Panic Disorder

Research Re: Treatment

Maier W, Roth SM, Argyle N, Buller R, Lavori P, Brandon S, Benkert O: AVOIDANCE BEHAVIOUR: A PREDICTOR OF THE EFFICACY OF PHARMACOTHERAPY IN PANIC DISORDER? European Archives of Psychiatry & Clinical Neuroscience 1991; 241(3):151-8. 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.

Bystritsky A, Ackerman DL, Pasnau RO: LOW DOSE DESIPRAMINE TREATMENT OF COCAINE-RELATED PANIC ATTACKS. Journal of Nervous & Mental Disease 1991; 179(12):755-8. Summary: Thirteen patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia that started during or shortly after cocaine exposure were treated in the UCLA Anxiety Disorders Program (Los Angeles, CA). Low starting doses (ranging from 2.5 to 10 mg/day) of desipramine were used. Doses were then slowly increased to an average daily dose of 25 mg. Eleven patients who were able to tolerate an initial increase in panic anxiety responded to this treatment strategy with almost full resolution of panic attacks. The authors discuss the possible value and mechanisms of low dose treatment of cocaine-related panic attacks.

Milrod B, Shear MK: DYNAMIC TREATMENT OF PANIC DISORDER: A REVIEW. [REVIEW]. Journal of Nervous & Mental Disease 1991; 179(12):741-3. Summary: A review was conducted of the psychoanalytic and psychodynamic literature in order to identify patients with panic disorder who received dynamic treatment. Thirty-five cases were located that fit the description of panic disorder. Their characteristics are compared with those of a current anxiety disorder clinic panic disorder population. Features of the successful dynamic treatment of panic disorder are summarized. [References: 21]

Pols H, Zandbergen J, de Loof C, Griez E: ATTENUATION OF CARBON DIOXIDE-INDUCED PANIC AFTER CLONAZEPAM TREATMENT. Acta Psychiatrica Scandinavica 1991; 84(6):585-6. Summary: Ten patients meeting the DSM-III-R criteria for panic disorder were treated with clonazepam. Prior to clonazepam treatment and after a 5-week treatment period, patients underwent a 35% carbon dioxide challenge procedure. Following clonazepam treatment, a significant reduction in carbon dioxide vulnerability was observed.

Ravaris CL, Friedman MJ, Hauri PJ, McHugo GJ: A CONTROLLED STUDY OF ALPRAZOLAM AND PROPRANOLOL IN PANIC-DISORDERED AND AGORAPHOBIC OUTPATIENTS. Journal of Clinical Psychopharmacology 1991; 11(6):344-50. Summary: We studied the efficacy of propranolol (Inderal) compared to alprazolam (Xanax) in 29 patients with a diagnosis of agoraphobia with panic disorder or panic disorder with or without limited phobic avoidance in a 6-week double-blind controlled experiment. Alprazolam is effective in those syndromes, whereas to date only negative or ambiguous results had been reported for propranolol. Fourteen patients received a mean daily dose of 5.0 +/- 2.3 mg of alprazolam and 15 patients received 182.0 +/- 60.5 mg mean daily dose of propranolol. We found both drugs to be effective to suppress panic attacks and reduce avoidance behavior. The only significant between-drug difference was a more rapid onset of alprazolam's panicolytic effect. Propranolol merits further study. We suggest patients worthy of a clinical trial.

Noyes R Jr, Reich JH, Suelzer M, Christiansen J: PERSONALITY TRAITS ASSOCIATED WITH PANIC DISORDER: CHANGE ASSOCIATED WITH TREATMENT. Comprehensive Psychiatry 1991; 32(4):283-94. Summary: Eighty-two subjects with panic disorder completed the Personality Diagnostic Questionnaire (PDQ) before treatment and again after a period of relatively stable improvement 3 years later. At baseline, panic subjects scored higher than normal control subjects, who had been matched for age and sex, on avoidant, dependent, histrionic, and paranoid personality subscales. Improvement in panic symptoms after 3 years was associated with reductions in these same subscale scores. Examination of individual items that distinguished panic from normal subjects showed themes of dependency, lack of self-confidence, emotional instability, and sensitivity to criticism that reflected demoralization in the panic disorder subjects. To a large extent, the findings reveal nonspecific, state-dependent effects of panic and agoraphobic symptoms on the personality functioning and morale of patients with panic disorder.

Wilkinson G, Balestrieri M, Ruggeri M, Bellantuono C: META-ANALYSIS OF DOUBLE-BLIND PLACEBO-CONTROLLED TRIALS OF ANTIDEPRESSANTS AND BENZODIAZEPINES FOR PATIENTS WITH PANIC DISORDERS. Psychological Medicine 1991; 21(4):991-8. Summary: Meta-analysis of 19 double-blind placebo-controlled trials of antidepressants (N = 13) and benzodiazepines (N = 6) for patients with panic disorders showed that active treatment had 25% greater success rate than placebo over a mean duration of 14 weeks. There were no statistically significant differences observed between treatment sub-groups (antidepressants--mean duration 16 weeks; and benzodiazepines--mean duration 7 weeks). On this basis antidepressants and benzodiazepines prescribed in clinical settings are likely to be equally effective in the short-term treatment of people with panic disorders.

Garvey M: BENZODIAZEPINES FOR PANIC DISORDER. ARE THEY SAFE? Postgraduate Medicine 1991; 90(5):245-6, 249-52. Summary: The incidence of benzodiazepine dependence in properly selected patients with panic disorder appears to be very low. Patients with a history of drug abuse should not be given benzodiazepines. Physical dependence manifested by withdrawal symptoms occurs in 5% to 45% of patients who discontinue benzodiazepine therapy. Withdrawal symptoms are usually mild and attenuated by use of a tapering schedule of several weeks' duration. Physical dependence should not be confused with substance dependence, a disorder characterized by multiple problems in daily life caused by use of a particular substance.

Alexander PE: MANAGEMENT OF PANIC DISORDERS. [REVIEW]. Journal of Psychoactive Drugs 1991; 23(4):329-33. Summary: Panic disorders are medical conditions requiring an eclectic treatment approach that often combines pharmacotherapeutics with education, cognitive-behavior therapy, and psychodynamic therapy. This article focuses on the management of medication within this framework. The medications that have been found to be effective include tricyclic antidepressants, fluoxetine, monoamine oxidase inhibitors, and higher potency benzodiazepines. Although alprazolam is the most studied medication and acts very rapidly, each type of medication has unique advantages and liabilities. The general treatment strategy with all the medications is to start with a low dose and increase it slowly until side effects develop or panic attacks cease. The treatment approach should be oriented toward a chronic illness that often requires long-term medication. [References: 28]

LaBounty LP, Hatsukami D, Morgan SF, Nelson L: RELAPSE AMONG ALCOHOLICS WITH PHOBIC AND PANIC SYMPTOMS. Addictive Behaviors 1992; 17(1):9-15. Summary: A group of 35 alcoholics who indicated they had symptoms of phobia, panic, or both (the anxiety problem group) were compared to their matched controls who did not indicate having anxiety problems. Comparisons of relapse rates, reasons for relapse, and rates of emotional problems at six months posttreatment were made. Results showed that although relapse rates were similar between the two groups, significantly more anxious subjects reported relapsing to cope with depression and experiencing problems with nervousness, tension, and anger posttreatment. Implications for treatment and the need for further research are discussed.

Otto MW, Pollack MH, Meltzer-Brody S, Rosenbaum JF: COGNITIVE-BEHAVIORAL THERAPY FOR BENZODIAZEPINE DISCONTINUATION IN PANIC DISORDER PATIENTS. [REVIEW]. Psychopharmacology Bulletin 1992; 28(2):123-30. Summary: The discontinuation of benzodiazepine treatment in patients with panic disorder may be associated with emergent withdrawal and anxiety symptoms, relapse of panic, and the inability to complete benzodiazepine taper. Although some patients may respond to slow taper strategies or the use of pharmacologic adjuncts, many continue to experience significant difficulties during benzodiazepine discontinuation. This paper presents a cognitive-behavioral conceptualization of benzodiazepine discontinuation difficulties, emphasizing "fear of fear" cycles. From this perspective the discontinuation process is seen as exposing panic disorder patients to somatic sensations associated with panic at a time when there is both increased anxiety and concern about re-emergence or worsening of panic episodes. As a consequence, patients may re-enter a cycle of catastrophic interpretations of symptoms, increased vigilance and fear, and panic. Cognitive-behavioral interventions may ameliorate discontinuation-associated difficulties and prevent the return of the panic disorder. Preliminary data supporting the efficacy of these interventions are described. [References: 39]

Yeragani VK, Pohl R, Balon R, Ramesh C, Glitz D, Weinberg P, Merlos B: EFFECT OF IMIPRAMINE TREATMENT ON HEART RATE VARIABILITY MEASURES. Neuropsychobiology 1992; 26(1-2):27-32. Summary: Recently, heart rate (HR) variability has received considerable attention, and a decreased HR variability has been linked to a significant risk of cardiovascular illness. We have previously reported such a decreased variability in panic disorder patients. In this study, we report on HR variability in 12 depressed and 6 panic disorder patients at baseline and 1 and 3 weeks of treatment with imipramine as measured by the standard deviation, mean consecutive difference and the standard deviation of the mean consecutive difference of the R-R intervals in supine, supine deep breathing and standing postures. In all subjects, imipramine (mean dose: 70 mg/day) produced a significant decrease in heart rate variability at week 3 as measured by the above variables. This decrease in HR variability during imipramine treatment is probably due to its anticholinergic effects.

Lydiard RB, Lesser IM, Ballenger JC, Rubin RT, Laraia M, DuPont R: A FIXED-DOSE STUDY OF ALPRAZOLAM 2 MG, ALPRAZOLAM 6 MG, AND PLACEBO IN PANIC DISORDER. Journal of Clinical Psychopharmacology 1992; 12(2):96-103. Summary: A recently reported multinational, 8-week double-blind, placebo-controlled study assessing the efficacy of alprazolam versus placebo in the treatment of panic disorder indicated significant differences favoring alprazolam. We now report the results of a three-site, 6-week, double-blind, fixed-dose study comparing alprazolam 2 mg, alprazolam 6 mg, and placebo in 94 patients with panic disorder with or without agoraphobia. Both alprazolam treatment groups (6 mg and 2 mg) improved significantly more than did the placebo treatment group on most outcome measures. Only a few statistically significant differences between the 6 mg and 2 mg alprazolam groups were discerned, although the pattern of treatment response across measures suggested a dose effect. Dropouts in the placebo group were primarily due to lack of efficacy and in the alprazolam 6 mg group were due to side effects, which may have contributed to the limited differences between groups at study end. The findings suggest that many patients may require less than 6 mg of alprazolam per day for effective treatment of panic disorder.

Mavissakalian M, Perel JM: CLINICAL EXPERIMENTS IN MAINTENANCE AND DISCONTINUATION OF IMIPRAMINE THERAPY IN PANIC DISORDER WITH AGORAPHOBIA. Archives of General Psychiatry 1992; 49(4):318-23. Summary: Several issues remain to be ascertained beyond the acute response to imipramine hydrochloride in patients with panic disorder. Study 1 consisted of a prospective, systematic characterization of half-dose 12-month maintenance in patients with panic disorder with agoraphobia who had shown marked and stable response to 6 months of acute-phase treatment with imipramine. Study 2 assessed the 6-month cumulative relapse rate following discontinuation of acute-phase imipramine treatment in a comparable sample of patients. The same assessment battery was used in both studies, and the integrity of experimental drug conditions was verified by plasma drug level determinations. In contrast to the high relapse rate following discontinuation of acute-phase treatment, none of the patients showed relapse or had sustained worsening in panic or phobia measures during the half-dose maintenance period. The results underscore the importance of pharmacological prophylaxis and provide empirical guidelines for a successful low-dose maintenance regimen for patients with panic disorder and agoraphobia who respond markedly to imipramine.

Mavissakalian M, Perel JM: PROTECTIVE EFFECTS OF IMIPRAMINE MAINTENANCE TREATMENT IN PANIC DISORDER WITH AGORAPHOBIA. American Journal of Psychiatry 1992; 149(8):1053-7. Summary: OBJECTIVE: This study was designed to assess and compare the differential relapse rates of patients with panic disorder and agoraphobia after discontinuation of acute treatment (6 months) or acute plus maintenance treatment (18 months) with imipramine. METHOD: Sixteen patients with panic disorder and agoraphobia who had shown marked and stable response to 6 months of acute imipramine treatment and a comparable group of 14 patients who had been in remission during an additional year of half-dose imipramine maintenance treatment entered a 3-month, double-blind discontinuation study followed by a 3-month drug-free period. Assessments of the patients were made according to operationalized response/relapse criteria, and plasma drug concentrations were monitored. RESULTS: Survival analysis revealed significantly different cumulative probabilities of continued response 6 months after discontinuation of imipramine treatment between the patients who had received only acute treatment and those who had received acute and maintenance treatment. CONCLUSIONS: The results support the hypothesis that successful imipramine maintenance treatment of patients with panic and agoraphobia can have protective effects against relapse, at least in the first 6 months after the maintenance treatment period.

Modigh K, Westberg P, Eriksson E: SUPERIORITY OF CLOMIPRAMINE OVER IMIPRAMINE IN THE TREATMENT OF PANIC DISORDER: A PLACEBO-CONTROLLED TRIAL. Journal of Clinical Psychopharmacology 1992; 12(4):251-61. Summary: A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.

Van Gool D, Igodt P, De Cuyper H: MODE OF ACTION OF THE TRIAZOLOBENZODIAZEPINES IN THE TREATMENT OF PANIC ATTACKS: A HYPOTHESIS. [REVIEW]. European Neuropsychopharmacology 1992; 2(4):433-41. Summary: Alprazolam (Xanax) or 8-chloro-1-methyl-6-phenyl-4H-S-triazolobenzodiazepine is a potent drug for the treatment of anxiety disorders. The chemical structure differs from the classical benzodiazepines by incorporation of the triazoloring. Due to the triazolo ring, the drug can have additional modes of action than the normal benzodiazepines. The triazolobenzodiazepines are potent inhibitors of the platelet-activating factor. This factor is a potent stimulator of the corticotropin-releasing hormone. This hormone has an effect on the hypothalamo-pituitary-adrenal axis but the corticotropin-releasing hormone is also known to be a stimulator of the locus coeruleus. The corticotropin-releasing hormone in patients with panic attacks is elevated. This could be a result of the hyperactive metabolism which is observed by positron emission tomographic (PET) studies of the right parahippocampal area. [References: 118]

Anonymous: DRUG TREATMENT OF PANIC DISORDER. COMPARATIVE EFFICACY OF ALPRAZOLAM, IMIPRAMINE, AND PLACEBO. CROSS-NATIONAL COLLABORATIVE PANIC STUDY, SECOND PHASE INVESTIGATORS [PUBLISHED ERRATUM APPEARS IN BR J PSYCHIATRY 1992 NOV;161:724]. British Journal of Psychiatry 1992; 160:191-202; discussion 202-5. Summary: The Cross-National Collaborative Panic Study, Phase Two, compared alprazolam with imipramine and with placebo in a sample of 1168 randomly assigned subjects. The study, conducted at 12 centres, assessed clinical change over eight weeks of double-blind drug treatment. Improvement occurred with alprazolam by week 1 and 2, and with imipramine by week 4. By the end of week 8, however, the effects of the two active drugs were similar to each other, and both were superior to placebo for most outcome measures.

Keck PE Jr, McElroy SL, Friedman LM: VALPROATE AND CARBAMAZEPINE IN THE TREATMENT OF PANIC AND POSTTRAUMATIC STRESS DISORDERS, WITHDRAWAL STATES, AND BEHAVIORAL DYSCONTROL SYNDROMES. [REVIEW]. Journal of Clinical Psychopharmacology 1992; 12(1 Suppl):36S-41S. Summary: A number of preclinical studies and preliminary clinical reports, in some cases augmented by controlled studies, suggest that valproate and carbamazepine may have therapeutic effects in the treatment of certain anxiety disorders (panic disorder, post-traumatic stress disorder), alcohol and sedative-hypnotic withdrawal states, and behavioral dyscontrol syndromes. We review the theoretical rationale and available clinical data supporting the potential value of these anticonvulsants in these psychiatric disorders. [References: 56]

Woods SW, Nagy LM, Koleszar AS, Krystal JH, Heninger GR, Charney DS: CONTROLLED TRIAL OF ALPRAZOLAM SUPPLEMENTATION DURING IMIPRAMINE TREATMENT OF PANIC DISORDER. Journal of Clinical Psychopharmacology 1992; 12(1):32-8. Summary: To investigate whether alprazolam (ALP) coprescription early in the imipramine (IMI) treatment of panic disorder would improve overall treatment response to IMI alone, 48 panic disorder patients were randomly assigned to receive either IMI plus placebo or IMI plus ALP for 4-6 weeks, followed by 2 weeks of IMI plus placebo-ALP taper and 2 more weeks of IMI alone. Although patients in the IMI plus ALP group improved more quickly, significantly more patients in the IMI plus ALP group could not follow the taper schedule. The results suggest that studies employing other benzodiazepines or other ALP dosage or taper schedules would be required to demonstrate any benefit for the IMI plus early benzodiazepine cotreatment strategy over IMI alone in the routine pharmacologic management of panic disorder.

Figiel GS, Zorumski CF, Doraiswamy PM, Mattingly GW, Jarvis MR: SIMULTANEOUS MAJOR DEPRESSION AND PANIC DISORDER: TREATMENT WITH ELECTROCONVULSIVE THERAPY. Journal of Clinical Psychiatry 1992; 53(1):12-5. Summary: BACKGROUND: Major depression and panic disorder commonly occur together. Patients with simultaneous depression and panic disorder may have a higher lifetime rate of suicide attempts and an overall worse prognosis than patients with either depression or panic disorder alone. In addition, preliminary work suggests that some of these patients may not respond satisfactorily to antidepressants. In this report, we describe the clinical courses of eight consecutive patients with simultaneous major depression and panic disorder who were referred for ECT at our institution. METHOD: Eight consecutive patients who met DSM-III-R criteria for simultaneous major depression and panic disorder received ECT. All eight patients were evaluated by a structured clinical interview and the patients' major depression and panic disorder were evaluated with a 7-point Clinical Global Impressions severity rating scale. RESULTS: Before ECT was begun, each subject's panic disorder and depression were rated as at least markedly ill. After receiving ECT, all eight showed improvement in their depression. In addition, none of the eight patients reported having a panic attack from the time of their fourth ECT treatment until discharge. CONCLUSION: In this report, eight consecutive patients with simultaneous major depression and panic disorder improved with ECT. Further work is required which examines the potential utility of ECT in treating these patients.

Schweizer E, Clary C, Dever AI, Mandos LA: THE USE OF LOW-DOSE INTRANASAL MIDAZOLAM TO TREAT PANIC DISORDER: A PILOT STUDY. Journal of Clinical Psychiatry 1992; 53(1):19-22. Summary: BACKGROUND: Drug therapy of panic disorder, despite the intermittent nature of the panic attack, requires daily administration of antidepressants, which are often not tolerated, or benzodiazepines, which can result in physical dependence and withdrawal. The use of rapidly acting, low-dose intranasal midazolam to prevent incipient panic suggested itself to us as a novel alternative treatment strategy. METHOD: We conducted a 6-week double-blind, placebo-controlled, crossover-design pilot study of the safety and efficacy of p.r.n. low-dose intranasal midazolam in five patients diagnosed with DSM-III-R panic disorder. RESULTS: One to two drops of midazolam (approximately 0.25 to 0.5 mg) was well tolerated and highly effective in preventing incipient panic attacks and in reducing the overall weekly frequency of attacks. CONCLUSION: Intermittent intranasal midazolam shows promise as a novel alternative treatment for panic, but a controlled study of its efficacy and safety (including abuse potential) must be conducted.

