title: Maintenance drug therapy of panic disorder. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? Cardiovascular and Symptomatic Reduction Effects of Alprazolam and Imipramine in Patients with Panic Disorder: Results of a Double-Blind, Placebo-Controlled Trial Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial. Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks A double‐blind comparison of zimeldine, imipramine and placebo Effect of fluvoxamine on panic disorder. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. Serotonergic anxiolytics in the treatment of panic disorder: a controlled study with buspirone. Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. The Galway Study of Panic Disorder. I: Clomipramine and lofepramine in DSM III-R panic disorder: a placebo controlled trial. Response of panic disorder to fixed doses of alprazolam or imipramine. Sertraline in the treatment of panic disorder: a double-blind multicenter trial. Chronology of panic and avoidance, age of onset in panic disorder, and prediction of treatment response Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Patients with panic disorder unaccompanied by depression improve with alprazolam and imipramine treatment. Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. A multiple imputation strategy for clinical trials with truncation of patient data. Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Global measures of outcome in a controlled comparison of pharmacological and psychological treatment of panic disorder and agoraphobia in primary care. A double-blind placebo-controlled trial comparing fluvoxamine and imipramine in the treatment of panic disorder with or without agoraphobia. Adverse effects associated with the short-term treatment of panic disorder with imipramine, alprazolam or placebo How "blind" are double-blind studies? Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomised, placebo-controlled trial. Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study Prevalence of psychiatric disorder in the general population: results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin Single data extraction generated more errors than double data extraction in systematic reviews. A placebo-controlled, randomized withdrawal study of sertraline for panic disorder in Japan Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. Consistencies and discrepancies in self- and observer-rated anxiety scales Citalopram controls phobic symptoms in patients with panic disorder: randomized controlled trial. The sequence of improvement of the symptoms encountered in patients with panic disorder. Comparison of aerobic exercise, clomipramine, and placebo in the treatment of panic disorder. Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder. Imipramine dose-response relationship in panic disorder with agoraphobia. Preliminary findings. Self- and observer assessment in anxiolytic drug trials: A comparison of their validity Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Emotion-focused psychotherapy for patients with panic disorder. Interactive Model of Therapeutic Response in Panic Disorder: Moclobemide, a Case in Point Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Long-term follow-up after a drug trial for panic disorder. The use of the Panic and Agoraphobia Scale (P & A) in a controlled clinical trial. Changes in Appetite and Weight during the Pharmacological Treatment of Patients with Panic Disorder * A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper. Alprazolam, imipramine and placebo treatment of panic disorder: predicting therapeutic response Treatment of Panic Disorder in Older Adults: A Pilot Study Comparison of Alprazolam, Imipramine, and Placebo Characteristics of panic disorder patients responding to placebo Comparative effects of low and high doses of clomipramine and placebo in panic disorder: a double‐blind controlled study A comparison of medication side effect reports by panic disorder patients with and without concomitant cognitive behavior therapy. Clomipramine in the treatment of agoraphobic inpatients resistant to behavioral therapy. The effect of citalopram in panic disorder. A 15-year follow-up study of patients with panic disorder. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder. Surreptitious drug use by patients in a panic disorder study. A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder. Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Cross-National Collaborative Panic Study, Second Phase Investigators. Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Minnesota Multiphasic Personality Inventory correlates of panic disorder with agoraphobia: changes with treatment. Imipramine-induced jitteriness and decreased serum iron levels. [Comparison of the effect of alprazolam, imipramine and placebo in the treatment of panic disorders in Cali, Colombia]. Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients A double-blind, placebo-controlled, parallel-group, flexible-dose study of venlafaxine extended release capsules in adult outpatients with panic disorder. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder? Is Buspirone Effective for Panic Disorder? A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder. Drug treatment of panic disorder: early response to treatment as a predictor of final outcome Sertraline in the treatment of panic disorder. A multi-site, double-blind, placebo-controlled, fixed-dose investigation. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study.
