Do antidepressants selectively suppress spontaneous (unexpected) panic attacks? A replication.

The purpose of this study was to test the following interrelated hypotheses in a larger sample by attempting to replicate supportive results from a small therapeutic study: (1) the pathogenesis of panic disorder includes at least two identifiable components: a biological component represented by spontaneous (unexpected) panic attacks, and a cognitive component represented by situational attacks and especially by phobias; (2) these components respond differently to treatment; (3) many biological processes respond to an effective intervention in proportion to their deviance from "normal" prior to treatment ("Law of Initial Value"); and (4) the response of spontaneous panic attacks to an effective treatment conforms to that model. Previously, the authors reanalyzed an 8-week therapeutic study of panic disorder that included groups treated with placebo and with imipramine (225 mg daily). The criteria of response were spontaneous panic attacks (biological component), situational panic attacks (both components), and agoraphobia ratings (cognitive component). The analyses compared the regression lines for posttreatment status on pretreatment status in the imipramine and placebo groups. The effect of imipramine on spontaneous panic attacks fitted the hypothesized model: the pre-post slope in the placebo group was approximately 1 (45 degrees), whereas the slope in the imipramine group was approximately 0. There was no significant difference in pre-post slopes between the imipramine and placebo groups for situational panic attacks or agoraphobia ratings. For this report, the authors applied the same approach to another larger data set from a study using a similar design, but a different antidepressant. In this multicenter, double-blind study, patients with panic disorder were randomly assigned to receive 10 weeks of treatment with placebo (N = 78) or fluoxetine 10 mg (N = 84) or 20 mg (N = 81) daily. Spontaneous and situational panic attacks were registered in a daily diary, and agoraphobia was rated at each visit. Using baseline and endpoint data, fluoxetine had a statistically significant, dose-dependent, suppressive effect on spontaneous panic attacks, as measured by the pre-post slopes in the three treatment groups. The placebo group showed some response (slope = 0.69). There were no significant drug effects on situational panic attacks. On ratings of agoraphobia, the slopes in the placebo and the fluoxetine 20 mg groups did not differ, but the slope in the fluoxetine 10 mg group was significantly less than that in the placebo group, suggesting a therapeutic drug effect on agoraphobia only at the lower dose. These results are consistent with the stated hypotheses. They suggest that the therapeutic effects of antidepressants on panic disorder may be due primarily to the specific suppression of spontaneous panic attacks among patients with high baseline pathologic findings. Implications of these results for concepts of pathogenesis, clinical practice, and therapeutic research regarding panic disorder are discussed.

Growing placebo response rate: the problem in recent therapeutic trials?

Recently the development of several promising new compounds for anxiety and depression was discontinued because of difficulty demonstrating therapeutic effects. This article explores alternatives to "increasing placebo response rate" as explanations. We reanalyzed a study of 81 panic patients treated with placebo, alprazolam 2 mg or 6 mg, or imipramine 225 mg daily to investigate the effect of baseline pathology and selective effects of treatment on biological and cognitive components of panic disorder. The regression of endpoint on baseline number of spontaneous panic attacks differed among treatment groups, with lower slopes for the more active compounds. Only patients with many panic attacks at baseline benefited from the active compounds. Also, treatment effects declined progressively on the more cognitive aspects of the disorder (situational panic attacks and phobia ratings) for alprazolam and were entirely absent for imipramine. Implications for the etiology of panic disorder, its treatment, and therapeutic research are discussed.

The drug treatment of panic disorder.

Reviews current information about panic disorder that establishes its prevalence, heritable nature, course and complications. With this brief introduction, develops a general strategy for the management of panic disorder that entails careful diagnostic assessment, recognition of the risk of complications (i.e. major depression, phobic avoidance, substance abuse), education, supportive psychotherapy and the use of medication in the acute control of symptoms and the long term management of the vulnerability to panic attacks.

Response of panic disorder to fixed doses of alprazolam or imipramine.

This paper reports the results of a double-blind comparison of fixed daily doses of 6 mg of alprazolam, 2 mg of alprazolam, 225 mg of imipramine, and placebo for 8 weeks in 81 patients who met DSM-III criteria for panic disorder with or without agoraphobia. Final scores on eight clinical measures were analyzed from all patients who entered the study and from the subset who completed at least 4 weeks of treatment. Eighty-six percent of the high-dose alprazolam patients completed the study. Only 50% of the imipramine patients completed 8 weeks of treatment, apparently because of activation early in treatment and slow onset of therapeutic effects. This study confirmed the therapeutic effectiveness and safety of alprazolam, especially at the higher dose, in panic disorder. It also confirmed the therapeutic effectiveness of imipramine among patients who tolerated the drug. It suggested the usefulness of a flexible, individual approach to dose escalation with imipramine. Methodologically the study underscored the importance of using multiple approaches to the analysis of clinical data from therapeutic trials of psychotropic agents with complex effects that may contribute to patients' premature termination.