Roth WT, Margraf J, Ehlers A, Haddad JM, Maddock RJ, Agras WS, Taylor CB: IMIPRAMINE AND ALPRAZOLAM EFFECTS ON STRESS TEST REACTIVITY IN PANIC DISORDER. Biological Psychiatry 1992; 31(1):35-51. Summary: The reactivity of 40 panic disorder patients on mental arithmetic, cold pressor, and 5% CO2 inhalation stressors was tested before and after 8 weeks of treatment with imipramine, alprazolam, or placebo. Mean levels of subjective and physiological stress measures were compared during a baseline before any stressors were given, and at anticipation, stressor, and recovery periods for each stressor. After treatment, imipramine patients differed from the other two treatment groups on the prestressor baseline in showing higher systolic blood pressure (mean difference about 10 mmHg), higher diastolic blood pressure (10 mm Hg), higher heart rate (15 bpm), less respiratory sinus arrhythmia, shorter pulse transit time, and lower T-wave amplitude. Respiratory measures, electrodermal measures, body movement, and self-reported anxiety and excitement did not distinguish the groups. Reactivity to the stress tests was unaffected by the medications, but tonic differences present in the baseline persisted.

Roy-Byrne PP: INTEGRATED TREATMENT OF PANIC DISORDER. American Journal of Medicine 1992; 92(1A): S. Summary: The purpose of this article is to provide the nonpsychiatric physician with a practical approach to the treatment of panic disorder by reviewing the literature on treatment efficacy. The author reviews studies and uncontrolled case series on pharmacologic and nonpharmacologic treatment of panic disorder and presents a clinical approach based on these. Setting the stage for treatment by educating patients and obtaining a detailed description of their particular clinical syndrome is a vital, but frequently neglected, precursor to treatment. Treatment selection is based on a risk-benefit analysis of the individual treatment and the particular exigencies of the patient's clinical presentation. Both pharmacologic and nonpharmacologic therapies are highly effective for acute treatment. Because panic disorder is a chronic illness, long-term treatment or reinitiation of acute treatment at a later date is often required.

Swinson RP, Soulios C, Cox BJ, Kuch K: BRIEF TREATMENT OF EMERGENCY ROOM PATIENTS WITH PANIC ATTACKS. American Journal of Psychiatry 1992; 149(7):944-6. Summary: OBJECTIVE: Most research on treatment for panic disorder has involved chronic forms of the illness. To determine the efficacy of early intervention, the authors examined the effects of treatment for patients with panic attacks who were seen in the emergency room, which is the first point of contact with the health delivery system for many persons with panic attacks. METHOD: The subjects were 33 patients with panic attacks seen in two emergency rooms. The presence of panic attacks was confirmed with a modified version of the Structured Clinical Interview for DSM-III-R; approximately 40% of the patients met the DSM-III-R criteria for panic disorder with agoraphobia. The patients were randomly assigned to groups receiving reassurance (N = 16) or exposure instruction (N = 17). Scores on the Fear Questionnaire agoraphobia subscale, Mobility Inventory, and Beck Depression Inventory and the frequency of panic attacks were determined at baseline, 3 months, and 6 months. RESULTS: The subjects who received exposure instruction significantly improved over the 6-month period on depression, avoidance, and panic frequency. The reassurance subjects did not improve on any measure and eventually reported more agoraphobic avoidance. CONCLUSIONS: These results suggest that early intervention with exposure instruction may reduce the long-term consequences of panic attacks. The exposure instruction was of value even though the subjects had relatively low levels of avoidance at the outset of the study.

Beck AT, Sokol L, Clark DA, Berchick R, Wright F: A CROSSOVER STUDY OF FOCUSED COGNITIVE THERAPY FOR PANIC DISORDER. American Journal of Psychiatry 1992; 149(6):778-83. Summary: OBJECTIVE: This study sought to determine the short- and long-term effects of focused cognitive therapy for panic disorder. METHOD: Thirty-three psychiatric outpatients with the DSM-III diagnosis of panic disorder were randomly assigned to either 12 weeks of individual, focused cognitive therapy or 8 weeks of brief supportive psychotherapy based on principles of client-centered therapy. The patients who received supportive psychotherapy were subsequently given the opportunity to cross over to cognitive therapy for 12 weeks. Patients were rated for panic and depression before therapy, after 4 and 8 weeks of therapy, and at 6-month and 1-year follow-up. RESULTS: Clinician ratings and self-ratings of panic frequency and intensity indicated that the focused cognitive therapy group achieved significantly greater reductions in panic symptoms and general anxiety after 8 weeks of treatment than did the group that received brief supportive psychotherapy. At 8 weeks, 71% of the cognitive therapy group were panic free, compared to 25% of the psychotherapy group. Moreover, 94% of the psychotherapy patients elected to cross over to 12 weeks of cognitive therapy. At 1-year follow-up, 87% of the group that received cognitive therapy only and 79% of the group that crossed over into cognitive therapy remained free of panic attacks. CONCLUSIONS: Focused cognitive therapy offers a promising nonpharmacological alternative for the treatment of panic disorder.

Humble M, Wistedt B: SEROTONIN, PANIC DISORDER AND AGORAPHOBIA: SHORT-TERM AND LONG-TERM EFFICACY OF CITALOPRAM IN PANIC DISORDERS. [REVIEW]. International Clinical Psychopharmacology 1992; 6 Suppl 5:21-39. Summary: A serotonin-anxiety connection has been widely recognized. In panic disorder (PD), however, most researchers have emphasized noradrenergic mechanisms. Serotonin related findings in PD, e.g. the documented antipanic potential of selective serotonin reuptake inhibitors (SSRIs), are reviewed, lending support for a serotonergic deficit contributing to the pathophysiology of PD. Since citalopram is the most selective SSRI described, it was chosen as a tool for testing whether the serotonin reuptake inhibition per se is responsible for this antipanic effect. Twenty patients with PD with or without agoraphobia (DSM-III-R criteria) were treated openly with citalopram and assessed with CAS, MADRS, SCL-90 the Agoraphobia Scale, other self-ratings, and a panic diary. Thirteen of the 17 patients completing 8 weeks of treatment were judged as responders. The response seemed similar to or better than that seen with other antidepressants. The response covered broad aspects of morbidity, e.g. anticipatory anxiety, agoraphobia and somatization. In the first week, a transient increase of panic-related symptoms was observed. Sixteen of the patients were enrolled in a 15 months' study of long-term maintenance treatment; 11 patients completed this phase. The gains were maintained during this follow-up, and further improvement was observed. Side-effects were similar to those of other SSRIs and mostly mild. For instance, weight-gain was not associated with citalopram treatment. The results support the hypothesis that serotonin reuptake inhibition is essential for the antipanic effect of antidepressants as well as for the initial paradoxical increase of anxiety often seen with these drugs. Thus, an initial deterioration, possibly due to transient decrease of serotonin transmission, turns to improvement when serotonergic potentiation has occurred. [References: 125]

Ontiveros A, Fontaine R: SODIUM VALPROATE AND CLONAZEPAM FOR TREATMENT-RESISTANT PANIC DISORDER. Journal of Psychiatry & Neuroscience 1992; 17(2):78-80. Summary: Sodium valproate (VA) and clonazepam (CLZ) were combined in the treatment of 4 patients with panic disorders (PD) who were resistant to several antipanic drug treatments. A significant improvement was found in the symptomatology of these patients, but relapses occurred when CLZ dosage was reduced. A potentiation of the GABAergic properties of VA and clonazepam is postulated. This combined treatment could be advantageous for some treatment-resistant PD patients but needs to be studied further.

Watts-Jones D: CULTURAL AND INTEGRATIVE THERAPY ISSUES IN THE TREATMENT OF A JAMAICAN WOMAN WITH PANIC DISORDER. Family Process 1992; 31(2):105-13; discussion 114-8. Summary: This article examines the treatment of a Jamaican woman with panic disorder, with a specific focus on the role of culture and the use of multiple formulations of the clinical problem. The work suggests that complex decisions are sometimes called for in assessing whether treatment should advocate against a cultural norm of the clients. The work further suggests that conceptualization of the problem from the vantage point of multiple frameworks is warranted in some instances, but that it requires considerable thought in order to achieve an integrated, coherent treatment plan.

Ballenger JC: MEDICATION DISCONTINUATION IN PANIC DISORDER. [REVIEW]. Journal of Clinical Psychiatry 1992; 53 Suppl:26-31. Summary: Current pharmacotherapy for panic disorder generally consists of a trial of antidepressants or benzodiazepines for at least 3 months, with continuation for 6 to 12 months when patients respond favorably. However, the most appropriate time to discontinue medication has not yet been determined. The author discusses reasons for discontinuation, both appropriate and inappropriate; optimal timing for discontinuation; outcomes of discontinuation (i.e., remaining well, relapse, rebound, and withdrawal); strategies, including dosage taper, to avoid or minimize unfavorable outcomes; and long-term outcomes in patients treated for panic disorder. The author concludes from the data available on long-term outcomes that, although there is preliminary understanding of the course of acutely treated panic disorder patients, additional data from long-term follow-up studies are needed. [References: 16]

Klerman GL: TREATMENTS FOR PANIC DISORDER. [REVIEW]. Journal of Clinical Psychiatry 1992; 53 Suppl:14-9. Summary: Research conducted since 1980 has resulted in a number of effective treatments made available for panic disorder. Panic is a serious condition with long-term consequences. The author prefaces a discussion of those treatments with a review of the history of panic disorder as a diagnostic entity and the presentation of data on the epidemiology of the disorder, including the prevalence of comorbidity. The author then reviews the pharmacologic treatments found to be effective for panic disorder, the tricyclic antidepressants, the monoamine oxidase inhibitors, and the high-potency benzodiazepines; the agents that show promise such as the serotonin reuptake blockers; the psychological treatments in current use; and the combination of pharmacologic and psychological treatment. The author also discusses medication dosage and length of treatment and concludes that there is now a range of options for treating panic disorder with likelihood of good therapeutic outcome. [References: 36]

Fahy TJ, O'Rourke D, Brophy J, Schazmann W, Sciascia S: THE GALWAY STUDY OF PANIC DISORDER. I: CLOMIPRAMINE AND LOFEPRAMINE IN DSM III-R PANIC DISORDER: A PLACEBO CONTROLLED TRIAL [PUBLISHED ERRATUM APPEARS IN J AFFECT DISORD 1992 JUL;25(3):214]. Journal of Affective Disorders 1992; 25(1):63-75. Summary: Among 79 volunteer, unpaid, family doctor-referred psychiatric out patients with DSM III-R panic disorder, with and without agoraphobia, 66 completed a six week placebo-controlled trial of lofepramine versus clomipramine and 57 survivors were followed up for 6 months. All subjects received one hour per week concurrent behavioural counselling in the acute phase. Of 13 dropouts in the first 3 weeks, 9 (of 27) were on clomipramine, 2 (of 26) were on lofepramine and 2 (of 26) were on placebo. The high (30%) early dropout from the clomipramine group was largely due to medication intolerance. Both drugs were superior to placebo by the end of week 6 on several standard rating scales but not on panic attack frequency. No significant differences in efficacy were found between the two drugs tested to the end of 6 months. No tendency for relapse was noted in the three months following taper-off of medication from week 12 to week 24. The study provides evidence that both drugs, in the dosages used, are superior to placebo in the acute phase of panic disorder in treatment-naive subjects concurrently receiving appropriate psychotherapy.

Gordon A: PANIC DISORDER: A CLINICAL PERSPECTIVE ON ACUTE TREATMENT AND FUTURE RESEARCH NEEDS. Rhode Island Medicine 1992; 75(5):262-4. Summary: Panic disorder is a common disorder for which there are highly effective treatments. Patients usually present for treatment in acute distress and initially have difficulty responding to cognitive behavioral therapies. In contrast there is a high response rate to pharmacologic treatments. Cognitive behavioral techniques can be helpful in facilitating the taper and eventual discontinuation of medication and may play a role in preventing relapse. The disorder appears to have a chronic course requiring maintenance medication for at least six months. Phobic avoidance appears to be primarily a learned response and is best treated with in vivo desensitization.

Preskorn SH, Fast GA: TRICYCLIC ANTIDEPRESSANT-INDUCED SEIZURES AND PLASMA DRUG CONCENTRATION. Journal of Clinical Psychiatry 1992; 53(5):160-2. Summary: BACKGROUND: This study identifies eight patients who during routine therapy with conventional doses of tricyclic antidepressants (TCAs) experienced elevated plasma concentrations and suffered a grand mal seizure. We correlate the incidence of TCA-induced seizures with TCA plasma level and suggest that the incidence of TCA-induced seizures can be significantly reduced with the judicious use of therapeutic drug monitoring. METHOD: Seven of the eight cases of TCA-induced seizures during routine pharmacotherapy represent all the cases known to the authors during their careers. Histories were evaluated for factors that would predispose patients to suffer seizures. The following data were also recorded: (1) duration of treatment with the dose that was associated with the seizure, (2) the time between last dose and the seizure, (3) a plasma TCA level obtained at the time of seizure, and (4) presence or absence of other manifestations of TCA toxicity. In addition, a MEDLINE search was conducted using the key phrases "tricyclic antidepressants" and "seizures" to obtain all English language articles published since 1966 on the occurrence of TCA-induced seizures. RESULTS: The mean +/- SD daily TCA dose was 250 +/- 80 mg/day. The mean +/- SD total plasma TCA concentration was 734 +/- 249 ng/mL (range, 438-1200 ng/mL). The only risk factor that emerged for experiencing seizures was an elevated plasma TCA concentration. Three patients presented with no other manifestations of TCA toxicity prior to seizure. CONCLUSION: The incidence of TCA-induced seizures for our inpatient population in which therapeutic drug monitoring is routinely used is 0.4%. This incidence is less than that reported in earlier inpatient series (1% to 4%). Our finding is consistent with the conclusion that therapeutic drug monitoring reduces the incidence of TCA-induced seizures by allowing for rational dose adjustment.

Coplan JD, Papp LA, King DL, Gorman JM: AMELIORATION OF MITRAL VALVE PROLAPSE AFTER TREATMENT FOR PANIC DISORDER. American Journal of Psychiatry 1992; 149(11):1587-8. Summary: Twenty panic disorder patients with mitral valve prolapse showed amelioration of prolapse on repeat echocardiogram after treatment for panic disorder. This effect was significant when compared to repeat echocardiograms in eight psychiatrically normal control subjects with mitral valve prolapse.

Garcia-Borreguero D, Lauer CJ, Ozdaglar A, Wiedemann K, Holsboer F, Krieg JC: BROFAROMINE IN PANIC DISORDER: A PILOT STUDY WITH A NEW REVERSIBLE INHIBITOR OF MONOAMINE OXIDASE-A. Pharmacopsychiatry 1992; 25(6):261-4. Summary: The therapeutic efficacy of brofaromine--a new reversible and short acting MAO-A inhibitor--was evaluated in 14 inpatients with a panic disorder. In an open trial, the patients were treated with placebo during the first week and with 150 mg brofaromine per day during the following four weeks. In all patients a distinct improvement in both anxiety and depressive symptoms was observed under the active drug. Treatment outcome was the same in patients with and without a concomitant major depressive episode. No side-effects of any note were reported. Our findings suggest that the MAO-A inhibitor brofaromine is an effective drug in the treatment of anxiety disorders.

Lesser IM, Lydiard RB, Antal E, Rubin RT, Ballenger JC, DuPont R: ALPRAZOLAM PLASMA CONCENTRATIONS AND TREATMENT RESPONSE IN PANIC DISORDER AND AGORAPHOBIA. American Journal of Psychiatry 1992; 149(11):1556-62. Summary: 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.

Robinson L, Walker JR, Anderson D: COGNITIVE-BEHAVIOURAL TREATMENT OF PANIC DISORDER DURING PREGNANCY AND LACTATION. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 1992; 37(9):623-6. Summary: The treatment of panic disorder during pregnancy and lactation poses special problems. It is important that both the practitioner and patient consider a number of issues to find the most appropriate treatment for the patient. New cognitive-behavioural treatment options often circumvent the problems of pharmacotherapy for pregnant or lactating women while providing therapeutic benefits which are at least equivalent.

Schittecatte M, Ansseau M, Charles G, Machowski R, Papart P, Pichot W, Wilmotte J: GROWTH HORMONE RESPONSE TO CLONIDINE IN MALE PATIENTS WITH PANIC DISORDER UNTREATED BY ANTIDEPRESSANTS. Psychological Medicine 1992; 22(4):1059-62. Summary: We report a non-significantly higher growth hormone (GH) response to intravenous clonidine administration (150 micrograms) in 10 male patients with panic disorder who had never received antidepressant therapy than in 10 matched controls. These results are consistent with data suggesting a normal or increased adrenergic receptor sensitivity in panic disorder patients.

Swinson RP, Cox BJ, Shulman ID, Kuch K, Woszczyna CB: MEDICATION USE AND THE ASSESSMENT OF AGORAPHOBIC AVOIDANCE. Behaviour Research & Therapy 1992; 30(6):563-8. Summary: Many anxiety disorder patients who present for behaviour therapy are already taking anxiolytic medications. The present study added a new subscale to the Mobility Inventory labelled 'Without Medication' to assess possible reliance on medication for coping with phobic situations. 121 Patients with panic-related disorders were administered the scale. The results supported the reliability and validity of the existing Mobility Inventory subscales in general and of the new subscale in particular. It appears to reliably assess a clinically important domain that is not measured in traditional self-report measures of phobic avoidance.

Louie AK, Louie EK, Lannon RA: SYSTEMIC HYPERTENSION ASSOCIATED WITH TRICYCLIC ANTIDEPRESSANT TREATMENT IN PATIENTS WITH PANIC DISORDER. American Journal of Cardiology 1992; 70(15):1306-9. Summary: In a sample of 114 patients, 6 patients developed hypertension while taking tricyclic antidepressants. All these patients were diagnosed as having panic disorder, with or without major depression. Half of the 6 patients had a previous diagnosis of hypertension, which had been well controlled by antihypertensive drugs for years. A comparison group of patients with major depression, who had never had panic attacks, had no cases of hypertension induced by these antidepressants. These findings raise the possibility that patients who have panic disorder may experience cardiovascular disregulation that increases their risk for antidepressant-induced hypertension.

Charney DS, Woods SW, Krystal JH, Nagy LM, Heninger GR: NORADRENERGIC NEURONAL DYSREGULATION IN PANIC DISORDER: THE EFFECTS OF INTRAVENOUS YOHIMBINE AND CLONIDINE IN PANIC DISORDER PATIENTS. Acta Psychiatrica Scandinavica 1992; 86(4):273-82. Summary: In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 micrograms/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine-induced panic attacks and had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine-induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.

