title: Imipramine in the treatment of agoraphobia: dose-response relationships. Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder. The Galway Study of Panic Disorder. I: Clomipramine and lofepramine in DSM III-R panic disorder: a placebo controlled trial. 12-month prevalence of panic disorder with or without agoraphobia in the Swedish general population Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Combined pharmacological and behavioral treatment for agoraphobia. Panic and avoidance in agoraphobia. Application of path analysis to treatment studies. Overcoming resistance to exposure in panic disorder with agoraphobia Pretreatment attrition in a comparative treatment outcome study on panic disorder. The management of severe agoraphobia: A comparison of iproniazid and systematic desensitization The effect of pharmacotherapist characteristics on treatment outcome in panic disorder. Phenelzine and exposure in the treatment of phobias. Global measures of outcome in a controlled comparison of pharmacological and psychological treatment of panic disorder and agoraphobia in primary care. How study design affects outcomes in comparisons of therapy. I: Medical. Autonomic changes after treatment of agoraphobia with panic attacks Imipramine and brief therapists-aided exposure in agoraphobics having self-exposure homework. Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. Specific phobia 10-16 years after treatment. Behavior therapy, supportive psychotherapy, imipramine, and phobias. Bias in treatment assignment in controlled clinical trials. Pharmacological treatment of agoraphobia: imipramine versus imipramine with programmed practice. A prospective naturalistic study of 326 panic-agoraphobic patients treated with antidepressants. Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Two-year follow-up of exposure and imipramine treatment of agoraphobia. Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. Treatment of phobias. II. Behavior therapy and supportive psychotherapy: are there any specific ingredients? Long‐term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2‐year naturalistic follow‐up Two-year follow-up of agoraphobics after exposure and imipramine. Duration of Imipramine Therapy and Relapse in Panic Disorder With Agoraphobia Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Surreptitious drug use by patients in a panic disorder study. Agoraphobics 5 Years after Imipramine and Exposure: Outcome and Predictors Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitive behavioral therapy for panic disorder? A pilot study Flooding with Brevital in the treatment of agoraphobia: countereffective? Treatment of agoraphobia with group exposure in vivo and imipramine. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Effects of panic disorder treatments on personality disorder characteristics. Randomised placebo-controlled trial of moclobemide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. Treatment of panic disorder with agoraphobia: comparison of fluvoxamine, placebo, and psychological panic management combined with exposure and of exposure in vivo alone. Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. Personality disorder and social anxiety predict delayed response in drug and behavioral treatment of panic disorder.
abstract: The authors examined dose-response relationships in 62 agoraphobic patients receiving either imipramine or placebo under double-blind conditions in conjunction with behavioral interventions .  At the end of 12 weeks , patients treated with imipramine had improved significantly more than placebo patients . Results revealed that the beneficial therapeutic effect of imipramine was dose dependent and suggested that optimal response in agoraphobia may require doses of 150 mg/day or more . The results also indicated that side effects can significantly interfere with the buildup of optimal dose in agoraphobic patients treated with imipramine . The authors briefly discuss the implication s of these findings for clinical practice and future research This study examined pretreatment factors associated with attrition from a clinical trial for panic disorder . The study group consisted of 162 patients who began 11-visit treatments .  Six domains ( demography , panic disorder severity , psychiatric comorbidity , illness/treatment attributions , coping styles , and personality styles ) with 52 variables were used to predict attrition . One hundred twenty-two patients completed and 40 dropped out from treatment . Final multivariate regression analyses showed that the following two variables were independently associated with attrition : lower household income and negative treatment attitudes ; attributing the panic disorder to life stressors and greater age were independently associated with attrition at the trend level . Preliminary analyses suggested , in addition , associations between attrition and lower education , shorter length of prior treatment , higher anxiety sensitivity , lower agoraphobic avoidance , and a coping style of seeking social support that were not confirmed by best predictor analysis . Psychiatric comorbidity and personality styles were unrelated to attrition . The implication s of these findings for future research and clinical practice are discussed 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 st and ard 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 Objective The present study examined the prevalence of  panic disorder  with or without agoraphobia according to DSM-IV criteria in the Swedish general population . Method Data were obtained by means of a postal survey administrated to 1000 r and omly selected adults . The panic disorder module of the World Health Organization 's Composite International Diagnostic Interview ( CIDI ) was included in the survey . Results 12-month prevalence was estimated at 2.2 % ( CI 95 % 1.02 % – 3.38 % ) . There was a significant sex difference , with a greater prevalence for women ( 5.6 % ) compared to men ( 1 % ) . Conclusion The Swedish panic disorder prevalence is relatively consistent with findings in most other parts of the western world In a controlled- outcome study of phobias , 218 adult phobic patients ( 147 women and 71 men ) received a course of 26 weekly treatment sessions that consisted of behavior therapy ( BT ) and imipramine hydrochloride , BT and placebo , or supportive psychotherapy and imipramine . The BT consisted of systematic desentization using fantasy and assertiveness training .  