Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder. 2.5 year naturalistic follow-up study

Sixty patients with agoraphobia with panic attacks or panic disorder who completed a 4-month combined drug and behavioral group treatment program and were discharged on a regimen of alprazolam were interviewed 1.7 to 4 years (mean, 2.5 years) after discharge. At follow-up (FU), 18 (30%) of the patients had discontinued alprazolam treatment, 36 (60%) continued with a lower dose, 3 (5%) received the same dose, and 3 (5%) received an increased dose compared with discharge. A lower frequency of panic attacks at admission was associated with an increased ability to discontinue alprazolam treatment. There was little evidence of tolerance to the antipanic effects of alprazolam. Panic attack frequency dropped from a mean of 4.4 attacks per week at admission to 1.2 attacks per week at discharge and remained decreased at 1.6 attacks per week at FU. Treatment gains in the program were maintained or enhanced on 11 of 14 behavioral measures at FU and were similar in the groups that were receiving and not receiving alprazolam. Patients receiving nonpharmacologic therapy in the FU period tended to have greater symptom severity, possibly due to self-selection. A lifetime diagnosis of major depression at admission was associated with higher levels of depressive and anxiety symptoms and higher alprazolam doses at FU. Episodes of major depression were common in the FU period and did not appear to be prevented by initial alprazolam and behavioral therapy or by low-dose alprazolam maintenance.(ABSTRACT TRUNCATED AT 250 WORDS)     

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 plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.     

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).     

Benzodiazepine treatment of panic disorder: a comparison of alprazolam and lorazepam

The antipanic efficacy of alprazolam and lorazepam was evaluated in 48 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder in a double-blind random assignment study. On the basis of rating scale scores, both drugs demonstrated similar efficacy in reducing panic attacks and phobic behavior compared with placebo baseline. The doses required to achieve response were approximately double those required for the treatment of generalized anxiety. These results suggest that most, if not all, benzodiazepines may be effective antipanic drugs at high doses. The implications of these findings for drug treatments of choice for recurrent panic attacks are discussed.     

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.     

Milnacipran in panic disorder with agoraphobia and major depressive disorder: a case report

A 51-year-old woman had panic disorder with agoraphobia and major depressive disorder sequentially. The aforementioned symptoms subsided significantly after treatment with milnacipran, 125 mg, administered daily for 2 months. However, panic attacks with agoraphobia were noted frequently when she tapered down milnacipran to 50 mg daily. She consequently experienced depression that gradually increased in degree, with poor energy, poor sleep, thoughts of helplessness, and ideas of death. After administration of a daily dose of 125 mg of milnacipran for 1 month, her panic attacks with agoraphobia and depressed mood were again alleviated. The present report shows significant effects of milnacipran on the comorbidity of panic disorder with agoraphobia and major depressive disorder.     

Tritiated imipramine binding to platelets is decreased in patients with agoraphobia

Controversy exists regarding the relationship between anxiety states and major depression. We studied the binding of tritiated imipramine to platelet membranes in order to determine if patients with agoraphobia and panic attacks differed from depressed subjects or healthy volunteers on this biological parameter. Mean (+/- SD) Bmax and Kd values were significantly lower in patients with agoraphobia and panic attacks (787 +/- 276 fmole/mg protein and 0.35 +/- 0.14 nM, respectively) than in healthy volunteers (1237 +/- 201 fmole/mg protein and 0.71 +/- 0.37 nM, respectively). In addition, patients with agoraphobia and panic attacks had binding parameters that were similar to those of patients with bipolar or familial pure depressive disorder, but significantly lower than those of patients with depressive spectrum or sporadic depressive disorder. These findings have implications for both the nosology and pathophysiology of anxiety disorders.     

Alprazolam treatment for panic disorders

Office records of 27 private patients who were treated with alprazolam for panic disorders were evaluated by a second psychiatrist. Alprazolam treatment led to a complete remission of panic attacks in 85% of the patients; panics ceased within an average of 6 days, at a mean dose of 2.2 mg/day. In addition, alprazolam was found to bring about a complete absence of phobic avoidance behavior in 21 of the 23 agoraphobic patients in the group. This is the first study to demonstrate the efficacy of medication alone as a treatment for agoraphobia.     

