functions in normal subjects

Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10.The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam.Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam.It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.     

Cyclic AMP in the rat cerebral cortex after stimulation of the locus coeruleus: decrease by antidepressant drugs.

The study concerned the effect of repeated treatment with antidepressant drugs on the elevation of cyclic AMP levels in the rat cerebral cortex following electrical stimulation of the locus coeruleus. Some of the tricyclic and tetracyclic antidepressant drugs inhibited the cyclic AMP response. Desmethylimipramine was the most potent (effective when given 5 mg/kg/day for 2 weeks). Imipramine and nomifensine (daily dose 10 mg/kg for 2 weeks) produced slight decreases, while iprindol and clomipramine were ineffective. After 6 weeks of treatment (daily 10 mg/kg) iprindol, clomipramine and mianserin were without effect. The cyclic AMP response was suppressed by higher doses of the latter two drugs (2 weeks, 20 mg/kg/day). These results indicate that tricyclic and tetracyclic antidepressant drugs are able to decrease cerebral noradrenergic neurotransmission of locus coeruleus neurons, as far as this is mediated by cyclic AMP. It is not clear, however, whether such modification is related to the therapeutic action of antidepressant drugs.     

Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.     

Clomipramine. An overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder

During the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focused on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder. Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity. In patients with panic disorder with or without agoraphobia (DSM-IIIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks' treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety. Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug's anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine less than or equal to 250 mg/day and 2.1% of patients receiving greater than or equal to 300 mg/day. In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically.     

A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder.

A recently reported multinational, 8-week double-blind, placebo-controlled study assessing the efficacy of alprazolam versus placebo in the treatment of panic disorder indicated significant differences favoring alprazolam. We now report the results of a three-site, 6-week, double-blind, fixed-dose study comparing alprazolam 2 mg, alprazolam 6 mg, and placebo in 94 patients with panic disorder with or without agoraphobia. Both alprazolam treatment groups (6 mg and 2 mg) improved significantly more than did the placebo treatment group on most outcome measures. Only a few statistically significant differences between the 6 mg and 2 mg alprazolam groups were discerned, although the pattern of treatment response across measures suggested a dose effect. Dropouts in the placebo group were primarily due to lack of efficacy and in the alprazolam 6 mg group were due to side effects, which may have contributed to the limited differences between groups at study end. The findings suggest that many patients may require less than 6 mg of alprazolam per day for effective treatment of panic disorder.     

Alprazolam withdrawal symptoms in agoraphobia with panic disorder: observations from a controlled Anglo-Canadian study

The study examines the effect of discontinuing alprazolam in panic disorder+agoraphobia patients. Fifty-seven alprazolam and 50 placebo agoraphobia+panic disorder patients, who had participated in an 8 week double- blind controlled study of alprazolam at average doses of 5 mg daily, were withdrawn gradually from their medication over the subsequent 8 weeks. The effects of discontinuation of medication on anxiety, panic, depression, phobia and withdrawal symptoms were examined during the taper phase and over the following 6 months. Alprazolam patients deteriorated on anxiety, panics, Hamilton depression and phobia. There was no difference between the two drug groups on rebound. Serious withdrawal symptoms did not arise, but weight loss, sweating and muscle twitching were more common in alprazolam patients. The deterioration in alprazolam patients persisted up to 6 months post-taper. A high dose of alprazolam at week 8 was the best predictor of subsequent deterioration. Discontinuation of alprazolam leads to recurrence of the original disorder in some patients. Rebound and severe withdrawal reactions were not found during gradual taper of alprazolam, but minor withdrawal symptoms did arise. The study shows the importance of using gradual taper to minimize withdrawal effects.     

Memory performance in panic disorder patients after chronic use of clomipramine

This study investigated the chronic use (6.3 +/- 0.5 years; mean +/- SEM) of therapeutic doses of clomipramine (57.0 +/- 8.0 mg/day) by outpatients with panic disorder/agoraphobia who were currently in remission to assess impairment of memory and psychomotor functions. In addition, the association between test performance and serum levels of clomipramine (CMI) and its active metabolite desmethylclomipramine (DCMI) was also assessed. Patients and healthy volunteers matched for sex, age and educational level were submitted to rating scales and to memory and psychomotor tests. There was no significant difference between groups regarding any variable, except for metamemory. Significant associations were found between (i) longer-term clomipramine treatment and poorer performance in the implicit test and (ii) higher serum levels of clomipramine or desmethylclomipramine, or both (CMI + DCMI) and lower performance in central executive tests and metamemory. The results showed that low doses of CMI chronically administered to panic patients are associated with diminished metamemory and impaired priming and working memory. Further investigations are needed to confirm these results and to determine whether the chronic use of higher therapeutic doses of tricyclic antidepressants is associated with more intense deleterious effects on memory and psychomotor functions.