DuPont RL, Swinson RP, Ballenger JC, Burrows GD, Noyes R, Rubin RT, Rifkin A, Pecknold JC: DISCONTINUATION OF ALPRAZOLAM AFTER LONG-TERM TREATMENT OF PANIC-RELATED DISORDERS. Journal of Clinical Psychopharmacology 1992; 12(5):352-4. Summary: Discontinuation of alprazolam after long-term treatment of 142 patients with panic-related disorders was examined in five study sites using a telephone interview. The majority (67%) of patients interviewed discontinued alprazolam for a period of at least 3 days after a gradual dosage reduction schedule over a 4-week period at the end of the long-term treatment study. A marked difference among the study sites in percentages of patients discontinuing therapy with alprazolam suggests that physician intervention played an important role in determining the ability of patients successfully to discontinue use of alprazolam: 90% and 95% of patients ceased therapy at two sites whereas only 21%, 38%, and 66% of patients discontinued therapy at the other three sites. The mean daily dosage for patients who continued using alprazolam decreased from 5.1 mg/day at the end of the long-term segment to 2.7 mg/day at the time of the poststudy interview. This decline indicates a lack of tolerance to the therapeutic effectiveness of alprazolam over an extended period of time.

Cox BJ, Endler NS, Lee PS, Swinson RP: A META-ANALYSIS OF TREATMENTS FOR PANIC DISORDER WITH AGORAPHOBIA: IMIPRAMINE, ALPRAZOLAM, AND IN VIVO EXPOSURE. Journal of Behavior Therapy & Experimental Psychiatry 1992; 23(3):175-82. Summary: 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.

Pary R, Lewis S: IDENTIFYING AND TREATING PATIENTS WITH PANIC ATTACKS. [REVIEW]. American Family Physician 1992; 46(3):841-8. Summary: Panic disorder occurs in up to 3 percent of the population and can be socially, emotionally and occupationally disabling. A thorough clinical evaluation is crucial to exclude illnesses with similar presentations, particularly acute cardiac, gastrointestinal or neurologic disease. The noradrenergic nervous system is involved in panic attacks. These attacks are described as sudden, unexpected episodes of intense fear or discomfort, usually lasting five to 30 minutes. Appropriate medications include benzodiazepines, tricyclic antidepressants and monoamine oxidase inhibitors. Alprazolam and clonazepam are quickly effective in alleviating panic, but they cause significant symptoms upon discontinuation. The best-studied drug in the treatment of panic disorder is imipramine; like other tricyclic antidepressants, it can cause increased jitteriness early in treatment. Monoamine oxidase inhibitors may be particularly helpful in patients with panic disorder who exhibit social avoidance. Behavior therapy, an important component of treatment, involves the patient's confrontation of fears or phobias. [References: 37]

Swinson RP, Cox BJ, Woszczyna CB: USE OF MEDICAL SERVICES AND TREATMENT FOR PANIC DISORDER WITH AGORAPHOBIA AND FOR SOCIAL PHOBIA. Canadian Medical Association Journal 1992; 147(6):878-83. Summary: OBJECTIVE: To examine the medical services and treatment for anxiety disorders reported by patients who had either panic disorder with agoraphobia or else social phobia. DESIGN: Archival research of consecutive records of psychiatric interviews conducted between January 1990 and December 1991. The records were examined by a trained research assistant who had had no contact with the patients. PATIENTS: One hundred patients who had panic disorder with agoraphobia and twenty-eight patients who had social phobia. SETTING: An anxiety disorders clinic in a university-affiliated psychiatric institute. OUTCOME MEASURES: Variables related to the use of medical services included history of hospitalization, emergency department visits and referrals to specialists. Variables related to treatment included types of medication received, whether behaviour therapy was received and types of health care professionals seen. RESULTS: Almost 30% of the patients with panic disorder and more than 20% of those with social phobia had a history of a major depressive episode at some time in their lives; 30% and 25% respectively had a current nonpsychiatric medical diagnosis. In the past year nearly one-third of both patient groups had seen three or more different health care professionals and almost one-fifth of those with panic disorder had gone to a general hospital emergency department. Of the patients with panic disorder 9% had previously been assessed by a cardiologist and 17% by a neurologist. At least two-thirds of each group had received benzodiazepines, often for use as needed. Although most of the patients in both groups had been seen by mental health professionals such as psychiatrists, few had received optimal treatment. Of those with panic disorder, only 15% had received the tricyclic antidepressant imipramine, 13% alprazolam and 11% cognitive-behavioural therapy. Only 4% of the patients with social phobia had received cognitive-behavioural therapy. CONCLUSIONS: Both groups of patients, and particularly those with panic disorder, are frequent users of medical services. Although most have had contact with mental health professionals, few have received appropriate treatment. Benzodiazepines appear to be overprescribed, whereas forms of treatment that have been shown to reduce the use of medical services, such as cognitive-behavioural therapy, are infrequently given.

Clair AL, Oei TP, Evans L: PERSONALITY AND TREATMENT RESPONSE IN AGORAPHOBIA WITH PANIC ATTACKS. Comprehensive Psychiatry 1992; 33(5):310-8. Summary: The present study investigated the association of specific personality characteristics with agoraphobia, and whether they predicted long-term outcome following a group cognitive behavior therapy program. Thirty-three patients with agoraphobia with panic attacks, 18 with social phobia, and 26 "normals" were used in the study. Personality factors were measured with the Maudsley Personality Inventory (MPI), the Hostility and Direction of Hostility Questionnaire (HDHQ), and the Fundamental Interpersonal Relations Orientation-Behavior Scale (FIRO-B). The results showed that (1) agoraphobics are more extroverted and more likely to include others in their activities than are social phobics; however, they are less extroverted, more neurotic, more hostile and intropunitive, and less likely to include others in their activities than are normals; (2) social phobics are similarly less extroverted, more neurotic, and more hostile and intropunitive than normals, but, in addition, are less likely to exert control over others, more likely to want to be controlled, and less expressive of affection than normals; and (3) personality characteristics did not predict treatment outcome.

Barlow DH: COGNITIVE-BEHAVIORAL APPROACHES TO PANIC DISORDER AND SOCIAL PHOBIA. [REVIEW]. Bulletin of the Menninger Clinic 1992; 56(2 Suppl A):A14-28. Summary: In the past several years, substantial progress has been made in developing relatively efficient and seemingly effective brief psychosocial treatments for anxiety disorders. Knowledge has advanced along both biological and psychological fronts, although the greater effort has been put into understanding the neurobiological basis of anxiety disorders and developing appropriate, effective pharmacological treatment. Nevertheless, psychological knowledge has also advanced, and a more recent trend is to integrate psychological and biological advances at the level of psychopathology and treatment. The author highlights recent developments in understanding the psychological basis of two anxiety disorders: panic disorder and social phobia. He then describes psychosocial treatment protocols for these disorders that have been developed at the Center for Stress and Anxiety Disorders at the State University of New York at Albany, and reviews data on their effectiveness. [References: 29]

Bowden CL: PSYCHOPHARMACOLOGICAL TREATMENT OF PANIC DISORDER. [REVIEW]. Bulletin of the Menninger Clinic 1992; 56(2 Suppl A):A29-41. Summary: Panic disorder is a serious, often chronic condition that warrants vigorous treatment. The benzodiazepines, particularly the high-potency compounds alprazolam and clonazepam, provide prompt relief, often with few side effects. Tricyclic antidepressants and monoamine oxidase inhibitors are also effective, although patient acceptance may be limited by a slower response and side effects that mimic some symptoms of panic attacks. The author suggests strategies for the most effective use of these agents. [References: 43]

Menninger WW: INTEGRATED TREATMENT OF PANIC DISORDER AND SOCIAL PHOBIA. Bulletin of the Menninger Clinic 1992; 56(2 Suppl A):A61-70. Summary: The integrated treatment of disabling anxiety disorders such as panic disorder and social phobia draws on an understanding of psychodynamic theory, cognitive-behavioral theory, and psychopharmacology. Regardless of the treatment employed, clinicians are encouraged to focus on interrelated factors affecting the course of the illness and its treatment, including differential diagnosis, etiology, patient education, symptomatic relief, underlying causes, and therapist anxiety. The author delineates eight key principles that foster the optimal choice or combination of treatment methods, and gives a case example to illustrate how these principles apply.

Agras WS: THE DIAGNOSIS AND TREATMENT OF PANIC DISORDER. [REVIEW]. Annual Review of Medicine 1993; 44:39-51. Summary: Panic attacks and panic disorder often first present in the emergency room or to the family practitioner. The presentation and differential diagnosis of this disabling disorder are described in this review, together with the etiology and health effects of the syndrome. Both medication and psychological treatments are described, as are the indications, side effects, and expected outcome for each therapy alone and in combination. [References: 43]

Bakish D, Saxena BM, Bowen R, D'Souza J: REVERSIBLE MONOAMINE OXIDASE-A INHIBITORS IN PANIC DISORDER. Clinical Neuropharmacology 1993; 16 Suppl 2:S77-82. Summary: Monoamine oxidase (MAO) inhibitors are known to be effective in panic disorder, but a high incidence of adverse reactions have limited their use. The new, selective, and reversible MAO-A inhibitors exemplified by brofaromine and moclobemide do not require dietary restrictions, have fewer drug interactions, and are better tolerated. This paper reports a randomized, double-blind, 8-week trial in which the efficacy and safety of brofaromine was compared to clomipramine in patients with panic disorder with or without agoraphobia. Both treatments achieved a significant and comparable reduction in the number of panic attacks, and were equally effective in all the parameters measured. Side effects were typical of the drug class. Further trials are required to evaluate this promising new treatment.

Ballenger JC: PANIC DISORDER: EFFICACY OF CURRENT TREATMENTS. [REVIEW]. Psychopharmacology Bulletin 1993; 29(4):477-86. Summary: As has been demonstrated in the numerous studies cited in this report, there are multiple effective treatments for panic disorder (PD), both pharmacological and psychosocial. Available evidence documents that at least 75 percent of patients will have a good response to three classes of medications (tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines) which are all approximately equal in efficacy and side effects. Medications may be even more effective when combined with cognitive and behavioral techniques. Several of the psychosocial treatments are also quite effective and appear to have certain advantages, including a low relapse rate. Currently a cognitive treatment specific for panic disorder is under active study and appears especially promising. It is clear that both pharmacological and cognitive-behavioral treatments for panic disorder are effective and can reduce or eliminate the multiple symptoms (panic attacks, phobic avoidance, depression, etc.) and the secondary disability in occupational and social and family roles associated with panic disorder. Untreated, panic disorder patients appear to generally remain chronically ill and worsen over time. What is less clear are issues of length of treatment, outcome after treatment is discontinued, relationship of pharmacological and nonpharmacological treatments, effect of comorbid disorders and presence of subclinical symptoms, and patient characteristics which predict a positive response. The relatively recent finding that panic disorder is a common condition, occurring in about 1-2 percent of the population within any 6-month period (Weissman 1990) has stimulated clinical interest in the development of effective interventions. Until the early 1980s available treatments were generally ineffective, leaving approximately 75 percent of patients unimproved (Doctor 1982). However, excellent pharmacological and nonpharmacological treatments are now available and provide significant improvement with complete resolution of symptoms and disability in the majority of patients. The advances in the knowledge base about panic disorder were underscored in the National Institutes of Health Consensus Development Conference held September 25-27, 1991 at the National Institutes of Health in Bethesda, MD. These conferences are convened periodically by the National Institutes of Health to evaluate available scientific evidence, resolve issues of both safety and treatment efficacy, and make these advances known to the public. One of the primary conclusions from this conference is that "Panic disorder is a distinct condition with a specific presentation, course, and positive family history and for which there are effective pharmacological and cognitive-behavioral treatments" (Panic Consensus Statement 1991).(ABSTRACT TRUNCATED AT 400 WORDS) [References: 77]

Burrows GD, Judd FK, Norman TR: LONG-TERM DRUG TREATMENT OF PANIC DISORDER. [REVIEW]. Journal of Psychiatric Research 1993; 27 Suppl 1:111-25. Summary: Drug treatment of panic disorder with benzodiazepines and antidepressants has been established as efficacious in the short-term (6-8 weeks). The efficacy of medications during long-term (i.e., continuous) treatment has not often been addressed and a review of the evidence is presented. Most data exists for the long-term effectiveness of benzodiazepines. Experience with the triazolobenzodiazepine, alprazolam, is reviewed together with some other high potency drugs, e.g., clonazepam. Tricyclic antidepressants are also effective in the long-term treatment of panic and the relevant studies are presented. Long-term efficacy for monoamine oxidase inhibitors is not as clearly established. The issue of relapse following drug withdrawal is addressed and some strategies for patient management in long-term therapy are discussed. [References: 65]

Curtis GC, Massana J, Udina C, Ayuso JL, Cassano GB, Perugi G: MAINTENANCE DRUG THERAPY OF PANIC DISORDER. Journal of Psychiatric Research 1993; 27 Suppl 1:127-42. Summary: The efficacy of tricyclics and benzodiazepines in the short term (approximately 2-4 months) treatment of panic disorder is well demonstrated, but efficacy over the longer term is not considered established. The present study provided systematic data from a double blind comparison of maintenance therapy (up to 8 months) of panic disorder with or without agoraphobia with alprazolam, imipramine, or placebo in 181 patients who had responded to the same regimen in a randomized 8-week treatment trial. All three groups had improved during the first 2 months (active treatments more than placebo and about equal to each other), and all maintained or extended their improvement over the next 6 months without any significant change in dose. More than twice as many alprazolam and imipramine than placebo patients (15%) remained in treatment for the full 8 months and did slightly better on symptom measures than the remaining placebo patients. Both medications were well tolerated during the maintenance period. The data suggest sustained efficacy and safety of imipramine and alprazolam over an extended period. More specifically, they suggest that tolerance does not develop to the therapeutic effects of either drug.

Gelder MG, Clark DM, Salkovskis P: COGNITIVE TREATMENT FOR PANIC DISORDER. [REVIEW]. Journal of Psychiatric Research 1993; 27 Suppl 1:171-8. Summary: Several kinds of evidence indicate that there are important psychological causes of panic disorder as well as the biological causes that have been demonstrated by others. These psychological causes are fears that physical symptoms of anxiety will be followed by an immediate medical emergency: for example, that palpitations will be followed by a heart attack. Evidence is presented to show (a) that such fears are more frequent among panic disorder patients than other anxious patients; (b) that activating the fears can produce panic; and (c) that reducing the fears can attenuate the effects of procedures that produce panic. For panic disorder, cognitive therapy, which reduces these specific fears, gives results comparable to those of imipramine and alprazolam. If further research confirms that these therapeutic effects of cognitive therapy are sustained well beyond the end of treatment, cognitive therapy could be the treatment of choice for panic disorder. [References: 28]

Keck PE Jr, McElroy SL, Tugrul KC, Bennett JA, Smith JM: ANTIEPILEPTIC DRUGS FOR THE TREATMENT OF PANIC DISORDER. [REVIEW]. Neuropsychobiology 1993; 27(3):150-3. Summary: Evidence from preclinical studies, preliminary clinical reports, pharmacologic challenge studies and a small number of controlled trials suggests that several antiepileptic agents--valproate, carbamazepine, and clonazepam--may have therapeutic effects in the treatment of patients with panic disorder. We review the theoretical basis and available clinical data supporting the use of these agents in panic disorder. [References: 39]

Lydiard RB, Morton WA, Emmanuel NP, Zealberg JJ, Laraia MT, Stuart GW, O'Neil PM, Ballenger JC: PRELIMINARY REPORT: PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF THE CLINICAL AND METABOLIC EFFECTS OF DESIPRAMINE IN PANIC DISORDER. Psychopharmacology Bulletin 1993; 29(2):183-8. Summary: Fifty-six males and females with panic disorder with or without agoraphobia participated in a 12-week, placebo-controlled treatment study of the efficacy of desipramine (DMI). Twenty-six of 28 patients receiving DMI completed the study; 17 of 28 placebo (PBO) recipients completed 12 weeks. Patients receiving DMI responded significantly better than did PBO recipients as measured by Hamilton Anxiety Scale (HAM-A) and global phobia ratings, with a trend toward greater global improvement, but no between-group differences on panic attack frequency were discerned. By Week 12, 22 of 26 (85%) DMI patients were panic-free; 13 of 17 (76%) PBO patients were panic-free. Resting metabolic rate (RMR) was tested on a subset of the patients. Patients receiving DMI showed no effects on RMR or thyroid indices but lost a significant amount of weight; the PBO recipients exhibited no weight loss or RMR effects. In this study, the high PBO response rate obscured treatment group differences on some measures. This study underscores the need for placebo comparisons in treatment studies. In summary, DMI appears to be an effective treatment for panic disorder. DMI appears to have little effect on RMR; a slight but significant weight loss was observed in the DMI but not PBO group.

Pecknold JC: DISCONTINUATION REACTIONS TO ALPRAZOLAM IN PANIC DISORDER. Journal of Psychiatric Research 1993; 27 Suppl 1:155-70. Summary: 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)

Roy-Byrne PP, Sullivan MD, Cowley DS, Ries RK: ADJUNCTIVE TREATMENT OF BENZODIAZEPINE DISCONTINUATION SYNDROMES: A REVIEW. [REVIEW]. Journal of Psychiatric Research 1993; 27 Suppl 1:143-53. Summary: The variety of pharmacologic and psychotherapeutic approaches to facilitate benzodiazepine discontinuation are reviewed. Strategies to attenuate physiologic withdrawal with clonidine, propranolol and carbamazepine have been inconsistently effective. Strategies to prevent relapse by substituting medications that could later be discontinued more easily (i.e., antidepressants and azapirones) appear more useful but have been less well studied. Psychotherapeutic approaches appear to work, but specific therapeutic components are unclear and non-specific "placebo" effects may play an important role. [References: 37]

Salzman C: BENZODIAZEPINE TREATMENT OF PANIC AND AGORAPHOBIC SYMPTOMS: USE, DEPENDENCE, TOXICITY, ABUSE. [REVIEW]. Journal of Psychiatric Research 1993; 27 Suppl 1:97-110. Summary: Benzodiazepines are widely prescribed drugs. Most patients are prescribed benzodiazepines for short periods of time for anxiolytic or hypnotic purposes. However, some benzodiazepines are also used for extended periods at high doses to treat panic and agoraphobic disorders. When chronically prescribed benzodiazepines are discontinued, a predictable pattern of discontinuance symptoms may develop, indicating physiological dependence. Benzodiazepines also produce a variety of side effects including sedation, reduced coordination, and impaired cognition, which are primarily related to dose and duration of treatment. Benzodiazepines are commonly used by polysubstance abusers but their abuse as recreational drugs when taken alone is rare, and high-dose treatment for panic and agoraphobic symptoms does not lead to abuse. Prescribing guidelines are offered. [References: 55]

Uhlenhuth EH, Balter MB, Mellinger GD: CLINICAL VARIABLES IN PHARMACOEPIDEMIOLOGY. Journal of Psychiatric Research 1993; 27 Suppl 1:89-95. Summary: Pharmacoepidemiology traditionally concerns itself with the rates at which drugs are prescribed and used in the general population. Interpretations of these data frequently assume that the rates--for psychotropic drugs--reflect primarily the reinforcing properties of the drugs. This paper, in contrast, focuses on the influence of certain clinical characteristics of consumers on patterns of psychotherapeutic drug use. The data are from a nationwide (US) probability sample of 3,161 persons aged 18-79 years surveyed in 1979. One-year prevalence rates of use and the longest period of regular daily use serve as indices of drug consumption. Scores on a 43-item checklist of psychological symptoms were used to compute two clinical descriptors of the respondents--a quantitative index of the level of psychic distress and a qualitative syndromal classification including depression, agoraphobia/panic, other phobias, and generalized anxiety. The data showed that, although anxiolytics and antidepressants have characteristic patterns of prevalence and duration of use, the clinical characteristics of users (severity and pattern of symptoms) strongly influence these patterns. Prevalence and duration of drug use alone do not suffice to illuminate the social functions and significance of psychotherapeutic agents, to provide a basis for value judgments about the use of such compounds, and to guide medical decision-making. Since clinical variables play such a major role in the consumption of these agents, it is crucial to include information about these variables in the analysis and interpretation of patterns of psychotherapeutic drug use.