Correlates of mitral valve prolapse among patients with panic disorder.

Mitral valve prolapse (MVP) has been observed more frequently than expected among patients who report the current experience of panic attacks. The MVP observed has been generally of a mild variety and has not been associated with clinically meaningful variables in studies to date. In the current study, 82 patients with panic disorder (PD) who were recruited for a study of the drug treatment of PD were assessed for the presence of MVP, and patients with and without MVP were compared on several variables. Statistically significant findings were that patients with MVP were younger and more often female; reported an earlier age of onset of PD and more frequent panic attacks; and had a higher ponderal index, lower weight, and lower levels of triiodothyronine than patients without MVP. Contrary to previous studies, these results suggest that the presence of MVP among patients with PD is associated with potentially meaningful differences. While generalizability may be limited and causal relationships speculative at this time, the variables identified in this study deserve more explicit attention in future studies of PD and MVP.

Mitral valve prolapse and thyroid abnormalities in patients with panic attacks.

Panic disorder has been associated with mitral valve prolapse and thyroid abnormalities. Mitral valve prolapse has also been associated with thyroid abnormalities. The authors studied a consecutive series of 65 patients self-referred for evaluation of panic attacks, who were examined for cardiac and thyroid abnormalities. Fifty percent of the patients had mitral valve prolapse according to both cardiac auscultation and echocardiography. Twenty-six percent of the women had some thyroid abnormality; 17% had thyroid microsomal antibodies. There was no apparent relationship between mitral valve prolapse and thyroid abnormalities. These observations suggest that panic attacks, mitral valve prolapse, and autoimmune thyroid disorders are associated.

Panic disorder, agoraphobia, and anxiety-relevant cognitive style.

We attempted to identify factors differentiating Agoraphobia with Panic Attacks (AG) from Panic Disorder (PD) patients. Twenty-three AG and 27 PD patients were compared. No significant difference in severity of illness was found. As predicted, the groups differed on a measure of anxiety-relevant cognitions developed for this study, the Anxious Thoughts and Tendencies scale (AT&T) (P less than 0.02). We suggest that differences in interpretation of panic attacks account for the development of of phobic avoidance behavior in some but not all PD patients. The intercorrelations among measures suggest that Panic Disorder may be conceptualized as having several independent although related components (panic attacks, general anxiety, phobic anxiety, and cognitive distortions).

Plasma dopamine-beta-hydroxylase in depressed patients.

Plasma dopamine-beta-hydroxylase (DBH) activity was determined for 28 patients with a major affective disorder (Research Diagnostic Criteria) and 34 controls with no current, past, or family history of a psychiatric disorder. Plasma DBH activity was higher among patients (24.6 IU +/- 25.4 IU) than controls (14.5 IU +/- 8.9 IU), and subjects with plasma DBH activity greater than 25 IU were more common among patients. Unemployment and never marrying were associated with plasma DBH activity greater than 25 IU. Finally, referred patients (n = 9) had higher DBH activity (41.8 IU +/- 37.2 IU) than those responding to newspaper advertisements (n = 19, 16.5 IU +/- 11.5 IU) although these groups differed on no other variable including past history of treatment. We conclude that high plasma DBH activity may represent a vulnerability factor for depression.

Subject-own-control design in evaluating clinical antidepressant effects.

This study tested the use of a subject-own-control, multiple crossover design for evaluating the clinical effects of an established tricyclic antidepressant drug, imipramine. Although significant physiological and cognitive performance effects were demonstrated, only one clinical measure, target symptom change rated by the patients, showed a statistically significant drug-placebo difference. This result is in considerable contrast to the sensitivity of similar designs in detecting the clinical effects of antianxiety drugs in studies employing less than 20 patients. Crossover designs appear to be most successful when the treated condition is continuous, rather than episodic, and the treatment effects have a rapid onset and offset.

Cognitive dysfunction and imipramine in outpatient depressive.

A group of moderately depressed, nonpsychotic outpatients had impaired performance on a short-term item-recognition memory task (compared with a group of matched normal controls) without evidence of impaired speed or attention on two simpler tasks. Compared with placebo, treatment with imipramine hydrochloride in a multiple crossover design using three-week treatment periods led to improved performance on the memory task without either clinically apparent improvement in depression or significantly improved performance on the other task rather than a specific impairment of short-term memory, but the data do support the presence of cognitive dysfunction in depression, even in ambulatory patients without substantial impairments of attention or motor functioning. The results also indicate that antidepressant drugs can produce improvement in cognitive function, possibly as a forerunner of clinical improvement.