HPA axis disturbance and treatment outcome in panic disorder

Some patients with panic disorder exhibit an abnormal response to dexamethasone. As this phenomenon may reflect disturbances in the central noradrenergic system and as alprazolam may work through this system to produce improvement, we predicted a particularly robust response among nonsuppressors. Fifty-two patients with panic disorder or with agoraphobia with panic attacks were given alprazolam as the sole treatment during either of 2, 8-week, double-blind, placebo-controlled trials. Though baseline clinical severity predicted globally rated outcome, baseline Dexamethasone Suppression Test results did not.     

Panic disorder with and without agoraphobia: comorbidity within a half-year of the onset of panic disorder

The present study was performed to compare the clinical features of patients with panic disorder with and without agoraphobia. The subjects were 233 outpatients with panic disorder (99 males and 134 females) diagnosed according to DSM-IV criteria. Sixty-three patients met the criteria for panic disorder without agoraphobia, and 170 met the criteria for panic disorder with agoraphobia. Patients with agoraphobia showed a significantly longer duration of panic disorder and higher prevalence of generalized anxiety disorder. However, there were no significant differences in prevalence of major depressive episodes, in current severity of panic attacks, or in gender ratio between the two groups. The second aim of the present study was to investigate the effects of onset age and sex differences on the development of agoraphobia within a half-year. The subjects were divided into two groups according to their self-report: patients who did or did not develop agoraphobia within 24 weeks of onset of panic disorder. A total of 40.6% of the patients developed agoraphobia within 24 weeks of the onset of panic disorder, and onset age and sex differences had no robust effect on the development of agoraphobia within 24 weeks.     

Treatment of panic disorder and agoraphobia with clonazepam

Clonazepam, a high-potency benzodiazepine marketed for the treatment of minor motor epilepsy, was used to treat 50 patients with panic disorder (N = 22) or agoraphobia with panic attacks (N = 28). Of the 50 patients, 41 had previously been poorly responsive to standard pharmacologic therapies. At a mean dose of only 1.9 (+/- 1.0) mg/day, 39 patients (78%) responded. No serious adverse effects were encountered. This study, although retrospective and uncontrolled, suggests that clonazepam, like alprazolam, may be effective in blocking panic attacks. A possible common mechanism for the two drugs as high-potency benzodiazepines is discussed.     

The diagnosis and management of panic disorder

The diagnosis of panic disorder without agoraphobia can very often be quite difficult because of the similarity with physical disorders particularly in the cardiac, gastrointestinal or neurological systems. The distinction must be made between panic attacks appearing as medical problems and medical problems appearing as panic attacks. Sometimes the diagnosis of panic attacks is made only after the medical diagnoses have been excluded. Panic disorder with agoraphobia however is much easier to detect if one carefully traces the historical development of agoraphobia and carefully distinguishes between the anxiety produced by agoraphobia and the panic attacks related to panic disorder. Panic disorder must also be distinguished from other anxiety disorders since the treatment for panic disorder still is quite specific. Once diagnosed however, the treatment of panic disorder without agoraphobia is rather simple. It involves the use of a benzodiazepine, either alprazolam or clonazopam, and perhaps the concomitant use of either imipramine or phenelzine sulfate for the rapid control of anxiety symptoms and continued treatment of the disorder. It is also very helpful to have the patient in psychotherapy either using a supportive or cognitive approach. If the patient has a panic disorder with agoraphobia, the pharmacological approach is the same, with the initiation of treatment using either alprazolam or clonazopam, but the psychotherapeutic approach is somewhat different in that behavioral therapy is emphasized rather than purely supportive or cognitive approaches. Given the fact that 1%-2% of the population is at risk for panic disorder, it is important that the condition be rapidly recognized and treated effectively since the currently available modalities of treatment result in almost total resolution of symptoms. Some individuals will remain on medication for several years while others will find it possible to decrease and/or discontinue their medications after only a few months or a few years. There is little excuse at this point for this disorder to be ineffectively diagnosed or treated.     

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.     