Patients were classified as agoraphobic , mixed phobic , or simple phobic . Although the conditions of most patients in each group showed moderate to marked improvement , the effects of imipramine were significantly superior to those of placebo in patients with spontaneous panic attacks , ie , patients with agoraphobia or mixed phobia . In patients with simple phobia , who do not experience spontaneous panic , there was not a significant difference between imipramine and placebo . This study clearly distinguished those phobic patients who experienced spontaneous panic from those who did not in terms of pharmacologic benefits Thirty-seven severely-disabled agoraphobics were r and omly assigned to ( 1 ) Imipramine-no exposure . ( 2 ) Imipramine + exposure or ( 3 ) Placebo + exposure groups . To provide a more stringent test of the pharmacological effects of imipramine independent of exposure to phobic stimuli , Ss in the Imipramine-no exposure condition received antiexposure instructions during the first 8 weeks of therapy . Assessment s were conducted at 0 , 8 and 26 weeks . At 8 weeks , the group receiving imipramine combined with exposure therapy displayed more improvement than the other two groups , and was the only group to show a reduction in panic attacks . Ss receiving imipramine with antiexposure instructions showed little improvement on phobic indices , no reduction in panic , but significant improvement in anxiety and dysphoric mood . At 26 weeks Ss receiving the combined imipramine + exposure treatment exhibited further improvement result ing in a significant superiority of Imipramine + exposure over Placebo + exposure across a number of different outcome indices . Ss who had received imipramine with antiexposure instructions showed some improvement during the subsequent 18 weeks in which the antiexposure instructions were no longer in effect . However , neither this group nor the Placebo + exposure group showed a reduction in panic attacks . The results of the present trial provide support for the beneficial effects of combining intensive exposure with imipramine , but call into question the thesis that imipramine exerts its effect through a pharmacological blocking of panic attacks . Alternative hypotheses concerning the mode of action of imipramine are presented We explored a causal sequence between panic and avoidance to provide recommendations for psychotherapy , pharmacotherapy , and their combination in treating agoraphobia . We produced a two-way [ ( imipramine hydrochloride vs placebo ] by [ office-based behavioral therapy vs in vivo exposure ] ) design by amalgamating two studies . We assessed agoraphobic patients for panic and avoidance at these time points : baseline ( week 0 ) , midcourse ( week 13 ) , and termination ( week 26 ) . The causal sequence model was tested by path analysis . Imipramine was superior to placebo in lowering panic and avoidance at both postbaseline time points . Exposure was superior to office-based treatment in lowering avoidance only at week 13 . Exposure appeared to produce quicker improvement of avoidance than office-based therapy , but relapse occurred if this improvement was not supported by medication . Exposure did not benefit panic . We believe patients should be informed that imipramine is superior to exposure in inducing a panic-free state . Exposure without imipramine is of benefit only in reducing avoidance , but adding imipramine to exposure is necessary for panic control and substantially improves exposure and exposure maintenance The issue of panic disorder resistant to treatment ( whether pharmacological or psychological ) has attracted little research attention , despite its clinical frequency and importance . The aim of this study was to compare three treatment modalities , namely exposure alone ( E ) , exposure associated with imipramine ( EI ) and cognitive therapy supplementing exposure ( EC ) , in a sample of 21 patients with DSM‐IV panic disorder and agoraphobia , who failed to respond to a first st and ard course of individual behavioural treatment based on exposure in vivo . Treatments were administered according to a cross‐over , controlled design ( E‐EI‐EC , EI‐EC‐E , EC‐E‐EI ) . Twelve of the 21 patients  achieved remission ( panic‐free status ) during the trial . In 8 cases this occurred after exposure alone ( E ) and in two cases each after the other treatments ( EI and EC ) . The results revealed a significant effect of the factor time on a number of variables , and the superiority of exposure alone compared to other treatment modalities with regard to some variables . These findings suggest that long‐term behavioural treatment based on exposure may be necessary in some patients , and may induce clinical remission . However , patients who do not respond to exposure show poor tolerance of and compliance with pharmacological treatment , and are unlikely to achieve remission  with imipramine or cognitive therapy , even though this may occur in individual cases OBJECTIVE Whereas the fact of attrition during the course of treatment is well documented , little is known about the factors that affect sample selection before the beginning of a study ( " pretreatment attrition " ) . The present study reports on the degree and sources of pretreatment attrition at two sites of a multicenter study on panic disorder that compared treatment outcomes for imipramine and cognitive behavior therapy . METHOD Data were collected at two clinical research sites , one with a pharmacological treatment orientation ( N = 420 ) and one with a psychosocial treatment orientation ( N = 208 ) . RESULTS The main source of pretreatment attrition was participant refusal . At both research sites , eligible patients most often refused participation because they were either unwilling to start treatment with imipramine ( 30.6 % and 47.4 % , respectively ) or discontinue their current medication ( 22.6 % and 35.1 % , respectively ) . CONCLUSIONS Results from comparative treatment outcome studies are limited not only to people who meet the study criteria but also to those who are willing to begin a medication treatment and discontinue their current medication Sixty out- patients with severe agoraphobia took part in a controlled prospect i ve clinical trial of combinations of methohexitone-assisted and st and ard systematic desensitization and monoamine oxidase inhibitor . Severity of agoraphobia in terms of avoidance and anxiety was rated both by the patients themselves and by an independent assessor during the eight weeks of treatment . The monoamine oxidase inhibitor produced a significant reduction in severity of anxiety but not of avoidance .  