abstract: 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 r and omized 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 CONTEXT Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions . OBJECTIVE To explore whether the association between funding and conclusions in r and omized drug trials reflects treatment effects or adverse events . DESIGN Observational study of 370 r and omized drug trials included in meta-analyses from Cochrane review s selected from the Cochrane Library , May 2001 . From a r and om sample of 167 Cochrane review s , 25 contained eligible meta-analyses ( assessed a binary outcome ; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment ) . The primary binary outcome from each meta- analysis was considered the primary outcome for all trials included in each meta- analysis . The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect , adverse events , and additional confounding factors ( method ological quality , control intervention , sample size , publication year , and place of publication ) . MAIN OUTCOME MEASURE Conclusions in trials , classified into whether the experimental drug was recommended as the treatment of choice or not . RESULTS The experimental drug was recommended as treatment of choice in 16 % of trials funded by nonprofit organizations , 30 % of trials not reporting funding , 35 % of trials funded by both nonprofit and for-profit organizations , and 51 % of trials funded by for-profit organizations ( P<.001 ; chi2 test ) . Logistic regression analyses indicated that funding , treatment effect , and double blinding were the only significant predictors of conclusions . Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice ( odds ratio , 5.3 ; 95 % confidence interval , 2.0 - 14.4 ) compared with trials funded by nonprofit organizations . This association did not appear to reflect treatment effect or adverse events . CONCLUSIONS Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results . Readers should carefully evaluate whether conclusions in r and omized trials are supported by data Seventy-nine patients with panic disorder were r and omized to an 8-week double-blind treatment with alprazolam , imipramine , or placebo . Patients kept daily records of panic attacks , activity , anxiety , sleep , and medication use . Weekly measures of anxiety , depression , somatic symptoms , fears , avoidance , disability , and improvement were obtained . All patients underwent a symptom-limited exercise treadmill and other cardiovascular measures . By physician and patient global assessment , patients receiving alprazolam or imipramine were significantly better than patients on placebo . The alprazolam effects were apparent by week 1 ; the imipramine effects by week 4 . All groups showed significant reductions in anxiety , depression , somatic measures , and panic attack frequency . At 8 weeks , patients in the alprazolam group reported significantly less fear than patients in the other two groups . Subjects in the imipramine group showed a significant increase in heart rate and blood pressure BACKGROUND The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder . We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder . METHODS One hundred seventy-six nondepressed out patients with panic disorder , with or without agoraphobia , from 10 sites followed identical protocol s that used a flexible-dose design . After 2 weeks of single-blind placebo , patients were r and omly assigned to 10 weeks of double-blind , flexible-dose treatment with either sertraline hydrochloride ( 50 - 200 mg/d ) or placebo . RESULTS Sertraline-treated patients exhibited significantly greater improvement ( P=.01 ) at end point than did patients treated with placebo for the primary outcome variable , panic attack frequency . Significant differences between groups were also evident for clinician and patient assessment s of improvement as measured by the Clinical Global Impression Improvement ( P=.01 ) and Severity ( P=.009 ) Scales , Panic Disorder Severity Scale ratings ( P=.03 ) , high end-state function assessment ( P=.03 ) , Patient Global Evaluation rating ( P=.01 ) , and quality of life scores ( P=.003 ) . Adverse events , generally characterized as either mild or moderate , were not significantly different in overall incidence between the sertraline and placebo groups . CONCLUSION Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder ABSTRACT A double‐blind clinical trial of zimeldine , a potent inhibitor of central serotonin reuptake , versus imipramine and placebo was carried out on 44 patients suffering from agoraphobia with panic attacks .  Zimeldine was a superior treatment on all rating scales other than a global rating scale which did not reach statistically significant superiority . Imipramine was not shown to be superior to placebo . The implication s of these results for further research on the underlying pathophysiology of agoraphobia with panic attacks are discussed 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 BACKGROUND Escitalopram , the therapeutically active isomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram , has shown significant anxiolytic effects in placebo-controlled clinical trials of social anxiety disorder , generalized anxiety disorder , and anxiety symptoms associated with major depression . This study evaluated the safety and efficacy of escitalopram in out patients diagnosed with panic disorder . METHOD Male and female out patients between 18 and 80 years of age meeting DSM-IV criteria for panic disorder , with or without agoraphobia , were r and omly assigned to 10 weeks of double-blind treatment with escitalopram , citalopram , or placebo in a study conducted from September 1999 to July 2001 . The primary measure of efficacy was panic attack frequency at week 10 relative to baseline , as assessed by the Modified Sheehan Panic and Anticipatory Anxiety Scale . RESULTS A total of 366 subjects ( 128 escitalopram patients , 119 citalopram patients , and 119 placebo patients ) received at least 1 dose of double-blind treatment . The frequency of panic attacks was