Cardiovascular and symptomatic reduction effects of alprazolam and imipramine in patients with panic disorder: results of a double-blind, placebo-controlled trial

Seventy-nine patients with panic disorder were randomized to an 8-week double-blind treatment with alprazolam, imipramine, or placebo. Patients kept daily records of panic attacks, activity, anxiety, sleep, and medication use. Weekly measures of anxiety, depression, somatic symptoms, fears, avoidance, disability, and improvement were obtained. All patients underwent a symptom-limited exercise treadmill and other cardiovascular measures. By physician and patient global assessment, patients receiving alprazolam or imipramine were significantly better than patients on placebo. The alprazolam effects were apparent by week 1; the imipramine effects by week 4. All groups showed significant reductions in anxiety, depression, somatic measures, and panic attack frequency. At 8 weeks, patients in the alprazolam group reported significantly less fear than patients in the other two groups. Subjects in the imipramine group showed a significant increase in heart rate and blood pressure.     

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 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 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.     

A Double-Blind Comparison of Sertraline and Imipramine in Outpatients with Major Depression: Acute (8 Weeks) and Continuation (16 Weeks) Treatment

In a double-blind multicentre trial in patients with major depression, the efficacy and the tolerability of sertraline were compared to those of imipramine, during an 8-week acute treatment phase followed by a 16-week continuation treatment phase in treatment responders. A total of 104 patients who met DSM-III-R criteria for major depression, HAM-D 17-item≥18 and Raskin Depression score>Covi Anxiety score, were randomized to receive either sertraline or imipramine. The initial daily dosage of 50 mg of sertraline or imipramine was rapidly titrated upwards in increments of 50 mg/day at weekly intervals, tolerability permitting, to a maximum of 200 mg/day by the fourth week. Eighty-eight patients completed at least 3 weeks of treatment and were included in the efficacy evaluable population. Both treatment groups demonstrated similar improvements on depression and anxiety rating scales during acute treatment, however, sertraline demonstrated significantly more improvement relative to imipramine on the HAM-D and Covi Anxiety scales after 1 week of treatment. Sertraline was more effective (HAM-D 17-item, CGI-S, SCL-56 Total score, SCL-56 Depression score, Covi Anxiety score) than imipramine in reducing depressive symptoms at the end of 24 weeks of treatment. There were significant improvements in all rating scales at week 24 relative to week 8 in the sertraline group but not in the imipramine group. The SCL-56 Total score, SCL-56 Depression score, Raskin Depression score and Covi Anxiety score at week 24 relative to week 8 showed significantly greater improvement in the sertraline group compared to the imipramine group. Imipramine was associated with a significantly higher incidence of dry mouth, sweating, constipation, palpitations, and a significantly higher heart rate and blood pressure. Sertraline was associated with a significantly higher incidence of diarrhoea/loose stools and insomnia. This study demonstrated a faster onset of therapeutic effect for sertraline relative to imipramine, reflecting the initiation of sertraline in a therapeutic dose of 50 mg/day and the need for gradual titration of imipramine to a therapeutic dose, at the beginning of treatment. Although efficacy was similar in both treatment groups at the end of the 8 weeks of acute therapy, sertraline-treated patients continued to manifest gradual improvements in depressive and anxiety symptoms during the 16 weeks of continuation therapy such that sertraline-treated patients were significantly more improved at the end of 24 weeks of therapy. © 1997 John Wiley & Sons, Ltd.     

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 (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.     

Alprazolam-reinforced medication use in outpatients with anxiety

The reinforcing effects of alprazolam were investigated in 14 patients who had generalized anxiety or panic disorder, but were not current users/abusers of other psychoactive substances. Using a double-blind outpatient choice procedure, color-coded alprazolam (0.5 mg) and placebo capsules were provided to patients for use ‘as needed’ in the treatment of anxiety symptoms. Comparisons of alprazolam and placebo during a 2 week sampling period in which placebo and alprazolam were available sequentially revealed no significant differences on measures of medication usage or anxiety levels, although alprazolam did increase subjective ratings of drug effects/side effects. During a 4 week choice period, alprazolam was strongly preferred over placebo in 11 out of 14 patients indicating that alprazolam functioned as a reinforcer. Medication usage ranged from zero to 4.0 mg alprazolam in a day. Variations in daily medication-use were positively correlated with anxiety level fluctuations for a majority of patients. For a majority of patients, the results indicate that alprazolam functioned as a reinforcer without accompanying signs of abuse or addiction.     

Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study

The effects of an abrupt interruption of agomelatine, a new melatonergic/serotonergic antidepressant, were explored in a double-blind, placebo-controlled study. Paroxetine was used as active control. After 12 weeks of double-blind treatment with agomelatine 25 mg/day or paroxetine 20 mg/day, sustained remitted depressed patients were randomized for 2 weeks, under double-blind conditions, to placebo or to their initial antidepressant treatment. Discontinuation symptoms were assessed at the end of the first and second week of discontinuation with the Discontinuation Emergent Signs and Symptoms (DESS) checklist. One hundred and ninety-two sustained remitted patients were randomized to the 2-week discontinuation period. Patients who discontinued agomelatine did not experience more discontinuation symptoms than those who continued on agomelatine. Patients who discontinued paroxetine for placebo experienced significantly more DESS discontinuation symptoms, during the first week, compared to those who continued with paroxetine (respective mean number of emergent symptoms: 7.3+/-7.1 and 3.5+/-4.1, P<0.001). No significant difference was shown between the continuing and interrupting groups in the second week of discontinuation. By contrast to paroxetine, abrupt cessation of agomelatine is not associated with discontinuation symptoms.     