Methohexitone-assisted systematic desensitization appeared to produce significantly greater improvement than either st and ard systematic desensitization or no systematic desensitization in both anxiety and avoidance . Assessors ' ratings showed that the monoamine oxidase inhibitor used in conjunction with methohexitone-assisted systematic desnsitization produced slightly greater clinical improvement than the other treatment combinations A large number of studies suggest that individual characteristics of psychotherapists affect the outcome of  psychosocial treatments  for psychiatric illness , but little work has been done to see if this is also the case for pharmacotherapy . In the context of a multicenter study that compared psychosocial and medication treatments for panic disorder , we assessed whether such characteristics as age of the psychiatrist , number of years of experience , and gender influence the outcome of treatment with the antipanic drug imipramine . Data were examined by multiple and logistic regression analyses for eight psychiatrists who treated a total of 57 patients with panic disorder . More physician experience , measured as years since completing residency , was associated with better response to imipramine on one of two main dichotomous measures ( the Clinical Global Impression-Improvement Scale ) and on six of nine continuous measure rating scales . Associations between psychiatrist age and outcome and between psychiatrist gender and outcome were also present but on fewer measures . Although these are post-hoc analyses that were not planned when the multicenter study was originally design ed and therefore there are limitations in the information available about the psychiatrists ' characteristics , the findings suggest that even in the context of a clinical trial that employs a specific protocol and single medication , physician experience may influence patient outcome . Depression and Anxiety 17:88 - 93 , 2003 A double-blind study was carried out on 40 agoraphobic and socially phobic patients , matched , then r and omly assigned to one of four treatment groups ; phenelzine-exposure , phenelzine-no exposure , placebo-exposure , and placebo-no exposure . Exposure consisted of encouraging the patient to face the phobic situation a predetermined number of times . Assessment s , made at the beginning and end of 8 weeks of therapy and 8 weeks thereafter , showed that the phobia ratings of groups decreased significantly . The combined exposure group improved significantly more than the combined no exposure group during treatment . At 8 weeks follow-up there was some deterioration in the phenelzine-exposure and placebo-no exposure groups . Exposure , with or without phenelzine , was the superior treatment modality . The antiphobic effect of phenelzine was not supported , although it seemed to reduce subjective anxiety during exposure experiences . The possibility that effect of phenelzine is dose-related is discussed BACKGROUND Panic disorder , with and without agoraphobia , is a prevalent condition which presents primarily in general practice . Previous clinical outcome studies have been conducted mainly in specialist university departments or hospital setting s , and have tended to employ complex rating scales that are not well suited for use as outcome measures in primary care . AIM To evaluate the outcome , in a primary care setting , of fluvoxamine versus cognitive behaviour therapy , each used alone and in combination in a double-blind placebo-controlled framework , balanced for therapist contact . METHOD A total of 149 patients satisfying DSMIII-R criteria for panic disorder were r and omly allocated to receive one of the following : fluvoxamine , placebo , fluvoxamine plus cognitive behaviour therapy , placebo plus cognitive behaviour therapy , and cognitive behaviour therapy alone . These five treatment groups represent the minimum number acceptable for such a comparison to be made . All patients received an identical schedule of contact over 13 weeks . Measures of symptom severity , general health and social disruption were taken at entry point and end point ; measures of change in symptoms were taken at end point only . Outcome was reported in terms of brief global ratings of severity of illness and change in symptoms , and of ratings of general health and social disruption that are suitable for use in general practice . RESULTS All active treatment groups showed statistically significant advantages over placebo over a range of outcome ratings . The groups employing cognitive behaviour therapy showed the most robust and consistent response . CONCLUSION The brief global measures reported here proved adequate to the task of assessing treatment outcome . Results indicate that treatments including cognitive behaviour therapy can be effective in the treatment of panic disorder and agoraphobia in primary care We analysed 113 reports published in 1980 in a sample of medical journals to relate features of study design to the magnitude of gains attributed to new therapies over old . Overall we rated 87 per cent of new therapies as improvements over st and ard therapies . The mean gain ( measured by the Mann-Whitney statistic ) was relatively constant across study design s , except for non-r and omized controlled trials with sequential assignment to therapy , which showed a significantly higher likelihood that a patient would do better on the innovation than on st and ard therapy ( p = 0.004 ) . R and omized controlled trials that did not use a double-blind design had a higher likelihood of showing a gain for the innovation than did double-blind trials ( p = 0.02 ) . Any evaluation of an innovation may include both bias and the true efficacy of the new therapy , therefore we may consider making adjustments for the average bias associated with a study design . When interpreting an evaluation of a new therapy , readers should consider the impact of the following average adjustments to the Mann-Whitney statistic : for trials with non-r and om sequential assignment a decrease of 0.15 , for non-double-blind r and omized controlled trials a decrease of 0.11 Twenty-three patients meeting DSM-III criteria for agoraphobia with panic attacks and 14 age- , race- , and sex-matched nonanxious controls were tested in the laboratory and on a test walk in a shopping mall . The patients were tested before and after about 15 weeks of treatment with placebo and exposure therapy , imipramine and exposure therapy , or imipramine and initial antiexposure instructions . Controls were tested twice at a similar interval , but without any treatment . On test day 1 , patients compared to controls showed higher average heart rate and skin conductance levels and greater numbers of skin conductance fluctuations in the laboratory , and higher heart rates before and during the test walk . Between pretreatment and posttreatment tests , clinical ratings improved and skin conductance levels decreased in all treatment groups . Heart rate levels in the laboratory , on the other h and , decreased in patients on placebo and rose in patients on imipramine . Thus , imipramine compromises the usefulness of heart rate as a measure of emotional arousal . Higher pretreatment heart rates predicted greater clinical improvement Forty-five chronic agoraphobics were r and omly assigned to treatment by placebo or