statistically significantly improved ( p = .04 ) , and the increase in percentage of patients with zero panic attacks reached borderline significance ( p = .051 ) , in the escitalopram-treated group relative to the placebo-treated group . Both escitalopram and citalopram statistically significantly reduced panic disorder symptoms and severity versus placebo at endpoint ( p < /=.05 ) , as measured by the Panic and Agoraphobia Scale total score , the Clinical Global Impressions scale , the Patient Global Evaluation , and the Quality of Life Enjoyment and Satisfaction Question naire . Treatment with escitalopram was safe and well tolerated , with a similar incidence of the most common adverse events for the escitalopram and placebo groups . The rate of discontinuation for adverse events was 6.3 % for escitalopram , 8.4 % for citalopram , and 7.6 % for placebo . CONCLUSION Escitalopram is efficacious , safe , and well tolerated in the treatment of panic disorder The efficacy of buspirone for panic disorder was tested in 60 patients who met Diagnostic and Statistical Manual of Mental Disorders ( 3rd ed . ) criteria for panic disorder or agoraphobia with panic attacks . Patients were r and omly assigned to treatment with buspirone ( mean dose 29.5 mg/day ) , imipramine ( mean dose 140 mg/day ) , or placebo , and treated for 8 weeks after a 4- to 7-day placebo lead-in period . Patients with 4 or fewer attacks per month and those without attacks at the baseline visit were excluded from panic frequency comparisons . Both buspirone and imipramine tended to be better than placebo on total number of panic attacks , global psychopathology , and the Hamilton Anxiety rating scale , but end point differences among treatments were not statistically significant . At the end of the study , 25 % of the buspirone patients were panic-free , as were 7 % of the imipramine patients and 14 % of the placebo patients ; again , these differences were not statistically significant . The results of this study were inconclusive , partly because of the relatively small number of patients ( 10 - 11 ) completing the study in each treatment group , and partly because of a robust placebo response in this population . Possible reasons for this high placebo response are discussed , as well as suggestions for changes in study design for future studies 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 r and om 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 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 This paper reports the results of a double-blind comparison of fixed daily doses of 6 mg of alprazolam , 2 mg of alprazolam , 225 mg of imipramine , and placebo for 8 weeks in 81 patients who met DSM-III criteria for panic disorder with or without agoraphobia . Final scores on eight clinical measures were analyzed from all patients who entered the study and from the subset who completed at least 4 weeks of treatment . Eighty-six percent of the high-dose alprazolam patients completed the study . Only 50 % of the imipramine patients completed 8 weeks of treatment , apparently because of activation early in treatment and slow onset of therapeutic effects . This study confirmed the therapeutic effectiveness and safety of alprazolam  , especially at the higher dose , in panic disorder . It also confirmed the therapeutic effectiveness of imipramine among patients who tolerated the drug . It suggested the usefulness of a flexible , individual approach to dose escalation with imipramine . Method ologically the study underscored the importance of using multiple approaches to the analysis of clinical data from therapeutic trials of psychotropic agents with complex effects that may contribute to patients ' premature termination OBJECTIVE This study determined the efficacy and safety of sertraline in the treatment of patients with panic disorder . METHOD The study was a r and omized , double-blind , parallel-group , flexible-dose comparison of sertraline and placebo in out patients with a DSM-III-R diagnosis of panic disorder with or without agoraphobia . After a 2-week single-blind placebo lead-in , 168 patients entered a 10-week double-blind phase in which they were r and omly assigned to treatment with either sertraline or placebo . RESULTS Sertraline was significantly more effective than placebo in decreasing the number of full and limited-symptom panic attacks . Among patients who completed the study , the mean number of panic attacks per week dropped by 88 % in the sertraline-treated patients and 53 % in the placebo-treated patients . Sertraline-treated patients also had significantly more improvement than placebo-treated patients in scores on the Quality of Life Enjoyment and Satisfaction Question naire , patient global evaluation , and Clinical Global Impression severity of illness and global improvement scales . Overall , patients tolerated sertraline well , and only 9 % terminated treatment because of side effects . CONCLUSIONS Sertraline is an effective and well-tolerated treatment for patients with panic disorder Summary The relevance of the chronology between panic disorder and avoidance behavior and of an early , medium or late onset of panic disorder was tested . Groups from the sample of the cross-national collaborative panic study ( CNCPS ) were compared for differences in basic characteristics and for the ability to predict treatment response . Patients who developed avoidance behavior before the full syndrome of panic disorder had less often a full agoraphobia but were not different in their response to treatment . Patients with an early onset of panic disorder suffered more often from agoraphobia . The treatment response was similar in the groups with early , medium or late onset of panic disorder . Neither the chronology between panic disorder and