Black DW, Wesner R, Gabel J: THE ABRUPT DISCONTINUATION OF FLUVOXAMINE IN PATIENTS WITH PANIC DISORDER. Journal of Clinical Psychiatry 1993; 54(4):146-9. Summary: BACKGROUND: We evaluated patients abruptly withdrawn from fluvoxamine, a serotonin selective reuptake inhibitor, for evidence of a discontinuation syndrome. METHOD: In an open-label study, 14 subjects were abruptly withdrawn from fluvoxamine after treatment lasting 8 months (7 months for 1 patient). Psychological, somatic, and perceptual symptoms were assessed at Day 5, Day 10, and Day 14 postdiscontinuation. Anxiety and depression were assessed using clinician and self-rated scales. RESULTS: Twelve (86%) of 14 subjects developed new symptoms. The most frequent symptoms reported were dizziness/incoordination, headaches, nausea, and irritability. Symptoms peaked on Day 5 postdiscontinuation. Only 1 subject had a recurrence of panic, but another developed anxiety and depression; both were remedicated. CONCLUSION: Abrupt fluvoxamine discontinuation is associated with a characteristic syndrome in many patients.

Clum GA, Clum GA, Surls R: A META-ANALYSIS OF TREATMENTS FOR PANIC DISORDER. Journal of Consulting & Clinical Psychology 1993; 61(2):317-26. Summary: In a meta-analysis, the authors compared the effectiveness of psychological and pharmacological treatments for panic disorder. Percentage of agoraphobic subjects in the sample and duration of the illness were unrelated to effect size (ES). Type of dependent variable was generally unrelated to treatment outcome, although behavioral measures yielded significantly smaller ESs. Dependent measures of general anxiety, avoidance, and panic attacks yielded larger ESs than did depression measures. Choice of control was related to ES, with comparisons with placebo controls greater than comparisons with exposure-only or "other treatment" controls. Psychological coping strategies involving relaxation training, cognitive restructuring, and exposure yielded the most consistent ESs; flooding and combination treatments (psychological and pharmacological) yielded the next most consistent ESs. Antidepressants were the most effective pharmacological intervention.

Pecknold JC, Luthe L, Scott-Fleury MH, Jenkins S: GEPIRONE AND THE TREATMENT OF PANIC DISORDER: AN OPEN STUDY. Journal of Clinical Psychopharmacology 1993; 13(2):145-9. Summary: Gepirone, an azapirone, is a potent 5-hydroxytryptamine 1A (5-HT1A) agonist. We report an uncontrolled 6-week study in 21 patients (4 men, 17 women: mean age, 36.71 years) with a concurrent DSM-III-R diagnosis of generalized anxiety disorder and panic disorder with agoraphobia. After a 2-week medication-free period, patients were started on 2 mg of gepirone per day increasing over 3 weeks to 12 mg/day. Three patients dropped out in the first week, and one patient violated the protocol. They were therefore excluded from analysis. Two patients who dropped out at weeks 4 and 5 because they found the treatment ineffective were included. Twelve of the 17 patients (70.6%) had at least a 50% reduction in their panic attacks by week 6, and 9 of them had at least a 50% reduction by week 3. Ten patients had "0" panic attacks by week 6 (59%). On the Hamilton Anxiety Scale, 65% had a 50% or greater reduction in total score, mostly beginning in week 1. On Global Assessment, by week 6, 11 were much improved or better (65%). Adverse effects were rare and consisted of stomach upset, dizziness, or headaches. This preliminary study suggests the possible efficacy of gepirone in panic disorder.

Schneier FR, Carrasco JL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick J, Liebowitz MR: ALPIDEM IN THE TREATMENT OF PANIC DISORDER. Journal of Clinical Psychopharmacology 1993; 13(2):150-3. Summary: Alpidem, an imidazopyridine that acts at the gamma-aminobutyric acid/benzodiazepine receptor complex, has been reported to be an effective anxiolytic with a more favorable side effect profile than benzodiazepines. The effect of alpidem was investigated in an 8-week, open, clinical trial in 13 patients with panic disorder, with or without agoraphobia. Three patients were responders (much improved or very much improved), five patients were nonresponders, and five patients dropped out after less than 6 weeks of treatment. Significant improvement was seen in the sample as a whole for spontaneous panic attacks, phobic avoidance, and anticipatory anxiety. Most improvement occurred during the first 4 weeks of treatment, and responders had milder panic disorder at baseline. Adverse effects were generally mild. After 8 weeks of treatment, taper of medication over 2 weeks occurred without significant worsening of panic disorder symptoms. The efficacy of alpidem in the treatment of panic disorder remains uncertain and requires assessment in a controlled trial.

Keck PE Jr, Taylor VE, Tugrul KC, McElroy SL, Bennett JA: VALPROATE TREATMENT OF PANIC DISORDER AND LACTATE-INDUCED PANIC ATTACKS. Biological Psychiatry 1993; 33(7):542-6. Summary: Several lines of evidence suggest that the anticonvulsant drug valproate may have antipanic properties: (1) It enhances gamma-aminobutyric acid activity in the brain; (2) it has anxiolytic effects in animal models of anxiety; and (3) it has been reported to be effective in panic disorder in several preliminary studies; however, valproate has not been studied in the prevention of lactate-induced panic attacks. Sixteen patients with panic disorder underwent a lactate infusion followed by a 28-day treatment period with valproate and subsequent rechallenge with lactate. Response was measured by change in panic attack frequency and Hamilton Anxiety Scale (HAS) scores and by the ability of valproate to block lactate-induced panic on rechallenge. Of the 14 patients completing the 28-day trial, 10 (71%) experienced a greater than 50% reduction in the weekly frequency of panic attacks. Six (43%) had complete remission. HAS scores dropped significantly from a baseline mean of 30.8 +/- 9.4 (SD) to 12.6 +/- 7 after 4 weeks of treatment. Valproate blocked reinduction of panic symptoms on lactate rechallenge in 10 (83%) of 12 patients who had initially experienced panic symptoms on initial infusion. The significant reduction in spontaneous panic attacks and the blockade of lactate-induced panic symptoms by valproate support earlier studies suggesting that the drug may be an effective treatment for panic disorder.

Goddard AW, Woods SW, Sholomskas DE, Goodman WK, Charney DS, Heninger GR: EFFECTS OF THE SEROTONIN REUPTAKE INHIBITOR FLUVOXAMINE ON YOHIMBINE-INDUCED ANXIETY IN PANIC DISORDER. Psychiatry Research 1993; 48(2):119-33. Summary: To assess the effects of the selective serotonin reuptake blocker fluvoxamine on noradrenergic function in patients with panic disorder, an intravenous yohimbine challenge test was administered to eight patients with panic disorder before and after 8 weeks of fluvoxamine treatment and to a parallel group of eight patients treated with placebo. Fluvoxamine treatment reduced yohimbine-induced anxiety while placebo treatment had no effect on this variable. Both fluvoxamine and placebo treatment had little effect on biochemical or physiologic responses to yohimbine.

Pollack MH, Otto MW, Tesar GE, Cohen LS, Meltzer-Brody S, Rosenbaum JF: LONG-TERM OUTCOME AFTER ACUTE TREATMENT WITH ALPRAZOLAM OR CLONAZEPAM FOR PANIC DISORDER. Journal of Clinical Psychopharmacology 1993; 13(4):257-63. Summary: The relative effectiveness of the available treatments for panic disorder may best be understood in the context of the longitudinal course of the disorder. This study examines a number of clinically relevant issues, including long-term outcome after acute treatment, the proportion of patients remaining on single-agent treatment or requiring multiple medications or nonpharmacologic interventions over time, evidence for dose escalation during maintenance high-potency benzodiazepine therapy, and predictors of acute and long-term response to treatment. Fifty-nine panic disorder patients originally randomized to treatment in a controlled trial comparing alprazolam, clonazepam, and placebo were reevaluated in a follow-up study. At a mean follow-up of 1.5 years, 78% of patients remained on medication and the mean dosage of alprazolam and clonazepam did not increase. Our data suggest that most patients maintain benefit with long-term pharmacotherapy but that residual symptomatology may require more intensive or additional treatment strategies. Response at the endpoint of the acute trial was significantly associated with pretrial baseline Clinical Global Impression Scale score and the presence of dysthymia. Poor outcome at follow-up was associated with total duration of the disorder, agoraphobic subtype, and the presence of comorbid social phobia. We underscore the potential importance of comorbid affective and anxiety disorders as well as phobic patterns in determining long-term response to treatment.

Schweizer E, Patterson W, Rickels K, Rosenthal M: DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF A ONCE-A-DAY, SUSTAINED-RELEASE PREPARATION OF ALPRAZOLAM FOR THE TREATMENT OF PANIC DISORDER. American Journal of Psychiatry 1993; 150(8):1210-5. Summary: OBJECTIVE: The goals of this study were to assess the antipanic efficacy of a new, sustained-release formulation of alprazolam and to assess the safety and tolerability of once-a-day administration of 1-10 mg of sustained-release alprazolam. METHOD: One hundred ninety-four patients with diagnosis of agoraphobia with panic attacks or panic disorder with limited phobic avoidance underwent a 1-week placebo washout before being randomly assigned to groups receiving 8 weeks of double-blind treatment with either sustained-release alprazolam or placebo. RESULTS: There was a significant treatment effect favoring sustained-release alprazolam (highest mean dose = 4.7 mg/day) across almost all measures of anxiety, panic, and phobic avoidance, despite a significantly higher dropout rate in patients receiving placebo. Eighty-five percent of the patients treated with sustained-release alprazolam, compared with 61% of the patients given placebo, reported complete blockade of panic attacks by the end of 6 weeks of treatment. Sedation was the most commonly reported adverse effect. Discontinuation of sustained-release alprazolam was associated with moderate but transient levels of distress in 48% of the patients; discontinuation of placebo led to distress in only 10% of the patients. Nonetheless, there was no difference in the proportion of patients who were able to remain off the study drug for at least 2 weeks. CONCLUSIONS: These results suggest that sustained-release alprazolam is highly effective in the acute treatment of panic disorder at doses comparable to those in the originally marketed compressed tablet of alprazolam. The medication was well tolerated but showed rebound effects during a rapid drug taper after 6 weeks of treatment.

Albus M, Scheibe G: OUTCOME OF PANIC DISORDER WITH OR WITHOUT CONCOMITANT DEPRESSION: A 2-YEAR PROSPECTIVE FOLLOW-UP STUDY. American Journal of Psychiatry 1993; 150(12):1878-80. Summary: In a prospective 2-year follow-up study, 32 patients with panic disorder alone and 20 with panic disorder and concomitant depression were investigated. After controlled treatment with either imipramine or doxepin, patients received naturalistic treatment with antidepressants, benzodiazepines, and supportive psychotherapy. They were evaluated for anxiety, depression, and social disability at least every 3 months during the follow-up period. The data showed fluctuation of symptoms in both groups and a less favorable outcome for the patients with comorbid conditions. However, the overall outcome was better than that reported in other studies and indicates that panic disorder is quite responsive to appropriate treatment.

Eldridge GD, Walker JR, Holborn SW: COGNITIVE-BEHAVIORAL TREATMENT FOR PANIC DISORDER WITH GASTROINTESTINAL SYMPTOMS: A CASE STUDY. Journal of Behavior Therapy & Experimental Psychiatry 1993; 24(4):367-71. Summary: A 25-year-old woman with a 12-year history of panic disorder with agoraphobia and gastrointestinal symptoms was treated using a cognitive-behavioral program which included: (a) correcting misconceptions about normal bowel functioning, (b) graduated in vivo exposure to internal stimuli which she misinterpreted as precursors of loss of bowel control, (c) graduated in vivo exposure to external stimuli associated with fears of loss of bowel control, (d) establishment of regular eating patterns, and (e) bowel control training. Self-ratings of avoidance and distress, frequency of panic attacks, diazepam use, and negative cognitions decreased with treatment. Treatment gains were maintained at 18-month follow-up. Tailoring of cognitive-behavioral treatment to panic with fears of loss of bowel control was emphasized.

Hoffart A, Due-Madsen J, Lande B, Gude T, Bille H, Torgersen S: CLOMIPRAMINE IN THE TREATMENT OF AGORAPHOBIC INPATIENTS RESISTANT TO BEHAVIORAL THERAPY. Journal of Clinical Psychiatry 1993; 54(12):481-7. Summary: BACKGROUND: Both behavior-modification methods and antidepressants have proved to be effective in the treatment of agoraphobia. The authors examined the effects of clomipramine on agoraphobia in patients who failed to respond to exposure-based behavioral treatment. METHOD: Eighteen patients with panic disorder with agoraphobia who had not responded to previous inpatient behavioral treatment were recruited to a 12-week, placebo-controlled, double-blind crossover study of clomipramine, at top doses of 150 mg/day for 3 weeks. The patients were assessed on measures of phobic avoidance, agoraphobic cognitions, panic, state and trait anxiety, subjective anxiety, and depression. RESULTS: One patient dropped out of the study after 6 weeks. On most outcome measures, the 17 study completers had significantly (p < .05) lower symptom scores at posttest in the active drug period than at posttest in the placebo period; however, the clinical gains were modest. CONCLUSION: The short-term efficacy of clomipramine for agoraphobic patients who failed to respond lastingly to behavioral treatment was demonstrated. It remains to be shown that clomipramine can lead to clinically significant and lasting benefits in these patients.

Laberge B, Gauthier JG, Cote G, Plamondon J, Cormier HJ: COGNITIVE-BEHAVIORAL THERAPY OF PANIC DISORDER WITH SECONDARY MAJOR DEPRESSION: A PRELIMINARY INVESTIGATION. Journal of Consulting & Clinical Psychology 1993; 61(6):1028-37. Summary: Controlled studies indicate that cognitive-behavioral therapy eliminates panic attacks in greater than 80% of patients who suffer from panic disorder. However, because most of the screening procedures used in those studies called for excluding patients who were depressed, a question arises as to the extent to which these results apply to patients who are clinically depressed in addition to having panic attacks. Accordingly, an attempt was made in the present study to determine whether or not panic patients who are clinically depressed could be treated as successfully as those who are not clinically depressed. Two multiple baseline A-A1-A-B across-subjects designs were used, one to test 8 panic Ss with major depression and the second to test 7 panic Ss without major depression. In Baseline (A), Ss monitored their panic attacks daily. During the A1 phase, a program of information on panic attacks presented as psychotherapy was instituted to assess the effects of nonspecific factors, followed by a second baseline phase (A). Cognitive-behavioral therapy (B) was then introduced. Results showed that cognitive-behavioral therapy was significantly superior to information-based therapy in the reduction of panic attacks. No significant differences were found between depressed and nondepressed patients.

Rachman S: A CRITIQUE OF COGNITIVE THERAPY FOR ANXIETY DISORDERS. [REVIEW]. Journal of Behavior Therapy & Experimental Psychiatry 1993; 24(4):279-88. Summary: Progress in the cognitive-behavioral treatment of anxiety disorders is reviewed. Significant advances have been made in treating panic disorders and there are promising signs of an expansion of cognitive theory and therapy to other disorders, notably hypochondriasis, obsessional disorders and circumscribed phobias. Nevertheless, some difficult obstacles have emerged to present serious problems for the prevailing cognitive theory. [References: 42]

Balon R, Yeragani VK, Pohl R, Merlos B, Sherwood P: CHANGES IN APPETITE AND WEIGHT DURING THE PHARMACOLOGICAL TREATMENT OF PATIENTS WITH PANIC DISORDER. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 1993; 38(1):19-22. Summary: Antidepressants reportedly increase appetite, carbohydrate craving and weight in some patients with depression and panic disorder. This paper presents the results of changes in appetite and weight in patients with panic disorder treated with imipramine, diazepam or placebo in a double-blind prospective study. Forty-four patients with panic disorder were randomly assigned imipramine, diazepam and placebo. The investigators monitored weight and the patients rated their appetite and cravings during the eight week study. No significant increases in weight or appetite were found in the patients with panic disorder patients.

Nagy LM, Krystal JH, Charney DS, Merikangas KR, Woods SW: LONG-TERM OUTCOME OF PANIC DISORDER AFTER SHORT-TERM IMIPRAMINE AND BEHAVIORAL GROUP TREATMENT: 2.9-YEAR NATURALISTIC FOLLOW-UP STUDY. Journal of Clinical Psychopharmacology 1993; 13(1):16-24. Summary: Twenty-eight patients with a DSM-III diagnosis of agoraphobia with panic attacks who completed a 4-month combined drug and behavioral treatment program and who were then discharged on imipramine were interviewed 1 to 5 years after being discharged. At the time of follow-up, half of the patients were medication free, eight were receiving a lower dose of imipramine, two were receiving the same dose as at the time of discharge, and four patients were receiving other antipanic medications. Panic attack frequency remained reduced at the time of follow-up, as did all anxiety and all impairment ratings. These improvements were similar between patients receiving and not receiving imipramine at this time. Long-term outcome was independent of nonpharmacological therapy during the follow-up interval and lifetime diagnosis of major depression at the time of admission. Our data suggest that improvement observed after 4 months of treatment with imipramine and behavioral therapy is maintained after 1 to 5 years, even for many patients who reduced the dose of or discontinued imipramine. Long-term, randomized studies are needed to compare the efficacy of treatments and to determine treatment duration.

Waddell KL, Demi AS: EFFECTIVENESS OF AN INTENSIVE PARTIAL HOSPITALIZATION PROGRAM FOR TREATMENT OF ANXIETY DISORDERS. Archives of Psychiatric Nursing 1993; 7(1):2-10. Summary: This study evaluates the effectiveness of a partial hospitalization program for the treatment of anxiety disorders. The 5-week program was based on an integration of biological, cognitive, and behavioral theories. Neuman's systems theory provided the framework for the study. The 32 participants were tested pre- and posttreatment. All three hypotheses were supported; "fear of fear," severity of impairment, and general emotional distress were all significantly lower posttreatment than pretreatment. The limitations, including the lack of a comparison group, possible sample bias, and the lack of long-term follow-up, are addressed.

Black DW, Wesner R, Bowers W, Gabel J: A COMPARISON OF FLUVOXAMINE, COGNITIVE THERAPY, AND PLACEBO IN THE TREATMENT OF PANIC DISORDER. Archives of General Psychiatry 1993; 50(1):44-50. Summary: Seventy-five outpatients with moderate to severe panic disorder were randomly assigned to receive 8 weeks of fluvoxamine, cognitive therapy, or placebo. Fifty-five patients completed the treatment protocol. Fluvoxamine was found to be an effective and well-tolerated treatment for panic using clinician- and patient-rated variables. Subjects receiving cognitive therapy also showed improvement, but this improvement did not significantly differ from the experience of the placebo-treated group for most comparisons. Fluvoxamine was superior to cognitive therapy for many ratings, but cognitive therapy was not superior to fluvoxamine on any rating. Fluvoxamine also produced improvement earlier than cognitive therapy. At the main comparison point (week 4), 57% (13/23) of patients receiving fluvoxamine were rated moderately improved or better vs 40% (8/20) of the group given cognitive therapy and 22% (5/23) of the placebo-treated group. At that point, 43% (10/23) of the fluvoxamine recipients vs 25% (5/20) of cognitive therapy and 4% (1/23) of placebo recipients were free of panic attacks.

