Long-term comparison of alprazolam, lorazepam and placebo in patients with an anxiety disorder

In a double-blind, placebo-controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam. Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam. The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg. Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale, with a trend toward more improvement in the alprazolam group in the later weeks of the study. Target Symptoms, Physician's and Patient's Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo. The major side effects were sedation and drowsiness; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo. An overall rating of side effect severity was not significantly different among the three groups.     

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.     

Treatment of depressive outpatients with lorazepam,alprazolam, amytriptyline and placebo

This randomized double-blind study in 342 mildly to moderately depressive outpatients investigated the antidepressant effectiveness and speed of action of lorazepam, alprazolam and amitriptyline versus placebo. Six weeks of drug treatment were followed by a drug taper period, a control period with placebo and a control period without placebo, of 2 weeks duration each. Clinical improvement was assessed by rating scales (Clinical Global Impressions, Hamilton Rating Scales for Depression and Anxiety) and patient's self-ratings (Patient's Global Impressions, Self-rating Depression Scale and Visual Analogue Scale). At the end of week 6 all active drugs showed similar efficacy which was significantly superior to placebo. Compared to placebo, onset of efficacy was earlier on benzodiazepines than on amitriptyline. While tapering by decreasing the dosage, replacing drug with placebo and finally discontinuing placebo, clear withdrawal phenomena were not seen, but 20% of patients, equally distributed to all treatment groups, did not want to stop taking tablets after replacing drug with placebo. Drop-out rate during the treatment period was very low (9%). Significantly interfering adverse effects were seen in 27 patients, without predominance in one of the active drug groups.     

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.     

Alprazolam versus buspirone in the treatment of outpatients with generalized anxiety disorder

The efficacy and safety of alprazolam and buspirone for treating generalized anxiety disorder (GAD) were compared in a 6-week, double-blind, randomized, placebo-controlled study of 94 outpatients. Mean daily doses at the end of the study were 1.9 mg alprazolam and 18.7 mg buspirone. As judged by the Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, Physician's Global Improvement Scale, and other efficacy scales, alprazolam and buspirone were similar in efficacy, but more effective than placebo, for treating anxiety and depression symptoms in these patients. Clinically important differences were noted between drugs in the onset of effect, with alprazolam producing rapid and sustained improvement within the first week of treatment and buspirone producing more gradual, continuous improvement throughout the study. Significantly more buspirone-treated than alprazolam-treated patients failed to complete the study, primarily because of side effects or inefficacy. No clinically important differences were noted between alprazolam and buspirone in side effects, vital signs, or laboratory test results. Alprazolam-treated patients most frequently reported central nervous system-related side effects (drowsiness and sedation), while buspirone-treated patients most frequently reported gastrointestinal system-related side effects (appetite disturbances and abdominal complaints).     

Alprazolam (Xanax, the Upjohn Company)

Alprazolam is a triazolobenzodiazepine, a derivative of the benzodiazepines. Comparison studies of alprazolam and diazepam or chlordiazepoxide in patients suffering from clinical anxiety secondary to anxiety neurosis or chronic alcohol withdrawal suggest an equal efficacy of those agents. Studies examining the use of alprazolam for the treatment of "primary depression" suggest that it is as effective as imipramine in the treatment of exogenous (reactive) depression. Although alprazolam may be effective in patients with exogenous depression, no extrapolation can be made to the treatment of endogenous depression. Mechanisms of action have not been fully elucidated, but probably are similar to those of other benzodiazepines. Peak blood levels are reached in 0.7-1.6 hours and the elimination half-life after steady state is approximately 19 hours. Daily dosages established from clinical studies ranged from 1 to 6 mg. Clinically, alprazolam appears to be ten times more potent than diazepam. Drowsiness, headaches, lightheadedness, dry mouth, and depression appear to be the most common side effects of the drug. It is concluded that alprazolam offers no striking therapeutic advantage over currently marketed benzodiazepines.     

A double blind comparison of alprazolam,diazepam and placebo in the treatment of anxious out-patients

The anxiolytic effects of alprazolam, a triazolobenzodiazepine, were evaluated in a double-blind 28-day comparison with diazepam and placebo in 46 out-patients suffering from anxiety states of moderate to severe intensity. Alprazolam 1.5-3 mg per day was found to be of at least equivalent anxiolytic effect to 15-30 mg diazepam per day, and there was evidence of antidepressant activity by alprazolam, but not diazepam, in neurotic depression. Side-effects occurred least often with alprazolam and were minor in nature. Laboratory data showed no changes attributable to alprazolam even in a patient who swallowed 15 capsules (7.5 mg). It was concluded that alprazolam is a safe and effective anxiolytic which is well-tolerated and also shows some antidepressant activity.     

Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression

Alprazolam is a triazolobenzodiazepine which is related to diazepam and other 1,4-benzodiazepines, and has a similar pharmacological profile. Relative to the newer benzodiazepines, alprazolam has an intermediate half-life of 10 to 12 hours in healthy young subjects. In placebo-controlled and double-blind comparative trials in patients with anxiety, alprazolam was of comparable efficacy to diazepam and generally caused a lower incidence of drowsiness. Alprazolam has antidepressant activity and has been shown to be similar in efficacy to imipramine in the treatment of unipolar depression. Thus, alprazolam may be particularly useful in patients with mixed anxiety/depression. However, its general acceptance as an antidepressant awaits further studies.     

Alprazolam and diazepam in the treatment of generalized anxiety

In a 4-week double-blind study comparing alprazolam with diazepam treatments, 48 outpatients suffering from mild to moderate generalized anxiety were evaluated after a 5-day placebo washout, and then after 1, 2, and 4 weeks of treatment. The optimal therapeutic doses without excessive sedation averaged 2 mg for alprazolam and 15.8 mg for diazepam. Results from the Hamilton Anxiety Rating Scale, the Clinical Global Impression Scale, a behavior checklist questionnaire, and a symptomatic patients' self-rating scale indicated that patients improved in both treatment groups. Results from the comparative phase suggest that diazepam is more efficient than alprazolam in the reduction of several symptoms of anxiety and depression in particular. Assuming that the first 2-week ratings depend on accuracy of dose adjustment and that week 4 ratings are an important evaluation of long-term efficacy, results from this study suggest that adequate control of anxiety is obtained more readily with diazepam and that symptoms of depression might benefit more from that drug. Few side effects were reported: mainly, drowsiness, tremor, light- headedness , and dry mouth. A toxic reaction to alprazolam, possibly allergic, was observed. Either alprazolam or diazepam appeared to be effective in the treatment of generalized anxiety disorder, and the statistically significant differences between the two drugs were not clinically striking.     

Effects of single doses of alprazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects of alprazolam, alone and in combination with ethanol, on psychomotor and cognitive performance were studied in healthy male volunteers and compared to effects of diazepam. Alprazolam 2 mg produced relatively long-lasting impairments on tests of tracking, verbal and nonverbal information processing, and memory, and decreased blood pressure without a change in heart rate or plasma norepinephrine levels. Although ethanol consumption was demonstrated to produce additive decrements in performance on certain tasks, there was little evidence to support a synergistic effect. Alprazolam 2 mg was accompanied by increased selfreports of side effects, especially drowsiness. Low dose alprazolam, diazepam, and ethanol produced significantly fewer side effects than 2 mg alprazolam, but significantly more than placebo.     

A double-blind clinical trial of alprazolam, imipramine, or placebo in the depressed elderly.

The efficacy and safety of alprazolam as compared to imipramine or a placebo added to weekly interpersonal psychotherapy was compared in a 6-week double-blind randomized clinical trial of 35 ambulatory elderly patients with major depression. The average maximum dosage of alprazolam was 2.2 mg and the average maximum dosage of imipramine was 97.5 mg. The findings showed a rapid onset of action of alprazolam within 1 week on symptoms of depression and anxiety. The effects for imipramine were seen later in the study. There were no serious side effects that interfered with treatment. The anticholinergic effects of imipramine were the ones that most commonly interfered with treatment. Alprazolam produced the greatest number of symptoms with discontinuation, most of which were alleviated within a week. We conclude that alprazolam may be useful as an antidepressant for the elderly. More clinical trials are needed to test its efficacy in the depressed elderly with concomitant medical problems, using plasma levels. A double-blind discontinuation study of alprazolam is needed to determine the degree of symptom return.     

Controlled Comparison of Tianeptine,Alprazolam and Mianserin in the Treatment of Adjustment Disorders with Anxiety and Depression

A multicentre study compared tianeptine (37·5 mg/day), an original psychotropic compound characterized by both antidepressant and anxiolytic potentials, with a reference antidepressant, mianserin (60 mg/day) and a reference anxiolytic, alprazolam (1·5 mg/day), in the treatment of 152 patients fulfilling DSM-III-R criteria for adjustment disorder with mixed emotional features (anxiety and depression). The study used a double-blind parallel design over a 6-week period. Clinical assessments included the Clinical Global Impressions (CGI), the Montgomery and Asberg depression rating scale (MADRS), the Hamilton anxiety rating scale, a visual analogue scale, and the somatic scale of the system developed by the Association for the Methodology and Documentation in Psychiatry (AMDP). Results showed very similar improvement in the three treatment groups on all rating instruments. Moreover, the number of patients exhibiting adverse events did not differ among the three groups. Therefore, these results show similar antidepressant and anxiolytic activity for tianeptine, mianserin and alprazolam in patients suffering from adjustment disorder with mixed emotional features. These promising findings should however be confirmed in a placebo-controlled trial.     

Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature

Alprazolam is a benzodiazepine derivative that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered. An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated. In addition to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clinical studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car.     

Alprazolam abuse in Texas, 1998-2004

Alprazolam (Xanax) is used in the treatment of anxiety, depression, and panic attacks, and is subject to abuse. The objective of this study was to describe the patterns of alprazolam abuse and drug identification (ID) calls received by several poison control centers. Cases were alprazolam calls received by 6 poison control centers during 1998-2004. Of 25,954 alprazolam calls received, 42% were drug ID calls and 51% were human exposure calls, of which 18% were abuse calls. The number of drug ID calls and the number of abuse calls both increased during the 7-yr period. Male patients accounted for 54% of abuse calls and females for 66% of nonabuse calls. Adolescent patients comprised 43% of abuse calls but only 12% of nonabuse calls. Although the majority of both types of human exposures occurred at the patient's own residence, abuse exposures were more likely than other exposures to occur at school (9% vs. 1%) and public areas (6% vs. 1%). While abuse calls were less likely than nonabuse calls to have no adverse clinical effects (19% vs. 23%), they were more likely to have minor medical outcomes (60% vs. 50%). Alprazolam abuse in Texas appears to be increasing. Alprazolam abusers are more likely to be male and often adolescent. Alprazolam abuse as compared to other exposures is more likely to occur outside of the person's home. Alprazolam abuse is more likely to involve some sort of adverse medical outcome.     

Anticipatory anxiety in moderately to highly-anxious oral surgery patients as a screening model for anxiolytics: evaluation of alprazolam

Alprazolam, a benzodiazepine anxiolytic, was evaluated in anxious patients prior to oral surgery. This population represents a possible acute screening model for novel anxiolytic agents. Healthy subjects, preselected for a moderate to high degree of dental anxiety based upon Corah's Dental Anxiety Scale, were enrolled in a three-arm parallel design study and randomly assigned to receive double-blind placebo (N=15), alprazolam 0.25 mg (N=16) or alprazolam 1 mg (N=16). Subjective self-reported anxiety was rated using the State Anxiety Inventory and visual analog scales. Objective measures included galvanic skin conductance, heart rate variability, blood pressure, pulse rate, and respiration. At 90 minutes after dosing, there were statistically significant (p<0.05) reductions compared with placebo in subjective anxiety and skin conductance mean level for the alprazolam-treated subjects. Changes from pre-dose (mean +/- SEM) at 90 minutes in the placebo, alprazolam 0.25 mg, and alprazolam 1 mg groups were -4.73 +/- 2.79, -13.75 +/- 2.49, and -12.81 +/- 2.32 for the State Anxiety Inventory and 5.44 +/- 6.71, -31.88 +/- 5.88, and -32.34 +/- 5.32 mm for analog anxiety scores. Corresponding skin conductance mean level at 100 minutes in the three groups (respectively) changed 0.64 +/- 0.24, -0.53 +/- 0.21, -0.71 +/- 0.22 microSiemens. The 0.25 mg and 1 mg dosages of alprazolam were not differentiated. Changes in heart rate variability, blood pressure, pulse rate, and respiration did not reflect subjective anxiety. Overall, the oral surgery anticipation anxiety model was found to be a sensitive test for benzodiazepine anxiolytic activity and may represent a potential screening model for evaluation of investigational agents.     

Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients

The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.     

Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder

Only 70% of patients respond to current treatments for panic disorder, and many discontinue drugs because of side effects. myo-Inositol, a natural isomer of glucose and a precursor for the second-messenger phosphatidyl-inositol system, has previously been found superior to placebo in the treatment of depression, panic disorder, and obsessive-compulsive disorder (OCD), but a direct comparison with an established drug has never been performed. A double-blind, controlled, random-order crossover study was undertaken to compare the effect of inositol with that of fluvoxamine in panic disorder. Twenty patients completed 1 month of inositol up to 18 g/day and 1 month of fluvoxamine up to 150 mg/day. Improvements on Hamilton Rating Scale for Anxiety scores, agoraphobia scores, and Clinical Global Impressions Scale scores were similar for both treatments. In the first month, inositol reduced the number of panic attacks per week (mean and SD) by 4.0 (2) compared with a reduction of 2.4 (2) with fluvoxamine (p = 0.049). Nausea and tiredness were more common with fluvoxamine (p = 0.02 and p = 0.01, respectively). Because inositol is a natural compound with few known side effects, it is attractive to patients who are ambivalent about taking psychiatric medication. Continuing reports of inositol's efficacy in the treatment of depression, panic disorder, and OCD should stimulate replication studies.     