avoidance behavior nor the age of onset of panic disorder predicted outcome in short-term treatment with alprazolam or impiramine OBJECTIVE Recently , pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available . The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines . METHOD A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project , a prospect i ve longitudinal study of anxiety disorders . These patients were interviewed over the course of 10 years to examine their use of psychotropic medications . RESULTS Despite efforts aim ed at increasing the use of selective serotonin reuptake inhibitors ( SSRIs ) in patients with panic disorder ( e.g. , APA 's practice guideline for panic disorder , Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder ) , only a modest increase in their use was found . Treatment patterns for psychotropic drugs  appear to have remained stable over the past decade , with benzodiazepines being the most commonly used medication for panic disorder . In comparison , SSRI use throughout the follow-up period has remained low . Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine , nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly . CONCLUSIONS These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed . Factors potentially associated with promoting and ignoring treatment recommendations are discussed 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 Patients with panic disorder ( N = 1168 ) were enrolled in a multicenter , 8-week , double-blind clinical trial of imipramine , alprazolam , and placebo to analyze whether the effectiveness of these agents is dependent on the depressive/dysphoric symptomatology which often coexists in panic disorder patients . In addition to analyses performed on the whole sample of patients , the authors conducted analyses on a sub sample ( N = 312 ) defined by multiple criteria to ensure the absence of depression and dysphoria . In both the overall sample and the nondepressed sub sample , the clinical response to imipramine or alprazolam was found to be independent of the presence of depression or dysphoria . In panic disorder patients for whom pharmacotherapy is being considered as treatment , the absence of depression is apparently not a contraindication BACKGROUND The Panic Disorder Severity Scale ( PDSS ) is promising to be a st and ard global rating scale for panic disorder . In order for a clinical scale to be useful , we need a guideline for interpreting its scores and their changes , and for defining clinical change points such as response and remission . METHODS We used individual patient data from two large r and omized controlled trials of panic disorder ( total n=568 ) . Study participants were administered the  PDSS and the Clinical Global Impression (CGI)--Severity and --Improvement .  We applied equipercentile linking technique to draw correspondences between PDSS and CGI-Severity , numeric changes in PDSS and CGI-Improvement , and percent changes in PDSS and CGI-Improvement . RESULTS The interpretation of the PDSS total score differed according to the presence or absence of agoraphobia . When the patients were not agoraphobic , score ranges 0 - 1 corresponded with " Normal , " 2 - 5 with " Borderline , " 6 - 9 with " Slightly ill , " 10 - 13 with " Moderately ill , " and 14 and above with " Markedly ill . " When the patients were agoraphobic , score ranges 3 - 7 meant " Borderline ill , " 8 - 10 " Slightly ill , " 11 - 15 " Moderately ill , " and 16 and above " Markedly ill . " The relationship between PDSS change and CGI-Improvement was more linear when measured as percentile change than as numeric changes , and was indistinguishable for those with or without agoraphobia . The decrease by 75 - 100 % was considered " Very much improved , " that by 40 - 74 % " Much improved , " and that by 10 - 39 % " Minimally improved . " CONCLUSION We propose that " remission " of panic disorder be defined by PDSS scores of five or less and its " response " by 40 % or greater reduction Seventy-five out patients with moderate to severe panic disorder were r and omly 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 Clinical trials of drug treatments for psychiatric disorders commonly employ the parallel groups , placebo-controlled , repeated measure r and omized comparison . When patients stop adhering to their originally assigned treatment , investigators often ab and on data collection . Thus , non-adherence produces a monotone pattern of unit-level missing data , disabling the analysis by intent-to-treat . We propose an approach based on multiple imputation of the missing responses , using the approximate Bayesian bootstrap to draw ignorable repeated imputations from the posterior predictive distribution of the missing data , stratifying by a balancing score for the observed responses prior to withdrawal . We apply the method and some variations to data from a large r and omized trial of treatments for panic disorder , and compare the results to those obtained by the original analysis that used the st and ard ( endpoint ) method 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 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 This study compared the efficacy , tolerability , and safety of fluvoxamine , imipramine , and placebo in the treatment of panic disorder with or without agoraphobia . Fifty-four out patients participated in the r and omized , double-blind trial as part of a multicenter trial . After meeting inclusion criteria and completing screening requirements ( e.g. , laboratory testing , electrocardiogram , physical examination ) , patients were entered in a single-blind placebo washout phase . They were then r and omized to either fluvoxamine , imipramine , or placebo . Measurements completed at each visit included the number and