Treatment of agoraphobia with group exposure in vivo and imipramine

Seventy-six white agoraphobic women, 21 to 45 years old, were treated with combined group exposure in vivo and imipramine or placebo in a randomized double-blind study. A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement. However, imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement: primary phobia, spontaneous panic, and global improvement. There was a negative correlation between depression and outcome; ie, the more depressed patients fared worse on several outcome measures than those who were less depressed. A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment, but no significant difference between the two groups at the completion of therapy.     

A meta-analysis of treatments for panic disorder with agoraphobia: imipramine, alprazolam, and in vivo exposure.

The most common pharmacological treatments for panic disorder with agoraphobia (PDA) include the use of imipramine and alprazolam while the most common behavior therapy is the use of graded in vivo exposure. Several studies have found these treatments to be superior to placebo in the treatment of PDA, but it has not been clear if there are differences among these three treatments. It has also not been clear for what aspects of PDA each treatment is the most effective. The purpose of this study was to conduct a meta-analysis of the results of relevant treatment outcome studies on a number of dependent variables (e.g., panic attack severity, dysphoria, avoidance behavior). Few studies satisfied the minimum criteria for inclusion and the final data pool consisted of 34 treatment studies. Imipramine was found to be generally ineffective for most variables. Alprazolam was significantly effective for panic and anxiety variables in PDA, while exposure was significantly effective for phobia variables. Exposure had the most consistently strong effect sizes.     

Phenelzine v imipramine in atypical depression. A preliminary report

Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranoia factors of the 90-item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to pheneizine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.     

Sequential combination of imipramine and self-directed exposure in the treatment of panic disorder with agoraphobia

Thirty-eight patients who had panic disorder with agoraphobia completed 8 weeks of treatment with imipramine followed by 8 weeks of treatment with imipramine combined with behavior therapy consisting of self-directed exposure. Sixty-three percent (24) of the patients responded markedly to this cost-effective combined pharmacologic and behavioral approach. Results also revealed that most of the improvement in panic occurred during the first 8 weeks of treatment when imipramine treatment alone was used, whereas improvement in severity, anxiety, depression, and phobias, in particular, continued to be significant between midtreatment and end of study. Further analysis revealed that improvement in phobic anxiety and avoidance in the first 8 weeks of treatment, rather than improvement in panic, predicted final outcome. Implications of these findings on the complex issue of differential antipanic and antiphobic effects of imipramine are briefly discussed.     

Treatment of panic and agoraphobia. An integrative review

There is now agreement about the clinical features of panic disorder and agoraphobia but less agreement about treatment because of controversy over whether the disorder is primarily biological or psychological. The authors were requested to produce an impartial review for continuing education and peer review. We chose to do this by using a quantitative review procedure, by providing a bibliography of studies, and by a literature review. We found that symptoms of panic and phobia did not change significantly while on wait-list control or while receiving placebo. The evidence for the efficacy of the low-potency benzodiazepines or of monoamine oxidase inhibitors was limited. It was also clear that only limited improvement can be expected from behavior therapies that do not involve exposure to the symptoms of panic or to the feared situation. Symptoms of panic, as well as the frequency of spontaneous panic, were shown to be substantially improved following imipramine, high-potency benzodiazepines such as alprazolam, exposure in vivo (especially if a cognitive anxiety management procedure was used), and the combination of imipramine and exposure in vivo. The effects on panic produced by the exposure therapies (with or without imipramine) were maintained over long follow-up periods. Imipramine, alprazolam, exposure therapy, and imipramine plus exposure each produced significant improvements in phobias. In the short term and in the long term, the larger improvements in phobias were associated with exposure therapy, particularly if used in combination with imipramine. We conclude that it would be unwise to theorize about the etiology of this disorder on the basis of response to a specific treatment because, both at the meta-analytic level and from the review of individual studies, it is clear that both drug and nondrug therapies can produce substantial and long-lasting changes in panic and in phobias.     

Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone

Data from 74 patients with panic disorder were evaluated to determine the comparative efficacy of imipramine, alprazolam, and trazodone. All patients were treated with placebo for 3 weeks and were then blindly switched to active treatment for 8 weeks. Both imipramine and alprazolam were highly effective in reducing the symptoms of generalized anxiety, the frequency of panic attacks, and phobic avoidance. However, the time course of these effects differed; alprazolam demonstrated therapeutic properties during the first week, whereas the therapeutic efficacy of imipramine was not clearly apparent until the fourth week of treatment. Relative to imipramine and alprazolam, trazodone was not an effective treatment for panic disorder and was poorly tolerated; only 17 trazodone-treated patients completed at least 4 weeks of treatment, and only 2 patients were considered good or complete responders. These findings support the hypotheses that drugs that are efficacious in the treatment of panic disorders act by altering noradrenergic function and that drugs with primary actions on serotonin function are likely to be less effective treatments. The different time courses of therapeutic action of imipramine and alprazolam indicate that these drugs ameliorate panic anxiety via different mechanisms. The possible therapeutic applications of this observation are discussed.     

Behavior therapy, supportive psychotherapy, imipramine, and phobias.

In a controlled outcome study of phobias, 111 adult patients (69% women, 31% men) received a course of 26 weekly treatment sessions consisting of (1) behavior therapy and imipramine hydrochloride (2) behavior therapy and placebo, or (3) supportive psychotherapy and imipramine. Patients were classified as agoraphobic, mixed phobic, or simple phobic. The great majority of patients in all groups showed moderate to marked global improvement (70% to 86%, depending on rater). In agoraphobics and mixed phobics (both groups experiencing spontaneous panic attacks), imipramine was significantly superior to placebo. There was no difference between behavior therapy and supportive therapy, both resulting in high improvement rates (76% to 100%, depending on rater). In simple phobic patients, there was a high rate of improvement with all treatment regimens (72% to 93%, depending on rater), with no significant difference between imipramine and placebo or between behavior therapy and supportive therapy. Of 88 moderately to markedly improved patients followed up for one year after completing treatment, 83% maintained their gains and 17% relapsed. No patients showed symptom substitution. Eighteen percent of the patients receiving imipramine hydrochloride showed marked stimulant side effects on from 5 to 75 mg/day.     

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.     

Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder?

Summary The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study (n=1134 patients); in this double blind randomized trial alprazolam, imipramine and placebo were compared during an 8-week treatment period. Patients with extensive avoidance behaviour (agoraphobia) had the most profit from the active drugs. Counter expectancy these specific drug effects were most pronounced in avoidance behaviour. Active drugs (in particular imipramine) were especially more effective than placebo if the patients presented with associated avoidance behaviour. The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder.     

Drug treatment of panic disorder: early response to treatment as a predictor of final outcome

One of the core problems in clinical research is the detection of early changes in target symptoms that predict future therapeutic outcome. To analyze potential predictors of outcome, data of a multicenter study on patients with panic disorder were used. A total of 1010 patients were randomly allocated either to alprazolam, imipramine or placebo treatment. Early improvement in the number of spontaneous panic attacks within the first week of treatment predicted outcome exclusively in the alprazolam group. In contrast, placebo responders and nonresponders were differentiated by early changes in anticipatory anxiety intensity. For tricyclic antidepressants such as imipramine an evaluation period of more than one week is required to allow conclusions about outcome.     

Psychopharmacological treatment of panic disorder and related states: a placebo controlled study of alprazolam

The paper consists of two parts. A review of the relationship of panic disorder to the phobic states and the treatment of these disorders by means of tricyclic antidepressants, MAOIs, beta blocking drugs and benzodiazepines. A double blind study of alprazolam and placebo in 118 patients with agoraphobia and panic is presented. In an eight week study alprazolam was found to be significantly superior to placebo in the treatment of panic attacks, phobic avoidance, anticipatory anxiety and general anxiety.     