imipramine in doses up to 200 mg/day for 28 weeks . All patients also had systematic self-exposure homework with an instruction manual . In addition , half of each drug group had therapist-aided exposure and half had therapist-aided relaxation , each totalling three hours . Patients in both drug groups improved substantially and maintained their gains for one year of follow-up . Imipramine had no significant therapeutic effect despite satisfactory plasma levels and significant drug side effects . Patients ' low initial Hamilton depression scores might explain the absence of any drug effect . Antidepressants may be ineffective for agoraphobics who have normal mood . Brief therapist-aided exposure improved phobias and panics to a significant but limited extent , and is a useful adjuvant to self-exposure homework , which can be a powerful therapeutic agency by itself BACKGROUND Current recommendations suggest that pharmacotherapy for patients with panic disorder should be continued for at least 1 year [ Am . J. Psychiatry 155 ( 1998 ) 1 ] , despite a paucity of data systematic ally examining outcome for periods greater than 3 - 6 months . It is critically important to obtain more information on the effectiveness of medications over time for patients who initially responded to pharmacotherapy for panic disorder . METHODS Long-term outcome was examined for 78 patients who attained a 2-month period of sustained remission on medication and received maintenance pharmacotherapy for up to 24 months during the Massachusetts General Hospital Longitudinal Study of Panic Disorder , a prospect i ve , naturalistic study . Participants were categorized by their maintenance treatment condition at remission : benzodiazepine alone ( N = 45 , 58 % ) , antidepressant alone ( N = 12 , 16 % ) , and combined treatment with a benzodiazepine and an antidepressant ( N = 21 , 27 % ) . RESULTS Approximately half ( N = 36 , 46 % ) of the patients who had achieved remission relapsed at some time over the 2-year naturalistic study period , despite continued and adequate pharmacotherapy . There was no difference in timing or frequency of relapse by type of maintenance pharmacotherapy . LIMITATIONS Interpretation of the data is limited by the naturalistic nature of the study , and by the relatively low sample size . CONCLUSIONS This data suggests that patients with panic disorder have a high rate of relapse even after acute response to pharmacotherapy , despite continued treatment . In addition , the use of combined pharmacotherapy with antidepressants and benzodiazepines does not appear to provide greater protection from relapse than monotherapy BACKGROUND Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors ( SSRIs ) have proved to be effective in the treatment of panic disorder . The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone . METHOD 161 patients with panic disorder with or without agoraphobia ( DSM-IV criteria ) underwent a manual-guided cognitive-behavioral therapy of 15 sessions . Forty-three unsuccessfully treated patients from this group were included in a double-blind , placebo-controlled , next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo . RESULTS Overall , patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior ( p < .05 ) and anxiety discomfort ( p < .01 ) , whereas patients in the cognitive-behavioral therapy plus placebo condition did not . Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition , from 0.4 to 1.0 . CONCLUSION Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality . The importance of timely evaluation of treatment results is emphasized Twenty eight participants , initially treated for specific phobia as part of a comparative treatment study , were evaluated 10 to 16 years ( X = 12 years ) later . A comprehensive , in-person , semi-structured diagnostic interview was utilized , which also assessed comorbid disorders . Of 21 patients who had been rated as responders ( much improved or very much improved ) at treatment termination , 13 ( 62 % ) had clinical ly significant avoidance or endurance with dread  subsequent to treatment . Among a subgroup of these responders who had been considered completely recovered ( n = 11 ) , 5 ( 45 % ) had clinical ly significant symptoms following treatment . None of the seven subjects who had been considered unimproved at treatment termination recovered from phobia symptoms in the intervening years . Positive response to treatment was associated with better long term outcome . Clinical characteristics , such as phobia subtype , age of onset , baseline severity , and lifetime comorbidity of other psychiatric disorders were not associated with long term outcome in this sample . Type of treatment was not associated with long term outcome . Results challenge the notion that recovery from specific phobia following treatment is characterized by complete and enduring cessation of symptoms In a controlled outcome study of phobias , 111 adult patients ( 69 % women , 31 % men ) received a course of 26 weekly treatment sessions consisting of ( 1 ) behavior therapy and imipramine hydrochloride ( 2 ) behavior therapy and placebo , or ( 3 ) supportive psychotherapy and imipramine .  Patients were classified as agoraphobic , mixed phobic , or simple phobic . The great majority of patients in all groups showed moderate to marked global improvement ( 70 % to 86 % , depending on rater ) . In agoraphobics and mixed phobics ( both groups experiencing spontaneous panic attacks ) , imipramine was significantly superior to placebo . There was no difference between behavior therapy and supportive therapy , both result ing in high improvement rates ( 76 % to 100 % , depending on rater ) . In simple phobic patients , there was a high rate of improvement with all treatment regimens ( 72 % to 93 % , depending on rater ) , with no significant difference between imipramine and placebo or between behavior therapy and supportive therapy . Of 88 moderately to markedly improved patients followed up for one year after completing treatment , 83 % maintained their gains and 17 % relapsed . No patients showed symptom substitution . Eighteen percent of the patients receiving imipramine hydrochloride showed marked stimulant side effects on from 5 to 75 mg/day Controlled clinical trials of the treatment of acute myocardial infa rct ion offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment . A group of 145 papers was divided into those in which the r and omization process was blinded ( 57 papers ) , those in which it may have been unblinded ( 45 papers ) , and those in which the controls were selected by a nonr and om process ( 43 papers ) . At least one prognostic variable was maldistributed ( P less than 0.05 ) in 14.0 per cent of the blinded-r and omization studies , in 26.7 per cent of the unblinded-r and omization studies , and in 58.1 