Margraf J, Barlow DH, Clark DM, Telch MJ: PSYCHOLOGICAL TREATMENT OF PANIC: WORK IN PROGRESS ON OUTCOME, ACTIVE INGREDIENTS, AND FOLLOW-UP. [REVIEW]. Behaviour Research & Therapy 1993; 31(1):1-8. Summary: Initial interest in the causes and treatment of panic disorder was triggered by biological theories and investigators. More recently, however, research on newly developed psychological approaches for panic has advanced our understanding of the disorder and has led to the development of specific treatment programs. Typically, these programs consist of a range of treatment components that more or less directly target panic attacks and the fears and behaviors associated with them. The paper reviews four studies evaluating these programs that have recently been completed or are close to completion in different centers in the United States (Albany, New York; Austin, Texas) and Europe (Oxford, England; Marburg, Germany). Conforming to strict methodological standards, these studies report consistently high success rates and temporal stability of the treatment gains. About 80% or more of the patients receiving combined cognitive-behavioral treatments achieved panic free status as well as strong and clinically significant improvement in general anxiety, panic-related cognitions, depression, and phobic avoidance. Furthermore, these gains were maintained at follow-ups of up to 2 years. The success of these psychological treatments compares favorably with the outcome for the established pharmacological treatments. In addition, the studies provide new insights into the active ingredients that may operate in cognitive-behavioral treatments for panic disorder and show the feasibility of group treatments. Together, these studies underscore the fact that cognitive-behavioral treatments rest on firm experimental evidence that justifies their application in everyday practice as well as continued research into their mechanisms of action. [References: 42]

Rickels K, Schweizer E, Weiss S, Zavodnick S: MAINTENANCE DRUG TREATMENT FOR PANIC DISORDER. II. SHORT- AND LONG-TERM OUTCOME AFTER DRUG TAPER. Archives of General Psychiatry 1993; 50(1):61-8. Summary: Forty-eight patients with panic disorder completing 8 months of maintenance treatment with alprazolam (mean dose, 5.2 mg [n = 27]), imipramine hydrochloride (mean dose, 175 mg [n = 11]), or placebo (mean dose, 8.0 pills [n = 10]) underwent a gradual taper from medication over a 4-week period. A withdrawal syndrome was observed in almost all alprazolam-treated patients but in only a few imipramine- or placebo-treated patients. The clinical worsening of withdrawal symptoms after discontinuation tended to subside over the course of 3 medication-free weeks, but 33% of alprazolam-treated patients were unable to discontinue their medication regimen successfully. Severity of panic attacks at baseline but not daily alprazolam dose appeared as a significant independent predictor of taper difficulty. Forty-nine percent of the total study population continue to receive drug therapy: 82% alprazolam and 18% imipramine. Among patients who received alprazolam during study treatment and at follow-up, the mean daily dose was substantially reduced (6.1 vs 1.6 mg [n = 14]). At follow-up, after 1 year of naturalistic treatment for panic symptoms and combining 8-month completers and study dropouts, there were no significant differences in remission (68% to 71%) or in antipanic medication intake (39% to 56%) at follow-up for the three original treatment groups. However, 8-month study completers compared with study dropouts had a significantly higher remission rate (85% vs 55%).

Schweizer E, Rickels K, Weiss S, Zavodnick S: MAINTENANCE DRUG TREATMENT OF PANIC DISORDER. I. RESULTS OF A PROSPECTIVE, PLACEBO-CONTROLLED COMPARISON OF ALPRAZOLAM AND IMIPRAMINE. Archives of General Psychiatry 1993; 50(1):51-60. Summary: One hundred six patients diagnosed according to DSM-III as suffering from agoraphobia with panic disorder, panic disorder with limited phobic avoidance, or uncomplicated panic disorder entered an acute 8-week treatment phase. Patients who improved received an additional 6 months' maintenance treatment. Significantly more patients treated with alprazolam than with imipramine hydrochloride or placebo remained in therapy and experienced panic attack and phobia relief during the acute treatment phase. During the maintenance phase, neither tolerance nor daily dose increase was observed. All patients who completed the maintenance phase (27 in the alprazolam group, 11 in the imipramine group, and 10 in the placebo group) were panic free at the end of 8 months of study treatment. Alprazolam therapy was effective and well tolerated at a mean daily dose of 5.7 mg. Imipramine hydrochloride (175 mg/d) also produced significant panic relief but was associated with poor patient acceptance.

Mavissakalian MR, Perel JM, de Groot C: IMIPRAMINE TREATMENT OF PANIC DISORDER WITH AGORAPHOBIA: THE SECOND TIME AROUND. Journal of Psychiatric Research 1993; 27(1):61-8. Summary: The purpose of the present study was to assess and compare the therapeutic effects of imipramine during the initial treatment and retreatment of panic disorder with agoraphobia patients. Seven women with panic disorder with agoraphobia who had shown a marked and stable response to imipramine (121.4 +/- 41.8 mg/day) during their initial treatment of 24 weeks were retreated with the same dose (125 +/- 40.8 mg/day) of imipramine when they relapsed, on average 3 months following discontinuation of the drug. Assessments included operationalized criteria for response and relapse and plasma drug concentrations to verify treatment compliance. Data on phobic, panic, anxiety and depression measures were analyzed for 6 assessment times common to all patients; pretreatment, week 8 and 24 weeks follow-up of initial treatment, relapse which was also the beginning of retreatment, week 8 and 16-24 weeks follow-up of retreatment. At the end of retreatment all patients were marked responders and there was no significant difference on any outcome measure between the end of initial and retreatment assessment periods. However, overall therapeutic response to retreatment was slower than during initial treatment, in particular on phobic and patient rated panic measures. Although the full restoration of remission is clinically reassuring, the results caution that relapse may have sensitizing effects which delay, and if repeated could impede the response of panic disorder with agoraphobia patients to imipramine.

Garvey MJ: PANIC DISORDER: GUIDELINES TO SAFE USE OF BENZODIAZEPINES [PUBLISHED ERRATUM APPEARS IN GERIATRICS 1993 AUG;48(8):63]. Geriatrics 1993; 48(7):49-53, 56-8. Summary: Panic disorder is relatively common in older patients and may have serious consequences. The diagnosis is based on an accurate history of symptom onset and intensity. Symptoms include shortness of breath, dizziness, increased heart rate, trembling, and sweating. Effective treatment can be achieved with several kinds of medication, including benzodiazepines. Although physician and patient fears about benzodiazepines persist, panic-disordered patients with no history of drug abuse rarely develop substance dependence problems. Physical dependence occurs in a minority of patients and can be minimized by a slow tapering schedule. As with most medications, benzodiazepines need to be used with caution in older patients, who are more susceptible to adverse effects.

Sheehan DV, Raj AB, Harnett-Sheehan K, Soto S, Knapp E: THE RELATIVE EFFICACY OF HIGH-DOSE BUSPIRONE AND ALPRAZOLAM IN THE TREATMENT OF PANIC DISORDER: A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY. Acta Psychiatrica Scandinavica 1993; 88(1):1-11. Summary: This 8-week double-blind placebo-controlled trial investigated the relative efficacy and safety of alprazolam and buspirone in the treatment of panic disorder. Alprazolam (mean +/- SD dose 5.2 +/- 2.6 mg) produced a rapid and sustained improvement in panic attacks, anxiety, phobias, and disability and was superior to buspirone (mean +/- SD dose 61 +/- 26.5 mg) and placebo on all of these measures on completer (n = 85) and endpoint analysis (n = 92). Although higher doses of buspirone were used in this study than in previous trials, buspirone was not superior to placebo on any of the outcome measures. The results were disappointing in light of buspirone's benign side effect profile and low abuse potential.

O'Brien LS, Payne RG: PREVENTION AND MANAGEMENT OF PANIC IN PERSONNEL FACING A CHEMICAL THREAT--LESSONS FROM THE GULF WAR. Journal of the Royal Army Medical Corps 1993; 139(2):41-5. Summary: During the Gulf War a number of subjects presented with panic, hyperventilation, and inability to wear respirators when chemical alarms were sounded, despite a perceived real chemical threat. Twenty-five such sufferers were seen at the Psychiatric Department of 33 General (Surgical) Hospital. This paper considers the aetiology of such responses, describes a mode of treatment which can be used in the threat situation, and considers issues of future training.

Rosenberg R: DRUG TREATMENT OF PANIC DISORDER. [REVIEW]. Pharmacology & Toxicology 1993; 72(6):344-53. Summary: Drug treatment of panic disorder is reviewed with focus on recent controlled studies. The efficacy of alprazolam, a triazolobenzodiazepine, and imipramine, a tricyclic antidepressant, has consistently been demonstrated, but there is reasonable evidence that other benzodiazepines or antidepressants might also be effective if equipotent doses are used. Most controlled studies demonstrate drug efficacy on several psychopathological symptoms, including the core symptom panic attacks. Limited evidence indicates that alprazolam may be more efficacious in treating panic attacks than avoidance behaviour, and the reverse when imipramine is concerned. Drug efficacy appears to be most consistently documented in moderately to severely ill panic patients. The benzodiazepines are better tolerated than antidepressants in terms of patient acceptance, and the improvement sets in faster with benzodiazepines. In the presence of depressive symptoms considered secondary to panic attacks and/or agoraphobia, both types of drugs appear efficacious. Difficulty discontinuing high-dose benzodiazepine treatment remains the most important side effect of the treatment but sedation can, like anticholinergic side effects of the tricyclic antidepressants, be troublesome, thereby diminishing patient compliance. The role of newly developed antidepressants with a more specific mode of action and milder side effects awaits evaluation in controlled trials. [References: 73]

Wingerson D, Sullivan M, Dager S, Flick S, Dunner D, Roy-Byrne P: PERSONALITY TRAITS AND EARLY DISCONTINUATION FROM CLINICAL TRIALS IN ANXIOUS PATIENTS. Journal of Clinical Psychopharmacology 1993; 13(3):194-7. Summary: Patients who discontinue early from clinical trials frequently give ambiguous or no reasons for leaving the study. Using Cloniger's Tridimensional Personality Questionnaire, we examined the potential role of personality traits in early discontinuation in patients with panic disorder and generalized anxiety disorder. Early dropouts and completers were comparable at baseline on demographic and clinical variables but differed significantly on the Tridimensional Personality Questionnaire. For panic disorder and generalized anxiety disorder patients combined, early dropouts scored higher on total novelty seeking, as well as on the novelty-seeking traits of both disorderliness/dislike of regimentation and impulsiveness. There was no significant interaction between dropout status and diagnosis for this finding, indicating it applied equally to both groups. This study suggests that personality traits involving novelty seeking may contribute to early discontinuation from clinical trials, independent of side effects, lack of efficacy, or at baseline, significantly worse symptoms of anxiety.

Bedi A, Smucker MR: SHORT-TERM FOCUSED COGNITIVE THERAPY OF PANIC DISORDER WITH AEROPHOBIA: A CASE REPORT. Wisconsin Medical Journal 1993; 92(3):125-7. Summary: The efficacy of focused cognitive therapy was evaluated in the short-term treatment of a flight instructor suffering from panic disorder with aerophobic and agoraphobic symptoms. A modified panic induction technique (hyperventilation) was used in session to activate the specific bodily sensations he typically experienced during panic attacks. The patient was then asked to articulate his catastrophic interpretations of the physiological sensations he was experiencing and taught to re-interpret them in a non-catastrophic manner, which enabled him to reduce his symptoms to a more manageable level. After four sessions of focused cognitive therapy, the patient's panic and phobic symptoms were significantly reduced and no longer interfered with his daily functioning. Posttreatment follow-up at 6 and 9 months revealed that the patient was completely free of panic while flying.

Maddock RJ, Carter CS, Blacker KH, Beitman BD, Krishnan KR, Jefferson JW, Lewis CP, Liebowitz MR: RELATIONSHIP OF PAST DEPRESSIVE EPISODES TO SYMPTOM SEVERITY AND TREATMENT RESPONSE IN PANIC DISORDER WITH AGORAPHOBIA. Journal of Clinical Psychiatry 1993; 54(3):88-95. Summary: BACKGROUND: Many investigators have reported that panic disorder (PD) patients with comorbid major depression (MD) have more severe symptoms and a poorer response to treatment than patients with PD alone. It is not known if this is due to a distinct and more serious underlying disorder in these patients or simply a result of the simultaneous presence of the two disorders. METHOD: Nondepressed patients presenting for treatment of panic disorder with agoraphobia (PDA) were studied before treatment (N = 180) and after 4 weeks of treatment with adinazolam sustained release (N = 89) or placebo (N = 91). Twenty-nine percent (N = 53) of the patients had a past history of MD. Symptom severity and treatment outcome were compared in patients with primary, secondary, single, recurrent, or no past MD. RESULTS: There were no consistent differences in symptom severity or treatment outcome in patients with a past history of primary, secondary, or single episode MD compared with patients with no history of MD. However, a small number of patients with history of recurrent MD exhibited consistently greater symptom severity and poorer response to treatment than patients with no history of MD. CONCLUSION: The greater severity and worse outcome of comorbid PD and MD observed in earlier studies are more likely due to the simultaneous presence of the two disorders than to a more serious and enduring underlying disorder. However, our results suggest that recurrent MD may indicate a more serious condition in patients with PDA. This possibility warrants further study.

Telch MJ, Lucas JA, Schmidt NB, Hanna HH, LaNae Jaimez T, Lucas RA: GROUP COGNITIVE-BEHAVIORAL TREATMENT OF PANIC DISORDER. Behaviour Research & Therapy 1993; 31(3):279-87. Summary: The present study examined the efficacy of an 8-wk, cognitive-behavioral group treatment for panic disorder. Patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia were randomly assigned to treatment (N = 34) or delayed treatment control (N = 33). The treatment consisted of: (a) education and corrective information; (b) cognitive therapy; (c) training in diaphragmatic breathing; and (d) interoceptive exposure. At posttreatment, 85% of treated Ss were panic free, compared to 30% of controls. Treated Ss also showed clinically significant improvement on indices of anxiety, agoraphobia, depression and fear of fear. Recovery, as estimated conservatively by the attainment of normal levels of functioning on each of the major clinical dimensions of the disorder (i.e. panic, anxiety and avoidance), was achieved in 64% of the treated Ss and 9% of the controls. At the 6 month follow-up, 63% of the treated patients met criteria for recovery. These findings mirror those from recently-completed trials of individually-administered cognitive-behavioral treatment, and suggest that CBT is a viable alternative to pharmacotherapy in the treatment of panic disorder.

Keller MB, Lavori PW, Goldenberg IM, Baker LA, Pollack MH, Sachs GS, Rosenbaum JF, Deltito JA, Leon A, Shear K, et al: INFLUENCE OF DEPRESSION ON THE TREATMENT OF PANIC DISORDER WITH IMIPRAMINE, ALPRAZOLAM AND PLACEBO. Journal of Affective Disorders 1993; 28(1):27-38. Summary: This paper presents findings from a multisite study of 126 subjects meeting DSM-III-R criteria for Panic Disorder who also met criteria for a concurrent Major Depressive Episode, Dysthymia, or Depressive Disorder NOS. The study's primary aim was to discern the influence of varying degrees of depression on the comparative efficacy of alprazolam, imipramine and placebo on anxiety outcomes. A placebo-controlled, double-blind, parallel random assignment design was utilized over a total of 16 weeks. There was no medication effect on panic outcomes. At endpoint, percent of anticipatory anxiety (i.e., time spent worrying about having an anxiety attack) was significantly lower in the patients taking active medications vs. placebo. Phobic measures were significantly improved by alprazolam, vs. both imipramine and placebo early in the study; however, by week 8 both active medications were equally superior to placebo in the reduction of phobic symptoms. In addition, both active medications were significantly more effective than placebo in reducing depression. The same efficacy pattern (i.e., active medications superior to placebo) was observed on measures of general functioning. Importantly, there were no significant interactions observed between medication and presence of major depression on the depression measures, indicating that both alprazolam and imipramine were equally efficacious in treating the depression in patients with panic disorder and major depression. Since the patients enrolled in this study suffered from major depressive disorder in the mild to moderate severity range, these results may not be transferrable to patients with panic disorder and severe major depression.

Ost LG, Westling BE, Hellstrom K: APPLIED RELAXATION, EXPOSURE IN VIVO AND COGNITIVE METHODS IN THE TREATMENT OF PANIC DISORDER WITH AGORAPHOBIA. Behaviour Research & Therapy 1993; 31(4):383-94. Summary: Forty-five psychiatric outpatients with DSM-III-R diagnosis of panic disorder with agoraphobia were assessed with a battery of self-report, behavioral and cognitive measures before and after therapy, and at a 1 yr follow-up. They were randomly assigned to either Applied Relaxation (AR; n = 15), Exposure in vivo (E; n = 15) or Cognitive Treatment (CT; n = 15) and received 12 individual therapy sessions, once weekly. All patients also had self-exposure instructions. The three treatments yielded significant improvements that were maintained at follow-up. One criterion of clinically significant improvement was fulfilled by 87% of the AR-, 80% of the E- and 60% of the CT-patients at the end of treatment, and 85, 79 and 67%, respectively, at follow-up. Between-group differences were observed on two measures only, both showing better results for AR than for CT. The conclusion that can be drawn is that the three treatments, focussed on different anxiety components, are about equally effective, and the results are maintained 1 yr after the end of treatment.

Shelton RC, Harvey DS, Stewart PM, Loosen PT: ALPRAZOLAM IN PANIC DISORDER: A RETROSPECTIVE ANALYSIS. Progress in Neuro-Psychopharmacology & Biological Psychiatry 1993; 17(3):423-34. Summary: 1. The charts of 78 panic disorder outpatients treated with alprazolam (mean dose 4.30 mg/day, mean duration 31.9 months) were reviewed for demographics, past history (including substance abuse and major depression), and evidence of alprazolam abuse. In addition, the patients were evaluated by Clinical Global Index for improvement at last contact. 2. Moderate to significant recovery was found in 77% of patients. Major depression was seen in 41%. Depressed patients were more likely to have coexisting agoraphobia and a past history of alcohol abuse than non-depressives. 3. There was no DSM-III-R anxiolytic abuse, but 12% showed unauthorized use of the alprazolam. These subjects were three times more likely to have a history of drug abuse than non-misusers. 4. These results indicate that alprazolam is effective in the long-term treatment of panic disorder, but that prolonged management may be required. Further, the data raise concerns about use in panic patients with substance abuse histories.