Behavioural and combined therapy in panic states

This review will focus only on those paradigms for treatment of panic states with agoraphobia. Until recently the behaviour therapy literature has completely ignored panic disorder and has focused exclusively on the agoraphobic aspect of this syndrome. To summarize the behavioural therapy of panic disorder and agoraphobia, it appears that exposure is in the short run the most effective behavioural paradigm in agoraphobia. However, when contrasted with cognitive approaches it does not appear to be as effective in the treatment of panic disorder. In conclusion, it is unclear whether we can speak of antiphobic medications. Certainly studies of imipramine, chlomipramine, monoamine oxidase inhibitors, and alprazolam have demonstrated an anti-panic affect of medications and a subsequent improvement in phobic avoidance. However, when exposure is not made a part of the treatment, there is a much poorer resolution and a tendancy for the patient to relapse.     

Autonomic changes after treatment of agoraphobia with panic attacks

Twenty-three patients meeting DSM-III criteria for agoraphobia with panic attacks and 14 age-, race-, and sex-matched nonanxious controls were tested in the laboratory and on a test walk in a shopping mall. The patients were tested before and after about 15 weeks of treatment with placebo and exposure therapy, imipramine and exposure therapy, or imipramine and initial antiexposure instructions. Controls were tested twice at a similar interval, but without any treatment. On test day 1, patients compared to controls showed higher average heart rate and skin conductance levels and greater numbers of skin conductance fluctuations in the laboratory, and higher heart rates before and during the test walk. Between pretreatment and posttreatment tests, clinical ratings improved and skin conductance levels decreased in all treatment groups. Heart rate levels in the laboratory, on the other hand, decreased in patients on placebo and rose in patients on imipramine. Thus, imipramine compromises the usefulness of heart rate as a measure of emotional arousal. Higher pretreatment heart rates predicted greater clinical improvement.     

Atypical depression, panic attacks, and response to imipramine and phenelzine. A replication

In an initial study with 120 patients with reactive mood and associated atypical symptoms, phenelzine sulfate was superior to imipramine hydrochloride and placebo. Since their response to phenelzine appears to be unique, this suggests that atypical depression may be a distinct subgroup of unipolar depressive illness. Unexpectedly, the benefit of antidepressants was limited to patients who also had spontaneous panic attacks. To help establish the validity of this syndrome, a new sample of 90 atypical depressives was studied. The clinical and demographic characteristics of the original and replication sample were virtually identical at baseline. In addition, the treatment response with either placebo, imipramine, or phenelzine was also indistinguishable in the two patient groups. The outcome in the replication study supports the hypothesis that this may be a distinct unipolar depressive subgroup. In the replication sample, a history of panic attacks did not appear to be a relevant predictor. We discuss the explanations for this discrepancy in the two patient samples.     

Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine

Sixty male veterans with posttraumatic stress disorder (PTSD) participated in an 8-week, randomized trial comparing phenelzine (N = 19), imipramine (N = 23), and placebo (N = 18). Mean treatment retention was better on phenelzine (7.4 weeks) than on imipramine (5.6 weeks) or placebo (5.5 weeks). By week 5, both medications significantly reduced PTSD symptoms, as assessed by the Impact of Events Scale (IES), but the 44% improvement on phenelzine was greater than the 25% improvement on imipramine. The intrusion, but not the avoidance, subscale of the IES showed significant improvement, and the initial mild to moderate depressive symptoms did not significantly improve.     

Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear

BACKGROUND: Traditional pharmacological approaches to treating psychiatric disorders focus on correcting presumed biochemical abnormalities. However, some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy. OBJECTIVE: To determine whether D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor that has previously been shown to improve extinction of fear in rodents, will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy. DESIGN: Randomized, double-blind, placebo-controlled trial examining DCS vs placebo treatment in combination with a precisely controlled exposure paradigm. SETTING: Participants were recruited from the general community to a research clinic. PARTICIPANTS: Twenty-eight subjects with acrophobia diagnosed by the Structured Clinical Interview for DSM-IV were enrolled. INTERVENTIONS: After we obtained pretreatment measures of fear, subjects were treated with 2 sessions of behavioral exposure therapy using virtual reality exposure to heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to each of the 2 sessions of virtual reality exposure therapy. Subjects, therapists, and assessors were blind to the treatment condition. Subjects returned at 1 week and 3 months posttreatment for measures to determine the presence and severity of acrophobia symptoms. MAIN OUTCOME MEASURES: Included were measures of acrophobia within the virtual environment, measures of acrophobia in the real world, and general measures of overall improvement. An objective measure of fear, electrodermal skin fluctuation, was also included during the virtual exposure to heights. Symptoms were assessed by self-report and by independent assessors at approximately 1 week and 3 months posttreatment. RESULTS: Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures. Subjects receiving DCS had significantly more improvement compared with subjects receiving placebo within the virtual environment (1 week after treatment, P相似文献   

Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder

OBJECTIVE: To assess the efficacy and tolerability of controlled-release paroxetine (paroxetine CR) in the treatment of adults with panic disorder. METHOD: Paroxetine CR (25-75 mg/day; N = 444) was compared with placebo (N = 445) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical, double-blind, placebo-controlled, 10-week clinical trials that were pooled for analysis. RESULTS: Paroxetine CR was statistically superior to placebo in the primary outcome measure, percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint. Of the total population that completed or prematurely terminated treatment, 63% and 53% of paroxetine CR-and placebo-treated patients, respectively, were panic-free during the final 2 weeks (p < .005; odds ratio [OR] = 1.63; 95% CI = 1.21 to 2.19). For week 10 completers (72% of total), 73% and 60% of paroxetine CR- and placebo-treated patients, respectively, were panic-free at week 10 (p < .005; OR = 2.11; 95% CI = 1.45 to 3.07). Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale. Adverse events leading to study withdrawal were minimal and occurred in 11% of the paroxetine CR group and 6% of the placebo group. Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study. There were no unexpected adverse events, and serious adverse events were uncommon (10 [2.3%] of the 444 patients treated with paroxetine CR vs. 8 [1.8%] of the 445 patients treated with placebo). CONCLUSION: Paroxetine CR is an effective and well-tolerated treatment for panic disorder. Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events.     

Imipramine dose-response relationship in panic disorder with agoraphobia. Preliminary findings

At the end of a two-week single-blind placebo baseline, 43 patients with a diagnosis of panic disorder with agoraphobia without significant dysphoria-depression and with moderate to severe panic and phobic symptoms were assigned to, and 32 of them completed, a placebo-controlled (n = 7) dose-response study with three weight-adjusted imipramine hydrochloride dosages: 0.5 mg/kg/d (n = 10), 1.5 mg/kg/d (n = 9), and 3 mg/kg/d (n = 6). Eleven patients, three from the medium-dose and eight from the high-dose conditions, dropped out owing to side effects. No instructions or encouragement for self-directed exposure to phobic situations or other coping strategies with panic or fear were given throughout the trial. Compliance, as assessed by pill counts and by plasma tricyclic levels, was high. Results provided strong evidence for a positive dose-response relationship on panic and phobic symptoms and confirmed earlier suggestions (1) that imipramine without concurrent exposure possesses a significant antipanic and antiphobic effect, (2) that improvement correlates primarily with imipramine but not N-desmethylimipramine plasma levels, and (3) that side effects prevent optimum dose buildup in a substantial proportion of patients with this disorder.     

Subtyping panic disorder by major depression and avoidance behaviour and the response to active treatment

Summary In order to establish the clinical validity of currently used ways of subtyping panic disorder the predictive power of associated current avoidance behaviour and (secondary) major depression for the response to active treatment (alprazolam, imipramine) was tested. The analysis was based on the data from the Cross-National-Collaborative-Panic-Study. Limited support for validity evidenced by predicting drug response was found for grading panic disorder by the severity of avoidance behaviour: patients with panic attacks and agoraphobia are more responsive to imipramine (compared with alprazolam) when using the reduction of the total number of panic attacks (or of spontaneous panic attacks) as the outcome criterion; patients without any avoidance behaviour did better with alprazolam (compared with imipramine).     

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.