per cent of the nonr and omized studies . Differences in case-fatality rates between treatment and control groups ( P less than 0.05 ) were found in 8.8 per cent of the blinded-r and omization studies , 24.4 per cent of the unblinded-r and omization studies , and 58.1 per cent of the nonr and omized studies . These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration Eighteen agoraphobic patients with r and omly assigned to 12 week treatment with imipramine ( I ) or imipramine and programmed in-vivo exposure practice ( I+BT ) to investigate the contribution of behavioural instructions to the clinical effects of pharmacotherapy . Significantly greater improvement on phobic measures was found in the I+BT group compared to the I group . Differences were less marked on measures of panic and anxiety . The results suggest that imipramine possesses an antiphobic effect which can be substantially enhanced with programmed practice . Controlled large-scale investigations of the pharmacological and instructional effects of the phamacotherapy of agoraphobia are needed for a definitive evaluation of the specific antiphobic effect of antidepressant drugs OBJECTIVE How far the results of r and omized controlled studies apply to everyday care can not be judged without regular measurements of outcomes in daily practice . We report on systematic data from a 3-year naturalistic prospect i ve study on panic disorder-agoraphobic ( PDA ) patients treated with antidepressants in a setting of routine clinical practice . Our aim is to describe the evolution of PDA in relation to the treatments employed , and to explore demographic and clinical characteristics that might be predictive of outcome . METHODS 326 DSM-III-R PDA patients treated with antidepressants in a setting of routine clinical practice were included in a 3-year naturalistic prospect i ve study . We utilized structured and semi-structures instruments , including the Structured Clinical Interview for Diagnosis and the Longitudinal Interview Follow-up Examination . The main antidepressants used were imipramine ( 39 % ) , clomipramine ( 28.5 % ) and paroxetine ( 23.3 % ) ; only 9 % of patients received other antidepressants . RESULTS 147 patients ( 45.1 % ) stayed on medication throughout the entire period of the follow-up . Of those who interrupted the treatment , 38 % stayed in remission . The probability of achieving at least one remission during the 3-year follow-up period was 96.5 % for PD and 95.9 % for Agoraphobia . Relapses after a period of at least 2 months of complete remission were also common , and the probability of presenting at least one relapse during the 3-years follow-up period was 67.1 % for PD and 39 % for Agoraphobia . The longest period of remission of PD is associated with low severity , medium-lasting course in patients with an onset of the illness in young adulthood . Less severe agoraphobia associated with moderately severe panic attacks appears to confer a better control of phobic behavior . All three major drugs were reasonably well tolerated ( only 9 % dropped out because of side effects ) , with sexual dysfunction and increased appetite being the most common side effects at the last evaluation ; in the first phase of the treatment anticholinergic effects and jitteriness were more common with TCAs . CONCLUSION Both classical antidepressants and paroxetine emerge as a useful treatment in the long-term management of PDA ; paroxetine appears particularly useful in PDA patients because it was significantly less likely to induce jitteriness , thereby reducing barriers to compliance Endogenous anxiety ( anxiety hysteria , agoraphobia with panic attacks ) is characterized by sudden , spontaneous panic attacks accompanied by multiple autonomic symptoms , overwhelming fear , a flight response , and polyphobic behavior . Psychotherapy , behavior therapy , and tranquillizers have been of limited success in treating this syndrome . Fifty-seven patients severely disabled by the syndrome for a mean period of 13 years completed the three-month study . R and omly assigned in a double-blind , placebo-controlled design to imipramine hydrochloride , pheneizine sulfate , or placebo , they were seen in supportive group therapy every two weeks . Patients in the pheneizine and imipramine cells showed significant improvement ovehe persistent trend for pheneizine to be superior to imipramine achieved significance only on the Work and Social Disability Scale and the Sympton Severity and Phobic Avoidance Scale . The implication s for classification and theory are discussed Sixty-two agoraphobic patient who had completed a controlled study of therapist-assisted in vivo exposure ( flooding ) and imipramine were assessed 1 month , 6 months , 1 year , and 2 years later . Overall , improvement during treatment was maintained throughout follow-up . At 1 month but not subsequently , imipramine and flooding had significant effects on central measures of agoraphobia . Patients who were marked treatment responders had a favorable clinical course and did not experience secondary depression , unlike patients who had not responded markedly to treatment . These findings suggest that treatments which evoke maximum therapeutic benefit initially are likely to foster long-term maintenance and reduce subsequent depressive sequelae Sixty-two chronically agoraphobic patients completed a controlled study to assess the effects of 1 ) imipramine up to 200 mg/day ( mean = 130 mg/day ) , 2 ) 12 weekly therapist-assisted in vivo exposure sessions ( flooding ) , and 3 ) imipramine plus flooding . The control group received systematic therapeutic instructions for self-directed in vivo exposure ( programmed practice ) .  Clinical measures of global severity , phobia , panic , anxiety , depression , and behavioral performance tests were administered before treatment and at Weeks 4 , 8 , and 12 of treatment . Results revealed significant improvement in all groups on all measures over the course of treatment ; almost a third of the control patients showed marked improvement . Imipramine had significant effects on improvement of phobias and markedly increased clinical response rates in patients receiving 150 - 200 mg/day . Less chronicity and severity of condition also predicted better clinical outcome . Flooding had limited effects above and beyond programmed practice , and no imipramine-flooding interactions effects were found Systematic hierarchical desensitization ( behavior therapy [ BT ] ) was compared with supportive psychotherapy ( ST ) during a 26-week treatment trial of patients with agoraphobia , mixed phobia , or simple phobia . We found essentially no difference in effectiveness , not because patients treated with BT had done badly , but because patients receiving ST had done well . A detailed method ologic review concludes that this finding