Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects.

Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolam-treated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolam-treated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where high doses are employed.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety.

In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment.

Following promising preliminary evidence, the benzodiazepine-derivative alprazolam was studied in a large, placebo-controlled, eight-week, flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder. Of 526 patients, 481 completed three weeks of treatment; however, significantly more placebo (102/234) than alprazolam (21/247) recipients subsequently dropped out of the trial, primarily citing ineffectiveness (of placebo) as the reason. Alprazolam was found to be effective and well tolerated. There were significant alprazolam-placebo differences in improvement for (1) spontaneous and situational panic attacks, (2) phobic fears, (3) avoidance behavior, (4) anxiety, and (5) secondary disability, all significant by the end of week 1. At the primary comparison point (week 4), 82% of the patients receiving alprazolam were rated moderately improved or better vs 43% of the placebo group. At that point, 50% of the alprazolam recipients vs 28% of placebo recipients were free of panic attacks.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.

Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

Phenelzine and exposure in the treatment of phobias.

A double-blind study was carried out on 40 agoraphobic and socially phobic patients, matched, then randomly assigned to one of four treatment groups; phenelzine-exposure, phenelzine-no exposure, placebo-exposure, and placebo-no exposure. Exposure consisted of encouraging the patient to face the phobic situation a predetermined number of times. Assessments, made at the beginning and end of 8 weeks of therapy and 8 weeks thereafter, showed that the phobia ratings of groups decreased significantly. The combined exposure group improved significantly more than the combined no exposure group during treatment. At 8 weeks follow-up there was some deterioration in the phenelzine-exposure and placebo-no exposure groups. Exposure, with or without phenelzine, was the superior treatment modality. The antiphobic effect of phenelzine was not supported, although it seemed to reduce subjective anxiety during exposure experiences. The possibility that effect of phenelzine is dose-related is discussed.

Studies of a neurochemical link between depression, anxiety, and stress from [3H]imipramine and [3H]paroxetine binding on human platelets.

We measured platelet [3H]imipramine and [3H]paroxetine binding in patients with major depression (n = 11), dysthymia (n = 9), generalized anxiety (n = 18) and panic disorder (n = 10), and in healthy controls (n = 13). The [3H]imipramine binding capacity (Bmax) was lower in all patient groups; [3H]paroxetine binding was reduced in anxiety disorders, however, decreases in depression and dysthymia were not significant. There were no differences in the affinity constant (Kd) for either radioligand. We also examined the effects of examination stress on platelet binding in medical students. Compared to after vacation, when binding was similar to controls, [3H]imipramine (n = 19) and [3H]paroxetine (n = 14) Bmax values were significantly decreased during examinations and similar to patient values. Examinations were also associated with an increase in plasma cortisol levels. These findings suggest that there is a neurochemical link between depression, anxiety, and stress, and that disturbances in neurochemical functioning may be associated with specific symptomatology, independent of psychiatric diagnosis.

Cardiovascular, neuroendocrine, and monoaminergic responses to psychological stressors: possible differences between remitted panic disorder patients and healthy controls.

Both clinical symptomatology and stress research suggest that panic attacks might be partially attributable to exaggerated psychophysiological responses to environmental stressors. In the present study, we aimed to explicitly test this idea by measuring the physiological responses to a mild psychological stressor in both healthy controls (n = 8) and fully remitted, medication-free panic disorder patients (n = 8). One hour before the stressor, former patients, compared to healthy controls, exhibited higher diastolic blood pressure. From a blood sample taken 30 min before the stressor, patients, compared to controls, had lower paroxetine platelet binding site densities. During the stressor, patients, compared to controls, had greater increases in plasma levels of cortisol. These preliminary findings suggest that remitted panic disorder patients might have disturbed physiological responses to mild psychological stressors. These disturbances might be related to the development of future episodes.

Alprazolam-induced manic episode in two patients with panic disorder.

Two patients treated with alprazolam for panic disorder and agoraphobia developed a manic episode. Two biological markers--shortened REM latency and nonsuppression on the dexamethasone suppression test--suggested that both patients may have had an underlying affective disorder.

Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale. RESULTS: In intent-to-treat endpoint analyses of 203 of the patients, significantly more of the 134 patients given sertraline (N=71 [53%]) than of the 69 patients receiving placebo (N=20 [29%]) were considered responders according to their CGI improvement scores at the end of treatment. The mean reductions in the social phobia subscale of the Marks Fear Questionnaire and in the total score on the Brief Social Phobia Scale were 32.6% and 34.3% in the sertraline group and 10.8% and 18.6% in the placebo group, respectively. Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures. Sertraline was well tolerated: 103 (76%) of the 135 sertraline-treated patients and 54 (78%) of the 69 placebo-treated patients completed the study. CONCLUSIONS: Sertraline is an effective treatment for patients with generalized social phobia.

Serotonin uptake in panic disorder and agoraphobia.

Because of reports of reduced serotonin uptake in depression and the frequent association between panic disorder and depression, this study was designed to assess the neurobiologic relationship between panic disorder and depression. Platelet serotonin uptake studies were done on 47 patients with panic disorder, 17 patients with primary major depression, and 15 healthy volunteers. The authors found that the rate of uptake of serotonin to platelets (Bmax) was significantly lower in both the depressed and panic disorder groups than the healthy control group. The panic disorder patients with a present or past history of major depression had slightly higher values than the panic disorder patients without such a history.

Trimipramine, anxiety, depression and sleep.

The presence of mixed symptoms of anxiety and depression are well known to every clinician. Panic, generalised anxiety and obsessive-compulsive disorder all have considerable overlap with major depressive illness. Factor analysis of anxiety and depression symptoms has sought to predict response to treatment as well as to establish a diagnosis. Sleep disturbances are important concomitants of both syndromes. The analysis of the architecture and phasing of sleep stages has been proposed as a biological marker to separate anxiety and depression. The modification of REM and delta sleep has been correlated with antidepressant action. The earliest studies of trimipramine noted antidepressant, anxiolytic and hypnotic effects. Further observations have shown this drug to have atypical effects on REM sleep. In addition, despite its structural similarity to other tricyclic antidepressants, its pharmacological profile in animals is very different: there is no synaptosomal reuptake of serotonin or noradrenaline, and no desensitisation of beta-adrenoceptors after long term administration. A series of studies was carried out on 99 patients. Admission criteria for the studies specified a minimum score of 20 on the Anxiety Status Inventory as well as the presence of moderate depression. An uncontrolled trial demonstrated the anxiolytic efficacy of trimipramine. Further controlled trials showed superior anxiolytic efficacy of trimipramine to amitriptyline and doxepin with comparable anxiolytic efficacy of trimipramine with maprotiline. All agents had equal antidepressant effects.

Prediction of lithium response in affective disorders.

Lithium carbonate has established itself as an effective therapeutic agent in primary affective disorders. As not all the patients with primary affective disorders respond to lithium therapy, it is necessary to identify responders prior to treatment. The important indicators of favourable lithium response include a definitive diagnosis of primary affective disorder, occurrence of less than four episodes of mania and depression within one year, psychotic features during both manic as well as depressive episodes, "grandiose-elated" picture during manic episodes; a family history of bipolar illness and response of affected family members to lithium treatment. While those with more than four episodes are not likely to respond to lithium therapy, those with episodes less frequent than once a year or two may not need prophylactic lithium. Among the depressed, hypersomnic depressed patients respond to lithium combined with a monoamine oxidase inhibitor. In addition to clinical predictors of response to lithium treatment, there are a number of pharmacokinetic, neurophysiological and biochemical indices which have been employed as supplementary predictors of response to lithium therapy.

Medication discontinuation in panic disorder.

This paper addresses current issues associated with medication discontinuation in panic disorder, with specific focus on one of the most frequently used medication classes for this indication, the benzodiazepines. The majority of patients, when slowly tapered, are able to discontinue the benzodiazepines without a great deal of difficulty, particularly after short-term therapy. Patients treated with long-term therapy at high therapeutic doses may experience greater difficulty with discontinuation. If patients are adequately prepared and if discontinuation is conducted slowly and gradually, discontinuation symptoms, if they occur, are transient, mild to moderate, and generally tolerable. However, return of the original condition (relapse) during discontinuation can greatly complicate clinical management.

