Use of medication and in vivo exposure in volunteers for panic disorder research

A survey of 794 subjects volunteering for studies of panic disorder with or without phobic avoidance revealed that fewer than 15% had received imipramine and fewer than 15% had undergone in vivo exposure, although the majority had engaged in some form of counseling and had used benzodiazepines. Subjects with spontaneous panic attacks reported more avoidance than subjects with situational attacks. One-half of the subjects were unemployed. The authors recommend wider use of the available effective treatments for panic disorder and phobic avoidance.     

A review of self-management interventions for panic disorders, phobias and obsessive-compulsive disorders

Objective: To review current evidence for the clinical and cost‐effectiveness of self‐management interventions for panic disorder, phobias and obsessive‐compulsive disorder (OCD). Method: Papers were identified through computerized searches of databases for the years between 1995 and 2003, manual searches and personal contacts. Only randomized‐controlled trials were reviewed. Results: Ten studies were identified (one OCD, five panic disorder, four phobias). Effective self‐management interventions included cognitive‐behavioural therapy (CBT) and exposure to the trigger stimuli for phobias and panic disorders. All involved homework. There was evidence of effectiveness in terms of improved symptoms and psychological wellbeing when compared with standard care, waiting list or relaxation. Brief interventions and computer‐based interventions were effective for most participants. In terms of quality, studies were mainly based on small samples, lacked long‐term follow‐up, and failed to address cost‐effectiveness. Conclusion: Despite the limitations of reviewed studies, there appears to be sufficient evidence to warrant greater exploration of self‐management in these disorders.     

Behavior therapy for panic disorder

Eleven patients who met DSM-III criteria for panic disorder were treated with behavior therapy techniques. Seven patients had mixed phobic avoidance and none were agoraphobic; three had no phobic symptoms. Mean duration of symptoms was 3.4 years. Treatment lasted a mean of 14 weeks and consisted of 1) education about physiology and management of panic symptoms; 2) relaxation, abdominal breathing, and cognitive anxiety management skills; and 3) imaginal and in vivo exposure. Upon termination of treatment, 10 of 11 patients were panic-free and six of seven mixed phobics showed complete remission or significant improvement of phobias. Follow-up data revealed excellent stability of remission. Clinical implications for the use of behavior therapy for panic disorder and directions for future research are discussed.     

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.     

A review of the psychopharmacology of panic disorder: individual differences and non specific factors

This paper critically examines the pharmacological provocation and treatment of panic disorder. An analysis of research findings on how panic attacks are induced indicates that there are psychological and non specific factors that may mediate biochemical etiological models, and these individual differences need to be investigated further. This has important implications for the psychopharmacological management of panic. A review of studies on treating panic disorder with imipramine and alprazolam emphasizes the importance of several non specific factors that include the role of self-directed in vivo exposure and changes in dysphoria and self-efficacy (subjective beliefs regarding personal competency) in predicting outcome. It is recommended that any treatment of panic-related disorders include self-directed, in vivo exposure.     

Virtual Reality Exposure Therapy for Post-Traumatic Stress Disorder and Other Anxiety Disorders

Anxiety disorders, including phobias and post-traumatic stress disorder, are common and disabling disorders that often involve avoidance behavior. Cognitive-behavioral treatments, specifically imaginal and in vivo forms of exposure therapy, have been accepted and successful forms of treatment for these disorders. Virtual reality exposure therapy, an alternative to more traditional exposure-based therapies, involves immersion in a computer-generated virtual environment that minimizes avoidance and facilitates emotional processing. In this article, we review evidence on the application of virtual reality exposure therapy to the treatment of specific phobias and post-traumatic stress disorder and discuss its advantages and cautions.     

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.     

Panic and avoidance in agoraphobia. Application of path analysis to treatment studies

We explored a causal sequence between panic and avoidance to provide recommendations for psychotherapy, pharmacotherapy, and their combination in treating agoraphobia. We produced a two-way [( imipramine hydrochloride vs placebo] by [office-based behavioral therapy vs in vivo exposure]) design by amalgamating two studies. We assessed agoraphobic patients for panic and avoidance at these time points: baseline (week 0), midcourse (week 13), and termination (week 26). The causal sequence model was tested by path analysis. Imipramine was superior to placebo in lowering panic and avoidance at both postbaseline time points. Exposure was superior to office-based treatment in lowering avoidance only at week 13. Exposure appeared to produce quicker improvement of avoidance than office-based therapy, but relapse occurred if this improvement was not supported by medication. Exposure did not benefit panic. We believe patients should be informed that imipramine is superior to exposure in inducing a panic-free state. Exposure without imipramine is of benefit only in reducing avoidance, but adding imipramine to exposure is necessary for panic control and substantially improves exposure and exposure maintenance.     

Recent advances in the psychopharmacological treatment of anxiety disorders

The authors review recent progress in the pharmacological treatment of anxiety disorders. Most research within the last five years has focused on panic disorder; the findings include support for the usefulness of imipramine and clomipramine and probably other agents; evidence that the benzodiazepines alprazolam, diazepam, lorazepam, and clonazepam are approximately equally effective as antipanic agents; and high variability in relapse rates after discontinuation of drug treatment. Further work is required to determine whether buspirone and other forthcoming serotonin agonist drugs have a role in treating panic disorder and other anxiety disorders. For generalized anxiety disorder, scientific studies do not support the effectiveness of beta blocker; tricyclics may be potentially useful. Psychopharmacological treatments for social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder are also reviewed.     

Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine

Sixty-two chronically agoraphobic patients completed a controlled study to assess the effects of 1) imipramine up to 200 mg/day (mean = 130 mg/day), 2) 12 weekly therapist-assisted in vivo exposure sessions (flooding), and 3) imipramine plus flooding. The control group received systematic therapeutic instructions for self-directed in vivo exposure (programmed practice). Clinical measures of global severity, phobia, panic, anxiety, depression, and behavioral performance tests were administered before treatment and at Weeks 4, 8, and 12 of treatment. Results revealed significant improvement in all groups on all measures over the course of treatment; almost a third of the control patients showed marked improvement. Imipramine had significant effects on improvement of phobias and markedly increased clinical response rates in patients receiving 150-200 mg/day. Less chronicity and severity of condition also predicted better clinical outcome. Flooding had limited effects above and beyond programmed practice, and no imipramine-flooding interactions effects were found.     

The sequence of improvement of the symptoms encountered in patients with panic disorder

Patients who meet DSM-III-R criteria for a diagnosis of panic disorder often show a complex mixture of psychopathological symptoms, including panic attacks (spontaneous and situational), anxiety (anticipatory and generalized), phobias (fear and avoidance), depression/dysphoria, and social and occupational disability. Various theories about the pathogenesis of these symptoms have been advanced that focus on a given symptom (e.g., panic, phobia) being primary in these disorders, with concurrent symptoms seen as epiphenomena or as secondary and reactive to a core symptom. This study, conducted on a large sample of panic disorder patients (N = 1,168), examines the temporal sequential pattern of symptom improvement in these patients, and explores how these relationships relate to various pathogenic theories. Our multiple analyses, when considered together, tend not to support any pathogenic theory that views a given symptom as being central to the overall disorder; our findings have obvious implications for theoreticians and clinicians interested in the study and treatment of panic and anxiety disorders.     

Treatment of specific phobias with Eye Movement Desensitization and Reprocessing (EMDR): protocol, empirical status, and conceptual issues

This paper considers the current empirical status of Eye Movement Desensitization and Reprocessing (EMDR) as a treatment method for specific phobias, along with some conceptual and practical issues in relation to its use. Both uncontrolled and controlled studies on the application of EMDR with specific phobias demonstrate that EMDR can produce significant improvements within a limited number of sessions. With regard to the treatment of childhood spider phobia, EMDR has been found to be more effective than a placebo control condition, but less effective than exposure in vivo. The empirical support for EMDR with specific phobias is still meagre, therefore, one should remain cautious. However, given that there is insufficient research to validate any method for complex or trauma related phobias, that EMDR is a time-limited procedure, and that it can be used in cases for which an exposure in vivo approach is difficult to administer, the application of EMDR with specific phobias merits further clinical and research attention.     

Medical utilization across the anxiety disorders

Individuals with panic disorder often seek medical care for their symptoms prior to receiving effective treatment. However, little is known about how often, and in what settings, patients with other anxiety disorders present for medical treatment. In the present study, utilization of general and specialty medical services was coded via electronic chart review for 171 consecutive outpatients referred to an anxiety disorders clinic. Results indicated that panic disorder patients accrued the most medical visits overall, as well as the most frequent visits to cardiology, family medicine, and emergency medicine. Few differences in medical utilization were evident among patients with generalized anxiety disorder, obsessive-compulsive disorder, social phobia, and specific phobias. Patients with anxiety disorders appear to be frequent utilizers of medical services prior to receiving effective treatment. Our findings highlight the need for improved recognition and treatment of anxiety disorders, particularly panic disorder, in a number of medical settings.     

Platelet [3H]imipramine binding in generalized anxiety disorder, panic disorder, and agoraphobia with panic attacks

The density of platelet [3H]imipramine binding sites is reported to be decreased in unipolar depression and, hence, is a putative biological marker. There is considerable evidence for a phenomenological and biological relationship of panic disorder with affective disorder. We studied platelet [3H]imipramine binding site density in unmedicated subjects with generalized anxiety disorder (GAD; n = 55), panic disorder (PD) with and without agoraphobia (n = 52), and normal controls (n = 26) in order to determine whether or not patients with panic disorder differed from controls in this biological assay. We found no differences in binding site density (Bmax) or affinity (Kd) among the PD, PD with agoraphobia, GAD, and control groups. Nor did we find a relationship between Bmax or Kd and the severity of depressive symptoms or the presence of a family history of affective disorder. In view of two conflicting prior studies, the use of [3H]imipramine binding in panic disorder remains problematic.     

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.     

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder

OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.     

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.     

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.     

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.     

Koinzidenz von schizophrener Psychose und Panikstörung mit Agoraphobie

The coincidence between panic disorder and depression is a well known phenomenon. However, only few studies investigated the coincidence of panic disorder with schizophrenia. This may in part be explained by the fact that both positive and negative symptoms of schizophrenia may mask the clinical symptoms of a panic disorder. We report on a female patient suffering both from agoraphobia with panic disorder and paranoid schizophrenia according to ICD-10. The productive psychotic symptoms responded well to treatment with a low dose of zotepine, whereas the panic disorder was effectively treated with a combined therapy with imipramine and cognitive behavioral therapy. Although it has to be questioned whether the coincidence between panic disorder and schizophrenia reflects two different diagnostic entities, the occurrence of symptoms of a panic disorder in schizophrenia deserve further attention because these may be treated efficiently by a specific pharmacotherapy and psychotherapy.