is entirely compatible with the major critical review s of the psychotherapy literature . Is the active ingredient in psychotherapy simply the generation of hopeful expectancies ? This is necessary but not sufficient . For phobics , the psychotherapy session serves primarily as an instigator . The specific corrective activity occurs outside of the formal session in the form of maintained exposure in vivo . Supposed differences between therapies may be entirely due to the rapidly with which the instigational function becomes effective Two years after completion of a controlled outcome study of treatments for panic disorder with agoraphobia , patients were revisited and interviewed about their complaints . In the initial study , four treatments had been compared : ( i ) fluvoxamine combined with exposure ; ( ii ) placebo medication plus exposure ; ( iii ) psychological panic management plus exposure : and ( iv ) exposure alone . Comparison of the results at post‐test had revealed superior efficacy of fluvoxamine combined with exposure over the other three treatments in reducing agoraphobic avoidance . The current naturalistic follow‐up study investigated the long‐term efficacy of the treatments with regard to abatement of complaints and reduced dem and for further treatment . In addition , we examined whether patients were able to taper off the study medication without a recurrence of complaints . In total , 71 of the 76 patients of the original trial ( 93 % ) were interviewed . Comparison of the mean level of psychopathology at follow‐up revealed no difference between the original treatment groups . The effect in the fluvoxamine plus exposure group was maintained , but was no longer superior , due to further improvements in the other treatment groups . Most patients received additional treatment during the follow‐up period , usually because the 12 treatment sessions in the controlled study had yielded insufficient improvement . There was a trend for patients who received the fluvoxamine plus exposure treatment to require less aftercare than those who received the other treatments . Finally , almost 50 % of the patients who had received medication in the original trial were able to taper off the use of fluvoxamine without a recurrence of complaints Forty-five agoraphobic out- patients were r and omly assigned to treatment with imipramine or placebo , and also to brief therapist-aided exposure or relaxation . All patients did systematic self-exposure homework and recorded this in a diary . Forty of these patients were followed-up two years later with self-ratings and ratings by interviewers blind to their treatment conditions . About two-thirds of the patients remained improved or much improved in their phobias , with no significant difference between any of the four treatment conditions . Spontaneous panics also remained improved . The absence of an imipramine effect may reflect the lack of initial dysphoria ( anxiety-depression ) in this sample compared with other studies where drug-effects have been found . The post-treatment superiority ( evident at week 28 ) of patients who had therapist-aided exposure was no longer present at the two-year follow-up ; the others had caught up , presumably because of their self-exposure homework It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse . This study further explores the relationship between relapse and duration of imipramine treatment in this population . Fifty-one patients , all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and r and omized to double-blind maintenance or placebo substitution , discontinued imipramine treatment eventually and were followed over a 12-month risk period : 27 during first year placebo substitution , 7 after 12 months of imipramine maintenance in placebo substitution , and 17 after variable duration s of imipramine maintenance in open discontinuation . There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation . Duration of imipramine treatment , the method of discontinuation ( open versus placebo substitution ) , or any of the 9 variables from the demographic , clinical , and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse . The rate of relapse after only 6 months of treatment ( 10 out of 27 , 37 % ) was identical to the rate of relapse after 12 to 30 months of treatment ( 9 out of 24 , 37.5 % ) . The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients . Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction CONTEXT Panic disorder ( PD ) may be treated with drugs , psychosocial intervention , or both , but the relative and combined efficacies have not been evaluated in an unbiased fashion . OBJECTIVE To evaluate whether drug and psychosocial therapies for PD are each more effective than placebo , whether one treatment is more effective than the other , and whether combined therapy is more effective than either therapy alone . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted in 4 anxiety research clinics from May 1991 to April 1998 . PATIENTS A total of 312 patients with PD were included in the analysis . INTERVENTIONS Patients were r and omly assigned to receive imipramine , up to 300 mg/d , only ( n=83 ) ; cognitive-behavioral therapy ( CBT ) only ( n=77 ) ; placebo only ( n=24 ) ; CBT plus imipramine ( n=65 ) ; or CBT plus placebo ( n=63 ) . Patients were treated weekly for 3 months ( acute phase ) ; responders were then seen monthly for 6 months ( maintenance phase ) and then followed up for 6 months after treatment discontinuation . MAIN OUTCOME MEASURES Treatment response based on the Panic Disorder Severity Scale ( PDSS ) and the Clinical Global Impression Scale ( CGI ) by treatment group . RESULTS Both imipramine and CBT were significantly superior to placebo for the acute treatment phase as assessed by the PDSS ( response rates for the intent-to-treat [ ITT ] analysis , 45.8 % , 48.7 % , and 21.7 % ; P=.05 and P=.03 , respectively ) , but were not significantly different for the CGI ( 48 . 2 % , 53.9 % , and 37.5 % , respectively ) . After 6 months of maintenance , imipramine and CBT were significantly more effective than placebo for both the PDSS ( response rates , 37.8 % , 39.5 % , and 13.0 % , respectively ; P=.02 for both ) and the CGI ( 37.8 % , 42.1 % , and 13.0 % , respectively ) . Among responders , imipramine produced a response of higher quality . The acute response rate for the combined treatment was 60.3 % for the PDSS and 64.1 % for the CGI ; neither was significantly different from the other groups . The 6-month maintenance response rate for combined therapy was 57.1 % for the PDSS ( P=.04 vs CBT alone and P=.03 vs imipramine alone ) and 56.3 % for the CGI ( P=.03 vs imipramine alone ) , but not significantly better than CBT plus placebo in either analysis . Six months after treatment discontinuation , in the ITT analysis CGI response rates were 41.0 % for CBT plus placebo , 31.9 % for CBT alone , 19.7 % for imipramine alone , 13 % for placebo , and 26.3 % for CBT combined with imipramine . CONCLUSIONS Combining imipramine and CBT appeared to confer limited advantage acutely but more substantial advantage by the end of maintenance . Each treatment worked well immediately following treatment and during maintenance ; CBT appeared durable in follow-up . JAMA . 