Past and current thyroid function in subjects with panic disorder.

Disturbances in thyroid function can result in symptoms similar to those occurring in patients with anxiety disorders, especially panic disorder. An association between thyroid illness and panic and phobic disorders has been suggested, but few studies have directly investigated this issue. To assess this possible relationship, the authors measured indices of thyroid function in 165 subjects who had a current DSM-III diagnosis of panic disorder, either with or without phobic avoidance. These subjects reported a higher prevalence of thyroid illness by history compared with the prevalence of thyroid illness in the general population; however, less than 1% of all subjects had current thyroid dysfunction. The presence of a major depressive episode (MDE) was unrelated to current thyroid function, although subjects with MDE reported a higher prevalence of thyroid disease by history. Indices of thyroid function were not correlated with the severity of panic attacks or phobias.

Trimipramine and maprotiline: antidepressant, anxiolytic, and cardiotoxic comparison.

A 5-week placebo washout comparison of trimipramine 150 mg/day and maprotiline 150 mg/day was carried out in 15 male and 24 female patients with unipolar major affective disorder. There were no significant differences between the two groups in age, sex, weight, height, or vital signs. Both groups showed significant improvement over time, with no difference between the groups on the Severity and Improvement factors of the Clinical Global Impression scale, on the total and factor subscales of the Hamilton Depression Rating Scale, and on the Anxiety Status Inventory. The maprotiline group showed a greater increase in weight over the study period than did the trimipramine group. There was a significant lowering of systolic blood pressure in the trimipramine group only and a significant and linear increase in pulse rate by Week 3 in the maprotiline group. Analysis of ECG showed that the atrial rates were significantly increased in the maprotiline group (p less than .002) but not in the trimipramine group. Trimipramine had significantly fewer anticholinergic, neurologic, and cardiovascular adverse effects than maprotiline.

A risk-benefit assessment of buspirone in the treatment of anxiety disorders.

Anxiety disorders include generalised anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD) and social phobia. Consideration of the chronicity of these disorders reveals that anxiety disorders first occur during early adolescence or young adulthood, and can wax and wane over periods of 5 to 10 years. Thus, in considering treatment, the emphasis must be placed on long term, rather than short term, management. Comorbidity studies reveal that untreated patients with anxiety disorders are at risk of social and psychological consequences, as well as disability resulting from comorbid and secondary disorders. Comparisons between buspirone and the benzodiazepines in treating patients with generalised anxiety disorder reveal that long term use of benzodiazepines is associated with adverse effects, particularly in elderly patients. Buspirone appears to have an onset of action equivalent to that of the benzodiazepines, to be well tolerated in the long term, to lack problems of habituation and withdrawal, and to be useful in patients with masked comorbid depression. In patients with panic disorder and social phobia, buspirone has not been clearly shown to be effective in comparison with the reference standards; in those patients with OCD, there are only preliminary indications of efficacy, which merit a more adjunctive role.

Comparison of lorazepam and flurazepam as hypnotic agents in chronic insomniacs.

Hypnotic efficacy and safety of 3 weeks of daily doses of 2 mg lorazepam or 30 mg flurazepam were compared in a double-blind cross-over study in eight chronic insomniacs between the ages of 29 and 60 years. Subjects were monitored in the sleep laboratory twice weekly for a total of 25 nights. Also, subjective estimates of sleep, vigilance tests, and adverse effects were recorded throughout the study. Findings indicated lorazepam performed better than flurazepam in most sleep parameters. With lorazepam there was improvement from baseline in percentage of sleep time (P less than .05); in total wake time after sleep onset (P less than .01) and in last third of night (P less than .05); in percentage of stage 2 (P less than .05) (weeks 1, 2, 3) and in percentage of night in stage 4 (weeks 2 and 3). Only total wake time from baseline improved (P less than .05) with flurazepam (week 2). Objective and subjective sleep parameters did not correlate well for either drug. Neither drug impaired REM sleep or vigilance test performance. Side effects (grogginess, lethargy; flurazepam only) were few and none was unexpected; neither rebound insomnia nor early morning insomnia occurred with either drug. In summary, both lorazepam 2 mg at bedtime and flurazepam 30 mg at bedtime were found to be effective and safe for treating chronic insomnia, as measured by parameters of sleep and daytime functioning. Lorazepam had more favorable effects on sleep than did flurazepam.