Westenberg HG, Den Boer JA: NEW FINDINGS IN THE TREATMENT OF PANIC DISORDER. [REVIEW]. Pharmacopsychiatry 1993; 26 Suppl 1:30-3. Summary: Research conducted during the past decade has resulted in a range of options for treating panic disorder. Favorable responses to tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and high-potency benzodiazepines have been reported. When costs and benefits are taken into account, the selective serotonin uptake inhibitors currently seem to be the treatment of choice. Studies with serotonin agonists and antagonists are as of yet disappointing. The introduction of cholecystokinin antagonists has opened up intriguing new areas of research. This paper reviews those findings and developments. [References: 30]

Pols H, Zandergen J, de Loof C, Fernandez I, Griez E: CLINICAL EFFECTS OF FLUVOXAMINE ON PANIC SYMPTOMATOLOGY. Acta Psychiatrica Belgica 1993; 93(3):169-77. Summary: In a double-blind randomized placebo-controlled cross-over design trial, the effects of a 4 week fluvoxamine versus a 4 week placebo treatment regimen on panic symptomatology were studied. Fluvoxamine seems to have specific antipanic properties, as a significant decrease in the number of panic attacks was observed. Other components of the disorder, like free-floating anxiety and avoidance behavior were not influenced during the short 4 week treatment period.

Realini JP, Katerndahl DA: FACTORS AFFECTING THE THRESHOLD FOR SEEKING CARE: THE PANIC ATTACK CARE-SEEKING THRESHOLD (PACT) STUDY. Journal of the American Board of Family Practice 1993; 6(3):215-23. Summary: BACKGROUND: This study was conducted to explore the phenomenon of seeking medical care for panic attacks and to identify factors associated with seeking care. METHODS: A community sample of adults was screened using the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition. Subjects who had experienced panic attacks participated in a structured interview concerning their health care access and utilization, panic characteristics, comorbidity, illness attitudes and perceptions, and family characteristics. RESULTS: Forty-one percent of the subjects had not sought medical care for their panic attacks. Having to get someone to drive (RR [relative risk] = 1.8; P = 0.0026), inability to work because of panic (RR = 1.6; P = 0.0054), and a high treatment experience score on the Illness Attitude Scales (RR = 1.5; P = 0.034) independently predicted seeking care. Seeking support was also significantly associated with seeking care (t = -4.05; P = 0.0001). Care seekers tended to have more severe symptoms, stronger symptom perceptions, and more bodily preoccupation and to abuse drugs more frequently. Seeking care was not influenced by sex, race or ethnicity, stress, psychiatric comorbidity, family function, social support, or access to health care. CONCLUSIONS: Nearly one-half of persons with panic attacks do not seek care for their attacks. Those who seek care differ from those who do not in ways that have important implications for the understanding of this illness.

Bradwejn J: BENZODIAZEPINES FOR THE TREATMENT OF PANIC DISORDER AND GENERALIZED ANXIETY DISORDER: CLINICAL ISSUES AND FUTURE DIRECTIONS. [REVIEW]. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 1993; 38 Suppl 4:S109-13. Summary: For several decades, benzodiazepines have shown their effectiveness in the treatment of various manifestations of anxiety. Recent diagnostic systems have divided these manifestations of anxiety into categories and separate pathologies, such as generalized anxiety disorder and panic disorder. Researchers have studied the use and efficacy of benzodiazepine receptor agonists in patients with these distinct diagnostic categories. Clinical studies on generalized anxiety disorder and panic disorder usually suggest equivalent efficacy among benzodiazepine agonists, although truly comparative studies with two or three drugs are scarce. Further work is needed on the differences in side-effects, pharmacokinetics and discontinuation reactions for benzodiazepines. Concerns about benzodiazepine dependency--justified or not--and about discontinuation reactions have motivated the search for newer benzodiazepines without these problems. This paper reviews the efficacy and comparative studies of benzodiazepines that are currently available and discusses recent developments in research on newer benzodiazepines molecules. [References: 12]

Louie AK, Lewis TB, Lannon RA: USE OF LOW-DOSE FLUOXETINE IN MAJOR DEPRESSION AND PANIC DISORDER. Journal of Clinical Psychiatry 1993; 54(11):435-8. Summary: BACKGROUND: Recent reports suggest that fluoxetine in doses less than the standard 20 mg/day may be effective in the treatment of depression and that some patients, particularly those with panic disorder, may be intolerant of the 20 mg/day dose. We examined the utility of starting fluoxetine at a low daily dose (5 mg) and increasing to the standard daily dose (20 mg) in depressed outpatients with and without concurrent panic disorder. METHOD: One hundred thirty-three consecutive outpatients meeting DSM-III-R criteria for major depression were studied. Patients were started on fluoxetine 5 mg/day and were gradually increased to 20 mg/day over a 1-week period. Patients who were unable to reach the 20 mg/day dose were instructed to take the highest tolerable dose for the duration of the study. After a month of fluoxetine treatment, patients were evaluated for compliance with treatment and improvement on the Clinical Global Improvement scale. RESULTS: Twenty-eight percent of the patients were unable to increase the dose to the full 20 mg. Of these patients, half could not tolerate doses lower than 20 mg and discontinued the drug, while the other half did well clinically on the lower doses. Patients who discontinued fluoxetine tended to have panic disorder in addition to depression. CONCLUSION: We conclude that starting fluoxetine at doses lower than 20 mg is a useful strategy because of the substantial fraction of patients who cannot tolerate a 20-mg dose but appear to benefit from lower doses. This dosing strategy may be of particular benefit for patients with panic disorder.

Ballenger JC, Pecknold J, Rickels K, Sellers EM: MEDICATION DISCONTINUATION IN PANIC DISORDER. [REVIEW]. Journal of Clinical Psychiatry 1993; 54 Suppl:15-21; discussion 22-4. Summary: 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. [References: 43]

Fux M, Taub M, Zohar J: EMERGENCE OF DEPRESSIVE SYMPTOMS DURING TREATMENT FOR PANIC DISORDER WITH SPECIFIC 5-HYDROXYTRYPTOPHAN REUPTAKE INHIBITORS. Acta Psychiatrica Scandinavica 1993; 88(4):235-7. Summary: Selective serotonin reuptake inhibitors (SSRI) have been established as effective drugs in the treatment of depressive and anxiety disorders. However, there are also reports that they can induce depressive symptoms and suicidal thoughts in patients. Eighty of 230 patients who met the DSM-III-R criteria for panic disorder received, during the course of treatment, fluvoxamine (a selective serotonin reuptake inhibitor) at a dose level between 50-200 mg/day. The patients were clinically evaluated for a history of affective disorder and for the presence of affective symptoms before the treatment and for emergence of depressive symptoms during the treatment. Seven of the 80 patients (9%) developed symptoms of depression despite a good antianxiety response. Five of the 7 patients received fluvoxamine as second choice after tricyclic antidepressants (TCA). These patients had no history of affective disorder, and no symptoms of depression were present before the treatment with fluvoxamine. The depressive symptoms abated after the fluvoxamine was discontinued and TCA or clonazepam was prescribed. The depressive symptoms reappeared when fluoxetine was administered. None of these 7 patients developed depressive symptoms while treated with TCA or clonazepam. Among the 150 patients treated with TCA and benzodiazepines, not a single case of depression was seen in patients without a previous history of depression. These results suggest a vulnerability among some of panic disorder patients to noradrenergic-serotonergic imbalance caused by SSRI, which has to be taken into clinical consideration.

Hoehn-Saric R, McLeod DR, Hipsley PA: EFFECT OF FLUVOXAMINE ON PANIC DISORDER. Journal of Clinical Psychopharmacology 1993; 13(5):321-6. Summary: Several reports suggest that selective serotonin reuptake blockers are helpful in the treatment of panic disorder. The aim of the study was to compare fluvoxamine with placebo in 50 panic disorder patients by using an 8-week, double-blind, parallel-groups design. Weekly assessment included a panic attack diary (frequency and severity), the Montgomery-Asberg Depression Scale, the Clinical Anxiety Scale, and the Sheehan Disability Scale. Although both groups improved on all measures, the fluvoxamine group experienced significantly less frequent major panic attacks from the third week on and significantly lower ratings on anxiety, depression, and disability from the sixth week on. Mean ratings of the severity of major and the severity and frequency of minor attacks were not affected differently by fluvoxamine and placebo. At the end of the study, significantly more patients on fluvoxamine were free of major and minor panic attacks. The results indicate that: (1) the administration of fluvoxamine, as compared with placebo, led to a significant reduction in the number of panic attacks. (2) The severity of panic attacks was not affected by fluvoxamine. (3) The effect of fluvoxamine on anxiety, depressive mood, and disability differed from placebo only after 6 weeks of treatment, after which the placebo group showed either no further improvement or a reversal of symptoms. (4) Participation in a drug study, even without additional psychotherapy, led to significant improvement in all patients.

Jonas JM, Cohon MS: A COMPARISON OF THE SAFETY AND EFFICACY OF ALPRAZOLAM VERSUS OTHER AGENTS IN THE TREATMENT OF ANXIETY, PANIC, AND DEPRESSION: A REVIEW OF THE LITERATURE. [REVIEW]. Journal of Clinical Psychiatry 1993; 54 Suppl:25-45; discussion 46-8. Summary: A review of the worldwide published literature was conducted to assess the efficacy and safety of alprazolam for the treatment of anxiety disorders, panic disorder, and depression in comparison with those of other active drugs (including other benzodiazepines and antidepressant medications). In all, a total of 8878 patients participated in the 84 active-drug-controlled studies that were reviewed: 3574 were treated with alprazolam, 3666 were treated with another active drug, and 1638 were treated with placebo. Two general findings emerged: (1) Alprazolam demonstrates efficacy for the treatment of anxiety disorders, panic disorder, and depression in the large majority of studies; for these illnesses, it appeared equal in efficacy to the active agents with which it was compared. (2) Medical events, such as depression, suicidality, hostility/aggression, mania/psychosis, abuse, withdrawal reactions, and seizures, were reported infrequently or not at all for alprazolam and the comparator drugs; there were no marked differences between drug classes in the frequencies of these events. [References: 104]

Leon AC, Shear MK, Klerman GL, Portera L, Rosenbaum JF, Goldenberg I: A COMPARISON OF SYMPTOM DETERMINANTS OF PATIENT AND CLINICIAN GLOBAL RATINGS IN PATIENTS WITH PANIC DISORDER AND DEPRESSION. Journal of Clinical Psychopharmacology 1993; 13(5):327-31. Summary: The Clinical Global Impression (CGI) is a standard assessment tool that generally shows good sensitivity to change in psychopharmacology trials. However, systematic assessment has not been conducted to determine how rating decisions are made. In this article, we examine the relationship between syndromal symptomatology and the CGI severity and improvement ratings in a study of 116 patients who met DSM-III-R criteria for both Panic Disorder and Depression. Anticipatory anxiety and depression ratings were significantly associated with each CGI item. Frequency of panic attacks was consistently related to the clinician's rating of severity but was only sporadically related to the clinician and patient improvement ratings. These findings are fairly consistent during the course of treatment. Our empirical examination of symptom determinants of the CGI demonstrates that it appears to be used systematically, yet global ratings are not merely a composite of symptomatology. Its widespread application in clinical trials is well justified.

Otto MW, Pollack MH, Sachs GS, Reiter SR, Meltzer-Brody S, Rosenbaum JF: DISCONTINUATION OF BENZODIAZEPINE TREATMENT: EFFICACY OF COGNITIVE-BEHAVIORAL THERAPY FOR PATIENTS WITH PANIC DISORDER. American Journal of Psychiatry 1993; 150(10):1485-90. Summary: OBJECTIVE: The primary disadvantage of high-potency benzodiazepine treatment for panic disorder is the difficulty of discontinuing the treatment. During treatment discontinuation, new symptoms may emerge and anxiety may return, preventing many patients from successfully discontinuing their treatment. In this controlled, randomized trial the authors investigated the efficacy of a cognitive-behavioral program for patients with panic disorder who were attempting to discontinue treatment with high-potency benzodiazepines. METHOD: Outpatients treated for panic disorder with alprazolam or clonazepam for a minimum of 6 months and expressing a desire to stop taking the medication (N = 33) were randomly assigned to one of two taper conditions: a slow taper condition alone or a slow taper condition in conjunction with 10 weeks of group cognitive-behavioral therapy. RESULTS: The rate of successful discontinuation of benzodiazepine treatment was significantly higher for the patients receiving the cognitive-behavioral program (13 of 17; 76%) than for the patients receiving the slow taper program alone (four of 16; 25%). There was no difference in the likelihood of discontinuation success between the patients treated with alprazolam and those who received clonazepam. At the 3-month follow-up evaluation, 77% of the patients in the cognitive-behavioral program who successfully discontinued benzodiazepine treatment remained benzodiazepine free. CONCLUSIONS: These findings support the efficacy of cognitive-behavioral interventions in aiding benzodiazepine discontinuation for patients with panic disorder.

Wade SL, Monroe SM, Michelson LK: CHRONIC LIFE STRESS AND TREATMENT OUTCOME IN AGORAPHOBIA WITH PANIC ATTACKS. American Journal of Psychiatry 1993; 150(10):1491-5. Summary: OBJECTIVE: Factors associated with response to treatment for agoraphobia are as of yet poorly understood. The authors investigated the relationship between chronic forms of life stress and clinical improvement and recovery in subjects with agoraphobia. METHOD: Subjects meeting the DSM-III criteria for agoraphobia with panic attacks (N = 73) completed measures of life stress, agoraphobic symptoms, and depressive symptoms at the initiation and completion of the 12-week treatment protocol. Chronic stressors were assessed during intensive structured interviews 3-5 years after the completion of treatment and were rated by using a reliable, and previously validated, contextual rating system. The contextual life stress interview was completed by 54 subjects. The relationship of chronic forms of stress to treatment response was assessed by comparing symptomatic improvement in the subjects who had and had not experienced chronic stressors. RESULTS: Of the 54 subjects, 23 (43%) reported chronic stressors of marked or moderate severity. Subjects experiencing chronic stressors evidenced less improvement after treatment on both self-report and objective indexes of agoraphobic symptoms. Additionally, more subjects identified as nonrecovered experienced chronic stressors than did recovered subjects. CONCLUSIONS: Chronic stressors appear to predict a relatively unfavorable treatment outcome, as defined by higher levels of symptoms after treatment, less improvement, and less likelihood of recovery. These results have important implications for enhancing psychotherapeutic outcomes.

Greenblatt DJ, Harmatz JS, Shader RI: PLASMA ALPRAZOLAM CONCENTRATIONS. RELATION TO EFFICACY AND SIDE EFFECTS IN THE TREATMENT OF PANIC DISORDER. Archives of General Psychiatry 1993; 50(9):715-22. Summary: A series of 237 patients with DSM-III-diagnosed panic disorder, or agoraphobia with panic attacks, received alprazolam as part of the placebo-controlled Cross-National Collaborative Panic Study. After a 1-week drug-free period, alprazolam dosage was titrated upward with the objective of reaching 6.0 mg/d in all patients. At week 3 of treatment, alprazolam plasma levels were significantly correlated with daily dosage (regression slope: 11.7 ng/mL per milligram per day) but with considerable individual variation. Among patients with spontaneous panic attacks, 70% of those with plasma alprazolam levels greater than 20 ng/mL achieved complete remission vs 31% of those with levels less than 20 ng/mL. Situational panic attack remission increased in frequency with increasing plasma levels, but the relationship was not significant. Patient- and physician-rated global improvement and Hamilton Anxiety and Depression Scale score reductions were maximal at 20 to 39 ng/mL, with no further benefit at higher levels. Central nervous system-depressant side effects increased in frequency with higher plasma levels. Between weeks 3 and 8 of treatment, physicians were permitted to adjust dosage (maximum: 10 mg/d) to optimize response. At week 8, the dose-concentration relationship was essentially identical (regression slope: 10.8 ng/mL per milligram per day), but plasma levels were no longer related to efficacy or side effects. Thus, monitoring of plasma alprazolam concentrations may have a clinically useful role during short-term treatment of panic disorder.

Lepola UM, Rimon RH, Riekkinen PJ: THREE-YEAR FOLLOW-UP OF PATIENTS WITH PANIC DISORDER AFTER SHORT-TERM TREATMENT WITH ALPRAZOLAM AND IMIPRAMINE. International Clinical Psychopharmacology 1993; 8(2):115-8. Summary: Fifty-five patients with moderate to sever panic disorder were treated for 9 weeks with alprazolam or imipramine and were then, except for one patient who had committed suicide, re-examined after on average 3 years of treatment. At follow-up most patients (74%) did not suffer from panic attacks at all. In the beginning of the study 87% exhibited phobic avoidance behaviour but after 3 years 68% no longer revealed phobic behaviour. At follow-up 28% of the patients were no longer having psychotropic drug treatment and 20% were completely free of overt psychopathology. No tolerance phenomena were associated with the long-term medication applied in the study.

Mavissakalian MR, Perel JM: DOSE-RESPONSE CHARACTERIZATION OF THE ANTIPANIC EFFECTS OF IMIPRAMINE. Psychopharmacology Bulletin 1994; 30(2):171-4. Summary: This article presents panic diary results of a dose-response study with imipramine hydrochloride in panic disorder with agoraphobia patients. Analysis of variance revealed significant time effects on panic frequency and severity measures, but group x time interaction effects were present for the severity measures only. Results also provided evidence for a positive dose-response relationship with 20 percent of patients in the placebo group, 31 percent in the low-dose group (0.5 mg/kg/day), 54 percent in the medium-dose group (1.5 mg/kg/day), and 70 percent in the high-dose (3 mg/kg/day) group being free of recurrent or severe panic attacks at posttreatment. Further stratified and logistic regression analyses revealed a direct linear relationship between total plasma tricyclic concentration and response. These findings affirm the dose-dependent nature and the specificity of imipramine's antipanic effects.

Beauclair L, Fontaine R, Annable L, Holobow N, Chouinard G: CLONAZEPAM IN THE TREATMENT OF PANIC DISORDER: A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL INVESTIGATING THE CORRELATION BETWEEN CLONAZEPAM CONCENTRATIONS IN PLASMA AND CLINICAL RESPONSE. Journal of Clinical Psychopharmacology 1994; 14(2):111-8. Summary: Thirty-two outpatients with a DSM-III diagnosis of panic disorder or agoraphobia with panic attacks were randomly assigned to 4 weeks of treatment with clonazepam or placebo, after a 1-week placebo washout period. Twenty-nine patients entered the double-blind phase of the study and were eligible for intent-to-treat analysis. Clonazepam-treated patients experienced significantly fewer panic attacks, and these were of lesser intensity and short duration than those in placebo-treated patients (p < 0.001). Clonazepam was also superior to placebo with respect to symptoms of anxiety and depression (p < 0.001). The mean dose of clonazepam at week 4 was 2.2 mg (standard deviation, 0.7 mg). There was significant (p < 0.05) correlation between drug concentration in plasma and decrease in the global measure of the severity of panic disorder (r = 0.68); similar trends were seen for the decreases in frequency (r = 0.60) and severity (r = 0.55) of panic attacks, but not between concentration in plasma and decline in generalized anxiety. The most common adverse event was drowsiness, which occurred in 9 of 13 clonazepam-treated patients.