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.     

Amoxapine in depressive illness

A double-blind trial was carried out in 29 patients recently admitted to hospital with depressive illness to compare the effectiveness and side-effect liability of treatment with amoxapine and imipramine. Both drugs were given in a dosage of 25 mg 3-times daily over a period of 4 weeks, and patients' progress was assessed using psychiatric and psychological rating scales for depression. Although amoxapine and imipramine proved equally effective, response to amoxapine was quicker and appeared to have the same effect after 1 week as did imipramine after 2 weeks. In addition, dryness of the mouth was complained of most frequently by patients taking imipramine.     

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.     

The relationship of alprazolam dose to steady-state plasma concentrations

Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM-III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and alpha-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as responders within the 60 ng/ml and above group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy

Pretreatment with imipramine, buspirone, or placebo was compared in 40 patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for panic disorder and in patients who were discontinuing long-term benzodiazepine use. The average duration of benzodiazepine use was 75 +/- 64 months, and the average benzodiazepine intake expressed as diazepam equivalents was 25.7 +/- 19 mg/d. We hypothesized that pretreatment with either imipramine or buspirone, in contrast to pretreatment with placebo, would lead to a significant decrease of symptoms of anxiety and depression before tapering benzodiazepines, thus making the taper process easier to complete. All 3 treatments (imipramine, buspirone, and placebo) caused a reduction in anxiety and depression symptoms as measured by changes in the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. Neither discontinuation severity nor taper-free status 12 weeks posttaper differed between the 3 treatment groups.     

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.     

Effects of clonidine on alprazolam discontinuation in panic patients: a pilot study

Effects of adjunctive clonidine (0.15 to 0.7 mg/day) on symptoms experienced during and for 4 weeks after gradual alprazolam discontinuation were observed in panic disorder patients after 6 weeks of successful treatment. Twelve of 14 entered patients were considered to have had a sufficient period of discontinuation (2 weeks) and clonidine administration (1 week) for effects to be assessed adequately. Nine of these 12 patients reached zero dose of alprazolam in 3 to 4 weeks. However, 10 of 12 patients experienced new withdrawal symptoms and 11 of 12 experienced recurrent panic attacks during tapering. Although a greater proportion of patients were successfully discontinued in a shorter time than in a previous nonclonidine trial, clonidine did not appear to have a specific effect on relapse or withdrawal. A placebo-controlled trial is needed to discriminate between possible contributions of clonidine and other factors (e.g., physician attitude, placebo effect of pill taking) to this improved outcome.     

Treatment of Alprazolam withdrawal with chlordiazepoxide substitution and taper

We describe the first case series (n = 6) of using chlordiazepoxide to accomplish a rapid, well-tolerated withdrawal from alprazolam. After abruptly discontinuing alprazolam, we substituted a 50-mg dose of chlordiazepoxide for each 1 mg of alprazolam (except for one elderly patient where we substituted 25 mg) and gave additional chlordiazepoxide doses (25–50 mg every 4–6 hours) as needed for the first 1–2 days of hospitalization. With this approach, the mean “substitution ratio” of chlordiazepoxide to alprazolam was 86 to 1. We then tapered chlordiazepoxide by an average of 10% each day over a 7- to 14-day period according to the symptoms manifested and tolerated by individual patients. No seizures or other serious side effects occurred. Incomplete cross- dependence, as described elsewhere in the literature, was not observed. The rapidity and familiarity of the method are advantages for inpatient units, but careful titration of dosage, diagnostic clarity, and extended follow-ups are necessary when applying this approach.     

Efficacy and safety of antidepressant monotherapy in the treatment of bipolar-II depression

Sparse data exist regarding the risks and benefits of treating bipolar-II depression with antidepressants alone. On the basis of studies of bipolar-I patients, treatment guidelines suggest antidepressants should be augmented with mood stabilizers. Whether these recommendations apply to bipolar-II is unclear. A post-hoc analysis of a double-blind study, which compared the relative efficacy of placebo, imipramine and phenelzine in depressed outpatients. Patients rated 1 ('very much improved') or 2 ('much improved') on the Clinical Global Inventory Scale were considered responders. In an intent to treat analysis, no significant differences between bipolar patients (N=62) and unipolar patients (N=248) in response rates to placebo, imipramine and phenelzine were seen. No patient developed manic symptoms that required medication discontinuation or mood stabilizer augmentation. Antidepressant monotherapy was found to be a safe and effective treatment for bipolar-II depression.     

Clinical evaluation of alprazolam in patients with panic disorder: A double-blind comparison with imipramine

The antipanic effect and tolerability of alprazolam and imipramine were compared during 9 weeks in 55 inpatients with panic disorder with or without agoraphobia. Both drugs decreased significantly the frequency of panic attacks, alprazolam as early as 3 weeks of treatment. The symptoms of generalized anxiety and depression decreased similarly in both groups. The tolerability of alprazolam appeared slightly better than that of imipramine. Drug-induced anticholinergic side-effects were more frequent in the imipramine group, whereas sedation, impotency, and myoclonic jerks appeared more often in the alprazolam group.