Discontinuation reactions to alprazolam in panic disorder.

Panic disorder is a chronic illness with only some degree of spontaneous recovery. It is not surprising therefore that discontinuation of an effective medical treatment may be followed by relapse. Therefore the timing and methodology of discontinuing that treatment are now recognized as essential facets of optimal clinical management. In addition to relapse, rebound and the withdrawal syndrome have been reported with many psychotropic agents, particularly with the benzodiazepines. This paper discusses data from three discontinuation studies with alprazolam i.e. the Phase I Cross-National Collaborative Panic discontinuation study after short-term treatment, the Phase I discontinuation study after long-term treatment, and data from the Montreal site of the Alprazolam SR discontinuation study. Phase I of the Cross-National Collaborative Study of Panic Disorder investigated the discontinuation of alprazolam in two populations. There was an intensive, placebo-controlled, time-limited study of discontinuation after short-term treatment (8 weeks) in the first population. For the second, there was a less rigorous open follow-up of patients who had been treated for 5-12 months with alprazolam. The dose-reduction regimen of alprazolam in both studies was approximately the same--a 1 mg decrease every 3-7 days. In the short-term treatment study, 109 patients were treated for 8 weeks, tapered for 4 weeks and observed for another 2 weeks post discontinuation. Significant relapse in the alprazolam-treated group occurred during discontinuation. Rebound of panic attacks occurred in 27% of patients given alprazolam, and distinct transient withdrawal syndrome occurred in 35%. Indicative of the withdrawal syndrome were confusion, clouded sensorium, heightened sensory perception, dysosmia, paresthesias, muscle cramps, muscle twitch, blurred vision, diarrhea, decreased appetite, and weight loss. The clinical course in the alprazolam-treated patients revealed a marked exacerbation of symptoms during the end of the tapering period and the first week without medication, which was followed by improvement during the second post-taper week. In the long-term treatment study, 142 patients were treated with alprazolam for periods ranging from 5 months to 1 year (mean, 27.5 weeks). In this naturalistic study, 76% of the patients reported improvement, 6.3% reported no change, and 10.6% reported that they were worse. During discontinuation, 12.8% of the 128 patients whose dosage was tapered reported some kind of nonspecified withdrawal symptoms. Of the 142 patients, 47.2% were able to taper their medication dosage and to discontinue treatment; 19.7% tapered but restarted alprazolam shortly after discontinuation; 33.1% were unable or unwilling to taper or discontinue alprazolam.(ABSTRACT TRUNCATED AT 400 WORDS)

Sequence of improvement in agoraphobia with panic attacks.

In a multi-center comparison of alprazolam to placebo in the treatment of agoraphobia with panic attacks, the sequence of sustained remission in both treatment groups, was panic attacks before phobias. This may suggest that phobias are secondary to panic attacks in the pathogenesis of the disorder, although other explanations may account for these data and are discussed.

Platelet imipramine binding in patients with panic disorder and major familial depression.

Platelet 3H-imipramine binding was investigated in 15 normal subjects, 17 patients with major depressive disorder and 43 patients with panic disorder, to further study the relationship between depressive and anxiety disorders. Whereas patients with major depression had a significantly lower mean Bmax value than healthy volunteers, mean Bmax values in patients with panic disorder did not differ significantly from normal controls. Furthermore, apparently normal Bmax values were observed even in those panic disorder patients who had concurrent major depression or a past history of depression. Thus, despite previous findings of an overlap between panic and depressive disorders, the present results suggest that the two syndromes may have distinct neurochemical substrates.