Black DW, Wesner RB, Gabel J, Bowers W, Monahan P: PREDICTORS OF SHORT-TERM TREATMENT RESPONSE IN 66 PATIENTS WITH PANIC DISORDER. Journal of Affective Disorders 1994; 30(4):233-41. Summary: Short-term treatment response in panic disorder was studies in 66 subjects who had completed 3 weeks of treatment with fluvoxamine (n = 23), cognitive therapy (n = 20), or placebo (n = 23). Clinical and self-rated assessments were gathered at baseline, during, and after treatment. Using multiple logistic regression, treatment with fluvoxamine, a low panic attack severity score, and absence of a comorbid personality disorder were identified as significant predictors of recovery. Personality disorder was an important negative predictor to outcome with cognitive therapy. The results support the efficacy of fluvoxamine, and show that patients with low symptom severity and a normal personality respond well to treatment.

de Groot CM, Mavissakalian MR: BLOOD PRESSURE AND HEART RATE RESPONSE OF PANIC DISORDER PATIENTS RECEIVING IMIPRAMINE IN A DOSE-RESPONSE TREATMENT PARADIGM. Journal of Clinical Psychopharmacology 1994; 14(2):107-10. Summary: This article reports the effects of imipramine on heart rate and blood pressure in panic disorder patients who participated in an 8-week double-blind dosage response treatment protocol. At the end of a placebo baseline, patients were randomly assigned to placebo or one of three weight-adjusted imipramine dosages: low (0.5 mg/kg per day), medium (1.5 mg/kg per day), or high (3.0 mg/kg per day). It was demonstrated that imipramine had no significant effect on sitting or standing diastolic or systolic blood pressure. Although there was a trend toward a systolic blood pressure drop with positional change, it did not reach statistical significance. There were no significant changes in diastolic blood pressure with postural change. Imipramine did increase sitting and standing heart rate without revealing a clear dosage correlation. In contrast to the pretreated state, the reflex heart rate response to postural change was significantly increased in the posttreatment state, also in a dosage-independent manner. Within the high-dose imipramine group, the baseline sitting to standing heart rate increase was significantly higher in those who dropped out because of drug side effects compared with those who remained. Evidence from this study suggests that imipramine has a dosage-independent effect on resting and reflex heart rate. Future studies should consider postural heart rate reactivity as a potential measure of intolerance to the side effects of high doses of imipramine.

Feet PO, Gotestam KG: INCREASED ANTIPANIC EFFICACY IN COMBINED TREATMENT WITH CLOMIPRAMINE AND DIXYRAZINE. Acta Psychiatrica Scandinavica 1994; 89(4):230-4. Summary: A double-blind 12 week trial was undertaken to compare the effects of clomipramine + dixyrazine with clomipramine + placebo in the treatment of panic disorder with or without agoraphobia. Of 45 patients included (21 dixyrazine, 24 placebo), 16 dropped out (6 dixyrazine, 10 placebo). The number of panic attacks and the scores on the panic disorder subscale of the Hamilton Anxiety Rating Scale were significantly reduced in response to both treatment regimens, but the reduction was significantly greater in the dixyrazine group. The patients' daily functioning was significantly more improved with the dixyrazine combination. The serum concentration of desmethylclomipramine monotherapy was significantly higher and the side effects significantly lower in the combined treatment with dixyrazine than with clomipramine monotherapy. Clomipramine combined with dixyrazine seems superior to clomipramine in the treatment of panic disorder.

Mant A: PANIC DISORDERS AND THE LISTING OF ALPRAZOLAM ON AUTHORITY ON THE PBS. BEWARE OF OVERDIAGNOSIS. Australian Family Physician 1994; 23(4):658-60. Summary: The RACGP guidelines on benzodiazepine use (Table 2) were endorsed in March 1993, and drew on the experience of hundreds of general practitioners. Following them should ensure that there is a rational response to the new listing.

Pollack MH, Otto MW, Sachs GS, Leon A, Shear MK, Deltito JA, Keller MB, Rosenbaum JF: ANXIETY PSYCHOPATHOLOGY PREDICTIVE OF OUTCOME IN PATIENTS WITH PANIC DISORDER AND DEPRESSION TREATED WITH IMIPRAMINE, ALPRAZOLAM AND PLACEBO. Journal of Affective Disorders 1994; 30(4):273-81. Summary: This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week, placebo-controlled trial of alprazolam and imipramine (n = 126). Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment. Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4. At endpoint, the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance. This relationship was not evident for completers, suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced.

Woodman CL, Noyes R Jr: PANIC DISORDER: TREATMENT WITH VALPROATE. Journal of Clinical Psychiatry 1994; 55(4):134-6. Summary: BACKGROUND: To determine the efficacy of divalproex sodium in the treatment of panic disorder, divalproex sodium was administered in a 6-week open clinical trial to 12 patients who had a primary DSM-III-R diagnosis of panic disorder. METHOD: Treatment was begun at 500 mg of divalproex sodium daily and was increased according to clinical response and side effects. Clinicians completed a Clinical Global Impressions Scale weekly and a Hamilton Rating Scale for Anxiety every other week. Patients completed a panic-attack diary and a Brief Symptom Inventory weekly. RESULTS: All 12 patients completed the study, and all were moderately to markedly improved. Measures of panic attacks and anxiety improved more quickly and robustly than measures of phobic avoidance. Eleven of the 12 patients elected to remain in treatment and at 6-month follow-up had sustained improvement. CONCLUSION: These findings suggest that valproic acid may be effective for the treatment of panic disorder. Double-blind studies will be required to further verify these findings.

Hassan R, Pollard CA: LATE-LIFE-ONSET PANIC DISORDER: CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF A PATIENT SAMPLE. Journal of Geriatric Psychiatry & Neurology 1994; 7(2):84-8. Summary: Although panic disorder is generally believed to begin in young adulthood, 13 cases of panic disorder with an initial onset after age 60 years have recently been seen at our clinics. Other than the time of life in which the first panic attack occurred, clinical and demographic profiles of these 13 patients were similar to those that have been reported for panic disorder patients whose panic began earlier in life. These findings indicate that panic disorder can affect older adults with no previous history of panic attacks, but further research is needed to determine the clinical and theoretical significance of late-life-onset panic disorder.

Beck JG, Stanley MA, Baldwin LE, Deagle EA 3rd, Averill PM: COMPARISON OF COGNITIVE THERAPY AND RELAXATION TRAINING FOR PANIC DISORDER. Journal of Consulting & Clinical Psychology 1994; 62(4):818-26. Summary: Current approaches to the treatment of panic disorder (PD) include a treatment package consisting of relaxation training (RT), cognitive therapy (CT), and exposure-based components. In an examination of the separate effects of RT and CT without formally taught exposure of any form, 64 PD patients were assigned randomly to one of these treatment protocols or to a minimal-contact control (MCC) condition. Both RT and CT were superior to the MCC condition on a variety of measures pertaining to panic, global psychological functioning, agoraphobic fear, and other associated fears. A significantly greater percentage of patients were classified as treatment responders (based on a composite index) after CT (82%) and RT (68%), compared with the control group (36%). On measures of agoraphobic fear, CT patients fared slightly better than RT patients. Some support was demonstrated for specific cognitive changes after CT, although treatment specificity was not strongly supported overall. These results are discussed in light of current theories of PD and the presumed importance of exposure in its treatment.

Davidson JR, Beitman B, Greist JH, Maddock RJ, Lewis CP, Sheridan AQ, Carter C, Krishnan KR, Liebowitz MR, Haack DG: ADINAZOLAM SUSTAINED-RELEASE TREATMENT OF PANIC DISORDER: A DOUBLE-BLIND STUDY. Journal of Clinical Psychopharmacology 1994; 14(4):255-63. Summary: Two hundred six outpatients with panic disorder and agoraphobia were randomly assigned to receive 4 weeks of treatment with placebo or sustained-release adinazolam under double-blind conditions. Eighty-eight percent of patients receiving drug and 85% of patients receiving placebo remained in the study at week 4. This report describes the "intent-to-treat" analysis of 202 patients who made at least one follow-up visit after randomization at baseline. On the basis of the Clinical Global Impressions-Improvement Scale, 69.7% of the adinazolam-treated patients were much or very much improved compared with 39.6% of the placebo-treated patients at week 4 or end-point (p = 0.0001). At week 4, panic attacks were completely blocked in 57.1% of adinazolam-treated patients and in 39.2% of the placebo-treated patients (p = 0.009). Adinazolam sustained-release treatment was statistically more effective than placebo treatment on measures of global improvement, number of panic attacks, SCL-90 phobia severity, main phobia severity, and anticipatory and general anxiety. No drug-placebo differences were found for overall self-rated phobia severity, unexpected or situational panic attacks, or for work, family, or social disability.

Labbate LA, Pollack MH, Otto MW, Tesar GM, Rosenbaum JF: THE RELATIONSHIP OF ALPRAZOLAM AND CLONAZEPAM DOSE TO STEADY-STATE CONCENTRATION IN PLASMA. Journal of Clinical Psychopharmacology 1994; 14(4):274-6. Summary: This report addresses the correlation between dose and concentration of both alprazolam and clonazepam in plasma. Patients were 43 participants in a double-blind, placebo-controlled study of alprazolam and clonazepam for the treatment of panic disorder. The concentration of clonazepam in plasma was linearly related with dose, measured as milligrams per day (R = 0.724; F = 24.2; p = 0.0001) or milligrams per kilogram per day (R = 0.863; F = 58.3; p = 0.0001). The correlation between drug concentration and daily dose of alprazolam was also significant (R = 0.60; F = 9.5; p = 0.007), although the correlation between dose measured as milligrams per kilogram per day and drug level was not significant (R = 0.361; F = 2.4; p = 0.14). This replicates previous findings that, for each additional milligram per day dose of alprazolam, there is a corresponding increase of approximately 10 ng/ml in the plasma and presents preliminary data that, for each added 1 mg/day dose of clonazepam, there is approximately an increase of 12 ng/ml in the plasma. For both drugs, however, there may be considerable variation in level in plasma for a given dose. Weight-adjusted clonazepam concentration may be more predictable than weight-adjusted alprazolam concentration.

Lidren DM, Watkins PL, Gould RA, Clum GA, Asterino M, Tulloch HL: A COMPARISON OF BIBLIOTHERAPY AND GROUP THERAPY IN THE TREATMENT OF PANIC DISORDER. Journal of Consulting & Clinical Psychology 1994; 62(4):865-9. Summary: This study investigated 2 methods of disseminating a cognitive-behavioral intervention for panic disorder (PD). Thirty-six Ss who met diagnostic criteria for PD according to the Anxiety Disorders Interview Schedule-Revised were randomly assigned to 1 of 3 conditions: bibliotherapy (BT), group therapy (GT), or a waiting-list control (WL) condition. Interventions lasted 8 weeks and were followed by a posttest, along with 3- and 6-month follow-up assessments. Results indicated that both the BT and GT treatments were more effective than the WL condition in reducing frequency of panic attacks, severity of physical panic symptoms, catastrophic cognitions, agoraphobic avoidance, and depression and that the BT and GT treatments were more effective in increasing self-efficacy. Both interventions maintained their effects throughout the follow-up periods and produced clinically significant levels of change among the majority of treated Ss.

Sanderson WC, Wetzler S, Asnis GM: ALPRAZOLAM BLOCKADE OF CO2-PROVOKED PANIC IN PATIENTS WITH PANIC DISORDER. American Journal of Psychiatry 1994; 151(8):1220-2. Summary: The primary aim of this study was to determine if pretreatment with a single dose of alprazolam reduces anxiety and panic provoked by the inhalation of 35% carbon dioxide (CO2) in patients with panic disorder. Ten panic disorder patients participated in a CO2 challenge test after pretreatment with a single dose of alprazolam (1 mg p.o.) or placebo in a randomized, double-blind, within-subjects design. Seventy percent of the subjects had a panic attack with placebo, compared to only 10% with alprazolam. Alprazolam reduced the number and severity of panic symptoms and baseline anxiety significantly more than placebo. This study demonstrates the efficacy of the acute administration of alprazolam to block panic attacks and supports the usefulness of the CO2 challenge as an analogue method to study panic disorder.

Klein E, Colin V, Stolk J, Lenox RH: ALPRAZOLAM WITHDRAWAL IN PATIENTS WITH PANIC DISORDER AND GENERALIZED ANXIETY DISORDER: VULNERABILITY AND EFFECT OF CARBAMAZEPINE. American Journal of Psychiatry 1994; 151(12):1760-6. Summary: OBJECTIVE: This study was designed to examine the possibility that patients with panic disorder are especially vulnerable to alprazolam withdrawal, as well as to evaluate the efficacy of carbamazepine as adjunctive treatment during alprazolam discontinuation. METHOD: After a 2-month open trial of alprazolam, 36 patients with panic disorder and 35 with generalized anxiety disorder entered a controlled discontinuation phase. Carbamazepine or placebo was added in a randomized, double-blind fashion, followed after 1 week by single-blind dose reduction of alprazolam, approximately 25% every third day. RESULTS: Fifty-two percent of the patients were able to discontinue alprazolam, but only 37% completed the study, maintaining alprazolam-free status for 4 weeks. Survival analysis revealed that among the patients receiving placebo as adjunctive therapy, panic disorder patients had a significantly greater dropout rate than patients with generalized anxiety disorder. While carbamazepine exerted no beneficial effect for patients with generalized anxiety disorder, it appeared to improve outcome in the panic disorder group. CONCLUSIONS: Results of this study indicate that panic disorder patients are more vulnerable to alprazolam withdrawal than patients with generalized anxiety disorder, and this may reflect a general diathesis of panic disorder patients to encounter more difficulty during drug withdrawal. Carbamazepine may selectively assist with alprazolam withdrawal in panic disorder patients. However, these data do not support its widespread use during benzodiazepine discontinuation, especially given its potential toxicity. In light of a proposed greater vulnerability of panic disorder patients to withdrawal, future studies need to account for differential effects related to specific diagnosis.

Basoglu M, Marks IM, Swinson RP, Noshirvani H, O'Sullivan G, Kuch K: PRE-TREATMENT PREDICTORS OF TREATMENT OUTCOME IN PANIC DISORDER AND AGORAPHOBIA TREATED WITH ALPRAZOLAM AND EXPOSURE. Journal of Affective Disorders 1994; 30(2):123-32. Summary: Pre-treatment predictors of treatment outcome were examined in a group of 144 patients with panic disorder and agoraphobia randomly allocated to alprazolam+exposure (AE), placebo+exposure (PE), alprazolam+relaxation (AR), and placebo+relaxation (PR). First-time psychotropic medication use, severity of agoraphobic disability, and longer duration of illness predicted less global improvement at post-treatment. Pre-treatment severity of agoraphobia predicted less improvement both in the short- and the long-term. Predictors of poorer outcome at 6-month follow-up were older age, past history of depression, severity of phobia targets, and longer duration of illness. Sex, source of referral, pre-treatment depression-anxiety-panic, and expectancy from treatment did not relate to outcome.

Deary IJ, Wilson JA: PROBLEMS IN TREATING GLOBUS PHARYNGIS. Clinical Otolaryngology 1994; 19(1):55-60. Summary: Twenty-four out-patients with globus were assessed for current and past psychiatric illness with the 'Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety' version. Patients then received amitriptyline or placebo in a double-blind fashion. Treatment outcome was assessed using an inventory of throat symptoms, Beck Depression Inventory, Spielberger State Anxiety Scale, Crown-Crisp Experimental Index and General Health Questionnaire. Nine patients met the DMS-III criteria for psychiatric disorder in the past; six had suffered from panic disorder. Two further patients had been troubled by classic panic attacks. Nine of the 12 patients treated with amitriptyline and two of the placebo group discontinued treatment. In conclusion, clinical and psychometric associations were found between pathological anxiety and globus, and it appears that the recommendation that globus be treated 'aggressively' with tricyclic antidepressants is likely to lead to a high proportion of treatment failures.

Fleishaker JC, Greist JH, Jefferson JW, Sheridan AQ: RELATIONSHIP BETWEEN CONCENTRATIONS OF ADINAZOLAM AND ITS PRIMARY METABOLITE IN PLASMA AND THERAPEUTIC/UNTOWARD EFFECTS IN THE TREATMENT OF PANIC DISORDER. Journal of Clinical Psychopharmacology 1994; 14(1):28-35. Summary: Adinazolam mesylate, a triazolobenzodiazepine with antidepressant and anxiolytic activity, has been shown in several studies to treat panic disorder effectively. This report presents the results of analysis of concentrations in plasma of adinazolam and its primary metabolite, N-desmethyladinazolam (NDMAD), determined as a part of a flexible-dose, double-blind study of the efficacy of adinazolam mesylate sustained release tablets in the treatment of panic disorder with agoraphobia. Dosages administered in the study were titrated from 30 mg/day up to a maximum of 120 mg/day. Concentrations in plasma were determined by high-performance liquid chromatography at clinical evaluations at the end of treatment weeks 1, 2, and 4. The concentrations of both compounds were proportional to the administered dose. An inverted U-shaped concentration-response curve was apparent, where response was based on a priori definitions contained in the study protocol. However, this was probably a result of the flexible-dose study design used. By use of the post hoc definitions of response, as measured by the Clinician's Global Improvement Scale and the total panic attack frequency, logistic regression analysis resulted in more adequate predictions of actual response frequencies. Results indicate that NDMAD contributes to the therapeutic effects of adinazolam mesylate sustained release tablets in the treatment of panic disorder. The exact contributions of adinazolam and NDMAD to response in panic disorder could not be determined, because of the correlation between adinazolam and NDMAD concentrations on multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Tiffon L, Coplan JD, Papp LA, Gorman JM: AUGMENTATION STRATEGIES WITH TRICYCLIC OR FLUOXETINE TREATMENT IN SEVEN PARTIALLY RESPONSIVE PANIC DISORDER PATIENTS. Journal of Clinical Psychiatry 1994; 55(2):66-9. Summary: BACKGROUND: Although panic disorder is generally responsive to single antidepressant pharmacotherapy, a substantial percentage of patients fail either to respond adequately or to maintain a therapeutic response. METHOD: The authors report on seven consecutive openly treated patients with panic disorder who showed inadequate antipanic responses to treatment regimens including either a tricyclic (TCA) or fluoxetine. Those patients taking a TCA had fluoxetine added and those patients taking fluoxetine had a TCA added. RESULTS: All seven patients showed an improvement in antipanic response to the combination treatment. CONCLUSION: The current case series is the first, to our knowledge, to suggest that the combination of a TCA and fluoxetine may provide a viable pharmacotherapeutic option for panic disorder patients who have failed to respond to an adequate trial of either a TCA or fluoxetine. Appropriate controlled studies are recommended.

Woodman CL, Noyes R Jr, Ballenger JC, Lydiard RB, Sievers G, Mihalko D: PREDICTORS OF RESPONSE TO ALPRAZOLAM AND PLACEBO IN PATIENTS WITH PANIC DISORDER. Journal of Affective Disorders 1994; 30(1):5-13. Summary: Date from a panic disorder treatment study with 506 patients, comparing alprazolam and placebo in a double-blind manner for 8 weeks, were analyzed to identify demographic and clinical characteristics of the patients that might predict response to treatment. The strongest predictors of response to alprazolam were age over 40, and lower baseline levels of anxiety and phobic symptoms. Predictors of response to placebo were weaker and, in addition to lower levels anxiety and panic attacks, included a lack of previous psychiatric treatment.