Clonazepam in the treatment of patients with recurrent panic attacks

Imipramine, phenelzine, and alprazolam have each been shown to be efficacious in the treatment of panic disorder and in agoraphobia with panic attacks. Clonazepam is a high-potency 1,4-benzodiazepine derivative with an intermediate to long elimination half-life that is used mainly in neurology as an antiepileptic. Eight cases of recurrent panic attacks successfully treated with clonazepam are reported.     

A 15-year follow-up study of patients with panic disorder

BACKGROUND: Panic disorder (PD) is generally regarded as a chronic condition with considerable variation in severity of symptoms. AIMS: To describe the long-term outcome of naturalistically treated PD. METHODS: Fifty-five outpatients with PD, who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study. RESULTS: Complete recovery (no panic attacks and no longer on medication during the last 10 years) was seen in 18% of patients, and an additional 13% recovered but were still on medication. Fifty-one percent experienced recurrent anxiety attacks whereas 18% still met diagnostic criteria for PD. The incidence of agoraphobia decreased from 69% to 20%. Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission, although both groups reported improved daily functioning at follow-up. Maintenance medication was common. No benzodiazepine abuse was reported. CONCLUSION: PD has a favourable outcome in a substantial proportion of patients. However, the illness is chronic and needs treatment. The short-term treatment given in the drug trial had no influence on the long-term outcome.     

Panic factor: Outcome variable in panic disorder

Several recent studies have failed to find significant improvement in the number of panic attacks treated with usually effective medication. We present the panic factor as a more appropriate outcome measure. We studied 208 patients who participated in a multicenter 6-week double-blind randomized trial to evaluate extended release alprazolam, alprazolam and placebo. Patients met DSM-III-R criteria for panic disorder and agoraphobia. Patients kept a panic diary. The panic factor equalled the total number of panic attacks multiplied by the duration and intensity of the attack. The log of the factor was used in combination with MANOVA. The results showed that using the log transformed panic factor there is a probable improvement for the two active treatments over placebo in the survivor analysis; this becomes a highly significant difference on endpoint analysis. Consistent trends favoring active treatment over placebo using traditional analysis become highly significant using the log transformed panic factor.     

Problems with tricyclic antidepressant use in patients with panic disorder or agoraphobia: results of a naturalistic follow-up study

The authors followed up 107 patients with panic disorder or agoraphobia with panic attacks who had been placed on a regimen of tricyclic antidepressant treatment 1 to 4 years earlier. Sixty-three percent reported at least moderate improvement during treatment; however, side effects were often difficult to tolerate, and 35% discontinued tricyclic treatment on this account. Overstimulation, which occurred in 20%, was the most frequent reason for early termination, and weight gain, which occurred in 34%, was the most common reason for stopping the drug later on. Seizures occurred in 2 patients. Even though they were encouraged to discontinue drug use, most of the patients who had responded were still taking their drugs at follow-up. More than half of those who had responded before stopping drug treatment subsequently relapsed. The findings highlight problems with safety, side effects, and patient acceptance resulting from the use of tricyclic antidepressants in patients with anxiety disorders.     

Four Clinical Types of Panic Disorders

Abstract: The authors attempted to classify panic disorders into four types according to a clinical course and accompanying neurotic or depressive symptoms. The characteristics of each type are as follows; type I: a single panic attack is the only symptom, type 11 : only panic attacks occur frequently without any accompanying neurotic or depressive symptoms, type III: a recurrence of panic attacks and the gradual development of neurotic symptoms, such as anticipatory anxiety, generalized anxiety, agoraphobia, or hypo-chondriasis, type IV: depressive symptoms develop in the course of recurring panic attacks. Type IV is further divided into three subtypes. Type IV- 1 : depressive symptoms develop secondary to panic attacks and major depression later coexists with panic disorder. Type IV- 2 : panic disorder continuously changed into major depression. Type IV- 3 : panic attacks and depressive symptoms are seen independently. The most common types are type III and type IV-1, and seem to be a core group of the panic disorder. Typical cases of each type are presented and underlying psychopathology is discussed.     

Three cases of panic disorder with agoraphobia in children

The authors report three cases of panic disorder with agoraphobia in children, with characteristic panic attacks, separation anxiety, and fear and avoidance of crowds and public places. The panic and agoraphobic symptoms responded to medications effective with agoraphobic adults, i.e., imipramine and alprazolam.