2000;283:2529 - In a double-blind , placebo-controlled trial comparing  alprazolam and imipramine for panic disorder  , serum analysis revealed that a substantial proportion of the patients took explicitly prohibited anxiolytic medication . Excluding these patients changed the results Five years after treatment in a controlled trial , in which all had received self-exposure homework , a group of 40 agoraphobic out patients retained marked improvement in agoraphobia , mood , and free-floating anxiety . Frequency of spontaneous panics decreased as much in those who had placebo and self-exposure as in those who received imipramine and self-exposure . Few patients , however , were completely well at 5 years and over half had received further treatment for agoraphobia during the follow-up . Patients who were still highly phobic at the end of the clinical trial were more often prescribed psychotropic medication during follow-up and remained phobic at 5 years . Phobic improvement had generalized more in those patients with very low than in those with moderate pretreatment Hamilton depression scores . Frequency of initial spontaneous panics did not predict outcome . Improvement in agoraphobia was associated with improved marital adjustment . Those who began with the best marital , work , and social adjustment were more improved in their phobias 5 years later Selective serotonin re-uptake inhibitors ( SSRIs ) and cognitive behavioral therapies ( CBTs ) are both considered as first-line treatments for panic disorder , but the advantages of a combined therapy have yet to be definitively demonstrated . We evaluated in this pilot study the effects of combining SSRIs ( vs. a placebo ) with a very brief form of cognitive-behavioral therapy provided to all participants . Thirty-three subjects with DSM-IV panic disorder , with or without agoraphobia , were r and omized to receive either paroxetine or a placebo with flexible dosing ( 10 - 50 mg/day ) . Medication visits were brief ( 15 min ) , infrequent ( 6 in total ) and non-directive . An expert cognitive-behavior therapist administered one initial 45-min session and one subsequent 30-min session of very brief CBT ( vbCBT ) at weeks 5 and 7 , respectively . Sessions were supplemented with educational and directive reading material s. Patients in both groups ( i.e. vbCBT+paroxetine ; vbCBT+placebo ) improved similarly and substantially on most measures during the 10 weeks of acute treatment . At week 10 , the proportion of panic-free patients was significantly higher in the paroxetine-treated group than in the placebo group ( 80 vs. 25 % ; P<0.007 ) , as was the proportion of subjects who rated themselves as ' very much improved ' at week 10 ( 60 vs. 13 % ; P<0.017 ) . These findings point to the need for additional studies to confirm the effectiveness of very brief forms of CBT , and to document the circumstances in which combined treatment with an SSRI would be warranted Summary Twenty-seven agoraphobic out patients received eight sessions of flooding in fantasy with anxiety , flooding in fantasy with intravenous Brevital , or an attention-control procedure . Results on subjective rating scales provide some support for the hypothesis that agoraphobic clients benefit more from experiencing anxiety during flooding . No significant differences were found on a behavioral task . These results differ from previous findings where diazepam ( Valium ) was found to have no effect on outcome or to enhance improvement in agoraphobics . The discrepancy may be due to differences in the procedure Seventy-six white agoraphobic women , 21 to 45 years old , were treated with combined group exposure in vivo and imipramine or placebo in a r and omized double-blind study . A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement . However , imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement : primary phobia , spontaneous panic , and global improvement . There was a negative correlation between depression and outcome ; ie , the more depressed patients fared worse on several outcome measures than those who were less depressed . A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment , but no significant difference between the two groups at the completion of therapy BACKGROUND A recent review suggested an association between using unpublished scales in clinical trials and finding significant results . AIMS To determine whether such an association existed in schizophrenia trials . METHOD Three hundred trials were r and omly selected from the Cochrane Schizophrenia Group 's Register . All comparisons between treatment groups and control groups using rating scales  were identified . The publication status of each scale was determined and cl aims of a significant treatment effect were recorded . RESULTS Trials were more likely to report that a treatment was superior to control when an unpublished scale was used to make the comparison ( relative risk 1.37 ( 95 % CI 1.12 - 1.68 ) ) . This effect increased when a ' gold-st and ard ' definition of treatment superiority was applied ( RR 1.94 ( 95 % CI 1.35 - 2.79 ) ) . In non-pharmacological trials , one-third of ' gold-st and ard ' cl aims of treatment superiority would not have been made if published scales had been used . CONCLUSIONS Unpublished scales are a source of bias in schizophrenia trials Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication . In this study , 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks . The medication was tapered over a period of four weeks , and patients were observed for another two weeks after all medication was discontinued . Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study . After improvement in the active treatment period , the alprazolam-treated group had significant relapse between the first and last week of taper . However , during the second postdiscontinuation week , outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper . Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13 % reported a rebound of anxiety on the Hamilton Anxiety Scale . No serious or life-threatening withdrawal symptoms were reported , but distinct , transient , mild to moderate withdrawal syndrome occurred in 35 % of the alprazolam-treated group and in none of the placebo-treated group . The coexistence of symptom rebound and a withdrawal syndrome occurred in 10 % of the alprazolam-treated group , but both subsided by the end of the second week without alprazolam . We recommend that patients with panic disorder be treated for a longer period , at least six months , and that medication be tapered over a more prolonged period , at least eight weeks , especially where high doses are employed Ninety-three patients with panic disorder and mild or no agoraphobia were treated for their panic disorder by using either 11 sessions of individual cognitive-behavior therapy or imipramine . Before and after treatment , their panic disorder symptomatology was assessed , and a self-report measure was administered to measure personality disorder characteristics [ Klein et al. , 1990 : Wisconsin Personality Disorders Inventory ] . In addition , some patients received this personality assessment  again after six monthly maintenance sessions . Both treatments were equally effective in reducing panic disorder symptomatology , and both treatments had a positive influence on personality disorder characteristics . Personality disorder characteristics did not predict treatment outcome in either group . The implication s of the findings for the assessment of personality and the treatment of panic disorder are discussed BACKGROUND In the treatment of panic disorder with agoraphobia  , the efficacy of pharmacological , psychological and combined treatments has been established . Unanswered questions concern the relative efficacy of such treatments . AIMS To demonstrate that moclobemide and cognitive-behavioural therapy ( CBT ) are effective singly and more effective in combination . METHOD Fifty-five patients were r and omly assigned to an eight-week treatment of : moclobemide plus CBT ; moclobemide plus clinical management ( ' psychological placebo ' ) ; placebo plus CBT ; or placebo plus clinical management . RESULTS Comparisons between treatments revealed strong effects for CBT . Moclobemide with clinical management was not superior to placebo . The combination of moclobemide with CBT did not yield significantly better short-term results than CBI with placebo . The CBT results remained stable during a six-month follow-up , although a substantial proportion of patients treated with placebo plus CBT needed additional treatment . CONCLUSIONS CBT was highly effective in the treatment of panic disorder with agoraphobia and reduced agoraphobia to levels that were comparable to those of non- clinical controls OBJECTIVE The purpose of this comparative outcome study was to investigate whether the effects of exposure in vivo treatment for panic disorder with agoraphobia could be enhanced by adding interventions specifically for panic attacks before the start of exposure treatment . The additional effect of two types of treatment for panic attacks -- pharmacological ( fluvoxamine ) and psychological ( repeated hyperventilation provocations and respiratory training)--was examined . Thus , the combined treatment of panic interventions with exposure in vivo could be compared to exposure in vivo alone . METHOD Ninety-six patients were r and omly assigned to four treatment conditions : double-blind , placebo-controlled fluvoxamine followed by exposure in vivo , psychological panic management followed by exposure , and exposure in vivo alone . Outcome was assessed by self-report measures , a st and ardized multitask behavioral avoidance test , and continuous monitoring of panic attacks .  Seventy-six patients completed the study . RESULTS All four treatments were effective and result ed in a significant decrease of agoraphobic avoidance . Moreover , the combination of fluvoxamine and exposure in vivo demonstrated efficacy superior to that of the other treatments and had twice as large an effect size ( difference between pre- and posttreatment scores ) on self-reported agoraphobic avoidance . The other treatments did not differ among each other in effectiveness . CONCLUSIONS Results of the study indicate that the short-term outcome of exposure in vivo treatment can be enhanced by adding fluvoxamine treatment . Psychological panic management combined with exposure was not superior to exposure alone of equal duration BACKGROUND This study compared the efficacy and tolerability of paroxetine with placebo in the treatment of panic disorder . METHOD After three weeks of placebo , patients received 12 weeks of treatment with paroxetine ( 20 , 40 , or 60 mg ) or placebo , and finally two weeks of placebo . Dosages were adjusted according to efficacy and tolerability . St and ardised cognitive therapy was given to all patients . The primary measure of outcome was reduction in the number of panic attacks . RESULTS Analysis of the results showed statistically significant differences in favour of paroxetine between the two treatment groups in two out of the three primary measures of outcome , i.e. 50 % reduction in total number of panic attacks and number of panic attacks reduced to one or zero over the study period . For the third measure of outcome , the mean change in the total number of attacks from baseline , there was a positive trend in favour of paroxetine . The results of the primary measures of outcome were strongly supported by the results of the secondary efficacy measures of outcome . In addition , paroxetine , at all doses , was very well tolerated . CONCLUSION Paroxetine plus cognitive therapy was significantly more effective than placebo plus cognitive therapy in the treatment of panic disorder BACKGROUND The aim of this study was to analyze the impact of pretreatment characteristics and personality disorders on the onset of response in the treatment of panic disorder . METHODS The data of 73 out- patients with panic disorder who had completed at least 6 weeks of a r and omized trial of 24 weeks of either paroxetine only or paroxetine combined with cognitive group-therapy  were analyzed in a Cox proportional hazards model . RESULTS The likelihood of having responded to treatment ( defined by a CGI rating of improvement ) was more than twice as high for patients without a personality disorder or social phobia than for Patients with a personality disorder or social phobia . CONCLUSIONS We suggest that patients with these characteristics do benefit from prolonged treatment , and they may profit from an additional treatment focused on social anxiety
target: After the acute phase treatment , as long as the drug was continued , the superiority of the combination over either monotherapy appeared to persist .
background: BACKGROUND Panic disorder can be treated with pharmacotherapy , psychotherapy or in combination , but the relative merits of combined therapy have not been well established .
  OBJECTIVES To review evidence concerning short- and long-term advantages and disadvantages of combined psychotherapy plus antidepressant treatment for panic disorder with or without agoraphobia , in comparison with either therapy alone .