O'Sullivan GH, Noshirvani H, Basoglu M, Marks IM, Swinson R, Kuch K, Kirby M: SAFETY AND SIDE-EFFECTS OF ALPRAZOLAM. CONTROLLED STUDY IN AGORAPHOBIA WITH PANIC DISORDER. British Journal of Psychiatry 1994; 165(2):79-86. Summary: BACKGROUND. The widespread use of benzodiazepines has led to increasing recognition of their unwanted effects. The efficacy of alprazolam and placebo in panic disorder with agoraphobia, and the side-effect and adverse effect profiles of both drug groups were measured. METHOD. In London and Toronto 154 patients who met DSM-III criteria for panic disorder with agoraphobia were randomised to alprazolam or placebo. Subjects in each drug group also received either exposure or relaxation. Treatment was from weeks 0 to 8 and was then tapered from weeks 8 to 16. RESULTS. Mean alprazolam dose was 5 mg daily. Compared with placebo subjects, alprazolam patients developed more adverse reactions (21% v. 0%) of depression, enuresis, disinhibition and aggression; and more side-effects, particularly sedation, irritability, impaired memory, weight loss and ataxia. Side-effects tended to diminish during treatment but remained significant at week 8. Despite this, the drop-out rate was low. CONCLUSIONS. Alprazolam caused side-effects and adverse effects during treatment but many patients were willing to accept these.

Dreessen L, Arntz A, Luttels C, Sallaerts S: PERSONALITY DISORDERS DO NOT INFLUENCE THE RESULTS OF COGNITIVE BEHAVIOR THERAPIES FOR ANXIETY DISORDERS. Comprehensive Psychiatry 1994; 35(4):265-74. Summary: Two studies are presented in which the presence of personality disorders (PDs) was assessed using a structured clinical interview (Structured Clinical Interview for DSM-III-R Personality Disorders [SCID-II] by an independent rater before the start of treatment. The therapy effect was measured by change scores. In the first study, patients (N = 31) with panic disorder (with or without agoraphobia) received standardized cognitive behavioral treatment protocols. The effect of treatment as assessed by questionnaires and panic frequency was comparable in the groups with and without PD. In a second study, patients (N = 57) with various anxiety disorders were assessed before and after an individually tailored cognitive behavioral treatment. In general, results showed that anxiety patients with PDs have more severe axis I pathology, but show a change parallel to the patients without PD. Thus, if the effect of therapy is measured by change scores, PD is not related to therapeutic failure of cognitive behavioral treatment of anxiety disorders in general and panic disorder in particular.

Bowen R, South M, Fischer D, Looman T: DEPRESSION, MASTERY AND NUMBER OF GROUP SESSIONS ATTENDED PREDICT OUTCOME OF PATIENTS WITH PANIC AND AGORAPHOBIA IN A BEHAVIOURAL/MEDICATION PROGRAM. Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie 1994; 39(5):283-8. Summary: From a list of 214 patients suffering from panic and agoraphobia and who had been treated with cognitive behaviour therapy, 30 patients who had very good outcomes and 32 who had poor outcomes were selected. The groups were selected by the nurse therapist and psychiatrist on the basis of personal knowledge of the patients. The distinction into good and poor outcome groups was confirmed by the results of a follow-up questionnaire completed by the patient. Of several clinical and demographic variables which had been hypothesized to be predictors of outcome, only depression, as measured by the Beck Depression Inventory, mastery, as measured by the Pearlin Mastery Scale and the number of group therapy sessions attended predicted outcome. Levels of depression and mastery might be clinically modifiable variables which affect the outcome of treatment for patients with panic and agoraphobia.

Clark DM, Salkovskis PM, Hackmann A, Middleton H, Anastasiades P, Gelder M: A COMPARISON OF COGNITIVE THERAPY, APPLIED RELAXATION AND IMIPRAMINE IN THE TREATMENT OF PANIC DISORDER. British Journal of Psychiatry 1994; 164(6):759-69. Summary: Recent studies have shown that cognitive therapy is an effective treatment for panic disorder. However, little is known about how cognitive therapy compares with other psychological and pharmacological treatments. To investigate this question 64 panic disorder patients were initially assigned to cognitive therapy, applied relaxation, imipramine (mean 233 mg/day), or a 3-month wait followed by allocation to treatment. During treatment patients had up to 12 sessions in the first 3 months and up to three booster sessions in the next 3 months. Imipramine was gradually withdrawn after 6 months. Each treatment included self-exposure homework assignments. Cognitive therapy and applied relaxation sessions lasted one hour. Imipramine sessions lasted 25 minutes. Assessments were before treatment/wait and at 3, 6, and 15 months. Comparisons with waiting-list showed all three treatments were effective. Comparisons between treatments showed that at 3 months cognitive therapy was superior to both applied relaxation and imipramine on most measures. At 6 months cognitive therapy did not differ from imipramine and both were superior to applied relaxation on several measures. Between 6 and 15 months a number of imipramine patients relapsed. At 15 months cognitive therapy was again superior to both applied relaxation and imipramine but on fewer measures than at 3 months. Cognitive measures taken at the end of treatment were significant predictors of outcome at follow-up.

Spiegel DA, Bruce TJ, Gregg SF, Nuzzarello A: DOES COGNITIVE BEHAVIOR THERAPY ASSIST SLOW-TAPER ALPRAZOLAM DISCONTINUATION IN PANIC DISORDER? American Journal of Psychiatry 1994; 151(6):876-81. Summary: OBJECTIVE: The authors investigated whether cognitive behavioral treatment could facilitate discontinuation of alprazolam therapy and maintenance of drug abstinence among panic disorder patients treated with alprazolam doses sufficient to suppress spontaneous panic attacks. METHOD: Twenty-one outpatients who met DSM-III-R criteria for panic disorder with mild to severe agoraphobia were made panic-free with alprazolam (mean dose = 2.2 mg/day) and were then randomly assigned to receive either supportive drug maintenance and slow, flexible drug taper or an identical medication treatment plus 12 weeks of concurrent, individual cognitive behavioral treatment. Taper in the combined treatment group was sequenced to conclude before cognitive behavioral treatment ended. RESULTS: Twenty subjects completed the study. There was no significant difference between groups in the rate of alprazolam discontinuation (80% and 90%, respectively, in the alprazolam-only group and the combined treatment group). However, during the 6-month follow-up period, half of the subjects who discontinued alprazolam without cognitive behavior therapy, but none of those who were given cognitive behavior therapy, relapsed and resumed alprazolam treatment. CONCLUSIONS: Cognitive behavioral treatment administered in parallel with alprazolam maintenance and taper was effective in preventing relapse after drug discontinuation. The results warrant further research on the thoughtful integration of these two therapeutic modalities.

Bradwejn J, Koszycki D, Couetoux du Tertre A, Paradis M, Bourin M: EFFECTS OF FLUMAZENIL ON CHOLECYSTOKININ-TETRAPEPTIDE-INDUCED PANIC SYMPTOMS IN HEALTHY VOLUNTEERS. Psychopharmacology 1994; 114(2):257-61. Summary: The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 micrograms) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.

Faludi G, Tekes K, Tothfalusi L: COMPARATIVE STUDY OF PLATELET 3H-PAROXETINE AND 3H-IMIPRAMINE BINDING IN PANIC DISORDER PATIENTS AND HEALTHY CONTROLS. Journal of Psychiatry & Neuroscience 1994; 19(2):109-13. Summary: High affinity 3H-paroxetine and 3H-imipramine binding sites were simultaneously studied in platelets of 29 untreated patients with panic disorder and 12 healthy controls. The maximum number of binding sites (Bmax) was found to be significantly lower in the panic patients compared to the controls using either ligand. No difference in the Kd values between the groups of subjects was found. The disturbance of serotonin neurotransmission in panic disorder--decrease in Bmax values--may be either a consequence or a reason of serotonergic dysfunction.

Page AC: PANIC PROVOCATION IN THE TREATMENT OF AGORAPHOBIA: A PRELIMINARY INVESTIGATION. Australian & New Zealand Journal of Psychiatry 1994; 28(1):82-6. Summary: The efficacy of panic provocation exercises in the treatment of agoraphobia is examined. Twenty six patients with agoraphobia were allocated to a cognitive-behavioural program with and without panic provocation exercises. Both programs significantly reduced symptoms. Despite a trend in favour of panic provocation, differences between treatments failed to reach significance. Results are discussed in terms of a cognitive model of panic and the manner in which future research into panic provocation should be conducted.

Fishman SM, Carr DB, Beckett A, Rosenbaum JF: HYPERCAPNEIC VENTILATORY RESPONSE IN PATIENTS WITH PANIC DISORDER BEFORE AND AFTER ALPRAZOLAM TREATMENT AND IN PRE- AND POSTMENSTRUAL WOMEN. Journal of Psychiatric Research 1994; 28(2):165-70. Summary: We tested the ventilatory and anxiety response to hypercapneic (CO2) challenge in women with panic disorder as well as in normal women in the premenstrual phase and mid-points of their menstrual cycles. Panic disorder patients were challenged on two occasions, each time while in the premenstrual phase of the menstrual cycle, receiving an open trial of alprazolam through the intervening 8 weeks between tests. This study confirms previous reports indicating increased sensitivity to CO2 in patients with panic disorder and that this sensitivity can be attenuated by treatment. We found a significant decrease in the ventilatory response of panic disorder patients comparing pre- and post-therapy. We also observed that normal females, while in the premenstrual phase of their menstrual cycle, have a heightened anxiety response to CO2 challenge.

Basoglu M, Marks IM, Kilic C, Swinson RP, Noshirvani H, Kuch K, O'Sullivan G: RELATIONSHIP OF PANIC, ANTICIPATORY ANXIETY, AGORAPHOBIA AND GLOBAL IMPROVEMENT IN PANIC DISORDER WITH AGORAPHOBIA TREATED WITH ALPRAZOLAM AND EXPOSURE. British Journal of Psychiatry 1994; 164(5):647-52. Summary: In a controlled trial of alprazolam and exposure in 154 patients with panic disorder with agoraphobia, relations between panic, anticipatory anxiety, and phobic avoidance were examined. The three symptoms were independent of one another at baseline and improved largely independently during treatment; only early improvement in avoidance predicted global improvement after treatment. Global improvement was more related to reduction of avoidance than a decrease in panics. Panic was not a valuable outcome measure in panic disorder with agoraphobia.

Basoglu M, Marks IM, Kilic C, Brewin CR, Swinson RP: ALPRAZOLAM AND EXPOSURE FOR PANIC DISORDER WITH AGORAPHOBIA. ATTRIBUTION OF IMPROVEMENT TO MEDICATION PREDICTS SUBSEQUENT RELAPSE. British Journal of Psychiatry 1994; 164(5):652-9. Summary: Patients with panic disorder plus agoraphobia had 8 weeks of drug treatment (alprazolam or placebo) plus psychological treatment (exposure or relaxation). At the end of treatment at week 8, 40 patients who had become much/very much improved rated how much their gains were attributable to medication or to their own efforts. During the tapering-off to week 16, and treatment-free follow-up to week 43, patients who at week 8 had attributed their gains to medication and felt less confident in coping without tablets had more severe withdrawal symptoms and greater loss of gains than did patients who at week 8 had attributed their gains to their own efforts during treatment. Baseline illness severity, greater age, higher expectations from drug treatment, and more side-effects of drugs during treatment all predicted more external attributions (i.e. to the effect of drugs) but did not independently predict relapse. Patients on alprazolam compared with placebo had more drug attributions. Though drug attributions predicted relapse in both alprazolam and placebo groups, predictions were stronger in the alprazolam group.

Pollack MH, Otto MW, Kaspi SP, Hammerness PG, Rosenbaum JF: COGNITIVE BEHAVIOR THERAPY FOR TREATMENT-REFRACTORY PANIC DISORDER. Journal of Clinical Psychiatry 1994; 55(5):200-5. Summary: BACKGROUND: The purpose of this pilot study is to assess the efficacy of cognitive behavior therapy for the treatment of patients with panic disorder who experience an incomplete response to a trial of pharmacotherapy. METHOD: Fifteen consecutive patients with a DSM-III-R diagnosis of panic disorder referred for further treatment because of an incomplete response to pharmacotherapy were treated with 12-weeks of group cognitive behavior therapy. Patients were evaluated at baseline, endpoint, and at a mean of 2-months' follow-up to assess changes in panic attack frequency and global outcome. Eight of the 15 patients were deemed to have received an inadequate prior trial of medication at baseline, mainly because of a desire to control their symptoms without medication or fear of withdrawal and/or addiction. Seven of the patients were symptomatic at baseline despite an adequate prior trial of medication. RESULTS: Overall, patients experienced a significant improvement in global function at the end of the cognitive behavior therapy intervention, as well as a decrease in panic attack frequency. Improvement was maintained at follow-up. CONCLUSION: This study is consistent with a growing body of evidence that many patients with panic disorder remain symptomatic over time and are receiving inadequate pharmacotherapeutic treatment. Further, we observed that patients with panic disorder who are incompletely responsive or resistant to pharmacotherapeutic management may benefit from the addition of cognitive behavior therapy.

Shear MK, Pilkonis PA, Cloitre M, Leon AC: COGNITIVE BEHAVIORAL TREATMENT COMPARED WITH NONPRESCRIPTIVE TREATMENT OF PANIC DISORDER. Archives of General Psychiatry 1994; 51(5):395-401. Summary: BACKGROUND: The efficacy of cognitive behavioral treatment for panic disorder has been established in controlled studies. However, little is known about the efficacy of other psychological treatments. We report the results of a study comparing cognitive behavioral treatment with a focused nonprescriptive treatment for panic. METHODS: Three sessions of panic-related information were provided in each treatment, followed by 12 sessions of either nonprescriptive, reflective listening (non-prescriptive treatment) or a treatment package that included breathing retraining, muscle relaxation, cognitive reframing, and exposure to interoceptive and agoraphobic stimuli (cognitive behavioral treatment). RESULTS: Posttreatment and 6-month follow-up assessments revealed a good response to both treatments. We observed a high rate of panic remission and significant improvement in associated symptoms in subjects in each treatment group. CONCLUSION: These findings raise questions about the specificity of cognitive behavioral treatment.

van den Hout M, Arntz A, Hoekstra R: EXPOSURE REDUCED AGORAPHOBIA BUT NOT PANIC, AND COGNITIVE THERAPY REDUCED PANIC BUT NOT AGORAPHOBIA. Behaviour Research & Therapy 1994; 32(4):447-51. Summary: Earlier studies showed that cognitive therapy has anti-panic effects and exposure has anti-agoraphobic effects while other studies suggest that agoraphobia is a secondary complication of panic disorder. It was therefore hypothesized that cognitive therapy not only reduces panic but also agoraphobia and that it potentiates the effects of exposure in vivo. Two groups of 12 severe agoraphobics were treated with 4 sessions of cognitive therapy followed by 8 sessions of cognitive therapy combined with in vivo exposure. The other 12 received 4 sessions of 'associative therapy', a presumably inert treatment that controls for therapist attention, followed by 8 sessions of in vivo exposure that was framed in common behavioral terms. The initial cognitive therapy produced a significant reduction in panic frequency, while associative therapy did not affect panic. Neither cognitive therapy alone, nor associate therapy alone significantly reduced depression, state or trait anxiety, self-rated agoraphobia or behavioral avoidance. After adding exposure however, these parameters were clearly and significantly reduced. Cognitive therapy did not potentiate exposure effects. The results are discussed.

Zarate R, Agras WS: PSYCHOSOCIAL TREATMENT OF PHOBIA AND PANIC DISORDERS. [REVIEW]. Psychiatry 1994; 57(2):133-41. Summary: Intervention packages combining cognitive restructuring techniques and exposure exercises have become the psychosocial treatments of choice for panic, agoraphobia, and social phobia. Exposure and related desensitization techniques are the treatment of choice for all variants of simple phobia. Combining psychotropic medication and cognitive-behavior therapy suggests strategies that offer new opportunities for increasing the number of individuals with anxiety disorders who can be effectively treated with a biobehavioral approach. [References: 76]

Fava GA, Grandi S, Belluardo P, Savron G, Raffi AR, Conti S, Saviotti FM: BENZODIAZEPINES AND ANXIETY SENSITIVITY IN PANIC DISORDER. Progress in Neuro-Psychopharmacology & Biological Psychiatry 1994; 18(7):1163-8. Summary: 1. Benzodiazepines were discontinued in 16 patients who had recovered from panic disorder with agoraphobia after exposure treatment. 2. Drug discontinuation yielded a significant decrease in anxiety sensitivity and state anxiety in these long-term users. 3. Several likely explanations for the findings are discussed. 4. In the short term, treatment of panic disorder with benzodiazepines may lower anxiety symptoms. However, in the long run, it may decrease the individual tolerance to anxiety and discomfort.

Malcolm DE, Yu PH, Bowen RC, O'Donovan C, Hawkes J, Hussein M: PHENELZINE REDUCES PLASMA VITAMIN B6. Journal of Psychiatry & Neuroscience 1994; 19(5):332-4. Summary: Plasma levels of the active form of vitamin B6 (pyridoxal phosphate) in 19 patients taking phenelzine were found to be reduced on the average to approximately 54% of the value in a control group. There was no correlation of pyridoxal phosphate level with phenelzine daily dosage over the range of 30 mg to 90 mg. No symptoms of vitamin B6 deficiency peripheral neuropathy were found.

Pecknold J, Luthe L, Munjack D, Alexander P: A DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY WITH ALPRAZOLAM AND EXTENDED-RELEASE ALPRAZOLAM IN THE TREATMENT OF PANIC DISORDER. Journal of Clinical Psychopharmacology 1994; 14(5):314-21. Summary: This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).

Van Hout WJ, Emmelkamp PM, Scholing A: THE ROLE OF NEGATIVE SELF-STATEMENTS DURING EXPOSURE IN VIVO. A PROCESS STUDY OF EIGHT PANIC DISORDER PATIENTS WITH AGORAPHOBIA. Behavior Modification 1994; 18(4):389-410. Summary: The purpose of this study was to evaluate the pattern of cognitive change, and in particular the role of negative self-statements, in relation to improvement during an in vivo exposure treatment. Eight panic disordered patients with agoraphobia, of whom 4 were most and 4 were least improved on a composite measure, were exposed to standardized agoraphobic situations. During the exposure, heart rate, self-statements, and subjective anxiety were registered throughout the sessions. Fixed criteria were set for habituation of heart rate and reduction of subjective anxiety within a session. Results showed that the total frequency of negative self-statements at the start, during, as well as at the end of treatment differentiated best between the most and least improved patients. These results suggest that it may be therapeutically wise to continue exposure therapy not only until habituation of anxiety (subjectively and physiologically) is achieved, but also until the frequency of negative self-statements is reduced until zero.

Rosenberg NK, Rosenberg R: THREE YEARS FOLLOW-UP OF PANIC DISORDER PATIENTS: A NATURALISTIC STUDY. Scandinavian Journal of Psychology 1994; 35(3):254-62. Summary: Forty Danish panic disorder patients participating in a placebo controlled study of alprazolam and imipramine (The Cross National Collaborative Panic Study, Phase II) were followed up by a telephone interview three years later, with essentially the same battery of evaluation procedures applied at baseline, end of study, and follow-up. The main finding was that panic disorder is a chronic disorder, but fluctuating in form and severity in the course of time. Twenty-five percent of the patients no longer fulfilled the DSM-III criteria for panic disorder, but had substantial disability due to a variety of symptoms, including panic attacks at infrequent rate, generalized anxiety symptoms, affective symptoms, and phobic avoidance behavior. Nearly three fourths of the patients were under treatment at follow-up. Benzodiazepines were the drugs most often prescribed, usually in combination with supportive psychotherapy. It was concluded that the different types of treatment offered were insufficient. Variables predicting panic disorder or substantial disability at 3-years follow-up were few.

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