Pilot study of zatosetron (LY277359) maleate, a 5-hydroxytryptamine-3 antagonist, in the treatment of anxiety

The aim of this study was to make a preliminary investigation of the efficacy and safety of zatosetron maleate, a selective 5-hydroxytryptamine-3 receptor antagonist for patients with a broad range of anxiety symptoms. A double-blind, parallel, placebo-controlled pilot study was conducted in 43 patients, aged 18 to 65 years, scoring >17 on the Hamilton Rating Scale for Anxiety (HAM-A). Patients were randomly assigned to either a fixed oral dose of 0.2, 1, or 5 mg of zatosetron or placebo for 4 weeks, followed by a 2-week placebo phase. Enhanced blinding procedures reduced the influence of side effects on efficacy ratings and obscured phases of the research design to patient and clinician. A change in HAM-A scores from baseline to endpoint was the principal efficacy measure; HAM-A Psychic and Somatic subscales, the Symptom Checklist-90, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions Scale subscales provided secondary change indices. Adverse events (AEs) (spontaneously mentioned and elicited with the Udvalg for Kliniske Unders?gelser side effect rating scale), vital signs, electrocardiographic findings, and laboratory analytes were compared among treatment groups. Eighty-eight percent of the patients met the criteria for generalized anxiety disorder. No statistically significant differences in outcome measures differentiated among the four treatment groups. However, a pattern of greater change in the HAM-A scores seemed to favor zatosetron over placebo. Placebo was associated with only modest HAM-A score changes and a 30% response rate. The greatest numeric decrease in the HAM-A score and the highest response rate (45%) occurred in the groups receiving 0.2 and 1 mg of zatosetron. The secondary measures of efficacy demonstrated similar outcomes. There were no deaths or serious AEs reported in this study. This pilot study demonstrated that zatosetron at doses of 0.2 to 5 mg/day was safe. Although statistical significance was not achieved, the results show a greater numeric trend toward reducing anxiety with zatosetron than with placebo.     

Predictors of individual differences in alprazolam self-medication

Twenty-seven patients with generalized anxiety or panic disorder participated in a 6-week outpatient study. Participants received capsules containing either alprazolam or placebo and were free to choose between them for anxiety treatment. Measures of drug use included alprazolam preference, amount, and frequency of use. Alprazolam clearly was preferred over placebo; however, there were large between-subjects differences in the amount of medication used. A variety of demographic, drug history, personality, mood, and expectational variables were examined for correlation with medication use. Findings indicated that a substantial amount of variance in medication use could be explained by patients' intake characteristics. Findings also suggested that the tendency to consume capsules frequently may signal a greater risk factor for dependence than does drug preference in and of itself.     

Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs

The objective of this study was to ascertain the relationship of alprazolam plasma levels and an anxiety-prone cognitive style to the characteristics and severity of early withdrawal after abrupt discontinuation of alprazolam in 26 patients with panic disorder. After 8 and 9 weeks of fixed-dose treatment, patients were hospitalized for 24 hours. On 1 admission, ordered at random, treatment was maintained; on the other, placebo was substituted double blind. The Anxious Thoughts and Tendencies questionnaire was administered before treatment. Alprazolam plasma levels were measured 7 times on the day after each admission. Before each blood sampling, the Profile of Mood States and performance tasks were administered, and vital signs were recorded. On the day after abrupt discontinuation of alprazolam, Profile of Mood States anxiety, depression, fatigue, and confusion increased; vigor and elation decreased; speed on the digit symbol substitution task improved; and systolic blood pressure increased substantially over time. High Anxious Thoughts and Tendencies scores were related specifically to more anxiety. Our findings (1) confirm that dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure are part of the early syndrome of withdrawal from alprazolam in patients with panic disorder, notably as the drop in plasma levels approaches 50%; (2) indicate a psychomotor deficit persisting beyond dose stabilization; (3) suggest that an anxiety-prone cognitive style measurable before undertaking treatment may be a risk factor for more severe anxiety upon discontinuation; and (4) provide a rationale for applying cognitive behavior therapy during benzodiazepine taper.