severity of panic attacks per week , the Sheehan Panic and Anticipatory Anxiety Scale , and the Clinical Global Impressions , and others . Results show that fluvoxamine is more effective than placebo and as effective as imipramine in reducing spontaneous panic attacks in moderate to severe panic disorder . However , starting doses of fluvoxamine and imipramine should be low to minimize untoward side effects ( such as insomnia and agitation ) and maintain compliance Side effects play a significant role in the selection of drugs to be used in panic disorder/agoraphobia whose polyphobic symptomatology often includes a suspiciousness about taking drugs and a fear of undesired side effects which may lead to the refusal of treatment . The safety , side effects and patients ' acceptance of alprazolam and imipramine versus placebo were evaluated in 1168 subjects with panic disorder/agoraphobia who had been enrolled in the second phase of the Upjohn World Wide Panic Study . Side effects that worsened over baseline to a greater extent with alprazolam than with imipramine and placebo were sedation , fatigue/weakness , memory problems , ataxia and slurred speech . In the imipramine group blurred vision , tachycardia/palpitations , insomnia , sleep disturbance , excitement/nervousness , malaise , dizziness/faintness , headache , nausea/vomiting and decrease in appetite were worse than in the other groups . In the placebo group the anxious symptoms were most prominent . The highest level of compliance was shown in the alprazolam-treated group and the lowest in the placebo-treated group . Strong predictors of side effects were not observed . If a side effect profile is known , it will be easier for a clinician to choose the right drug and the appropriate management by taking into account compliance , safety and efficacy in each patient under treatment . Further information about side effects in long-term maintenance treatment would be of great clinical pertinence in ensuring safety and enhancing patients ' quality of life Psychopharmacological studies usually attempt to eliminate " nonspecific " influences on outcome by double-blind design s. In a r and omized , double-blind comparison of alprazolam , imipramine , and placebo , the great majority of panic disorder patients ( N = 59 ) and their physicians were able to rate accurately whether active drug or placebo had been given . Moreover , physicians could distinguish between the two types of active drugs . Inasmuch as correct rating was possible halfway through treatment , concerns about the internal validity of the double-blind strategy arise BACKGROUND Although serotonin reuptake inhibitors are effective in panic disorder , questions concerning whether doses associated with antidepressant efficacy are also effective for panic disorder remain . AIMS To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks . METHOD Patients with panic disorder were r and omised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily . The trial lasted 12 weeks , but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily . RESULTS Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point . CONCLUSIONS Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder . Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases As part of the cross‐national collaborative panic study , a double‐blind comparison of alprazolam , imipramine and placebo was performed in Sc and inavian out patients with panic disorder according to DSM‐III ; 41 patients were r and omly allocated to each drug . Doses were increased for 3 weeks to an average of about 6 mg alprazolam , 150 mg imipramine and a corresponding number of placebo capsules , which were then given for 5 weeks . No more than supportive psychotherapy was given . Key symptoms were rated weekly . The drugs were tapered for 4 or 8 weeks and the patients were followed up for 6 months . Compliance at 3 weeks was 95 % for alprazolam , 83 % for imipramine and 88 % for placebo ; at 8 weeks 95 % for alprazolam , 73 % for imipramine and 46 % for placebo . At 3 weeks plasma determination showed that the proportion taking  diazepam  outside the protocol was 0 % for alprazolam , 19 % for imipramine and 31 % for placebo ; at 8 weeks the corresponding proportions were 3 % , 11 % and 16 % . Intention‐to‐treat analysis showed that freedom from panic attacks was obtained for 68 % with alprazolam , 61 % with imipramine and 34 % with placebo . Alprazolam was more effective than imipramine and placebo on anticipatory anxiety and phobic symptoms . Globally rated by physicians and patients , about 60 % had complete remission  with alprazolam and imipramine and 30 % on placebo .  At least partial remission was obtained in about 85 % with alprazolam , 70 % with imipramine and 40 % with placebo . Alprazolam  had a more rapid onset of action than imipramine on all symptoms . Side effects were generally mild , with a preponderance of drowsiness  for alprazolam and anticholinergic effects for imipramine . Tapering was uneventful without significant discontinuation phenomena . During taper and follow‐up , several patients in remission relapsed , leaving approximately 30 % patients in complete remission in all groups . To obtain more stable improvement , either long‐term drug treatment or combinations of drug treatment and psychotherapy should be evaluated Abstract This article reports the initial results of a prospect i ve study on the prevalence of  psychiatric disorders in the Dutch population aged 18–64 . The objectives and the design of the study are described elsewhere in this issue . A total of 7076 people were interviewed in person in 1996 . The presence of the following disorders was determined by means of the CIDI : mood disorders , anxiety disorders , eating disorders , schizophrenia and other non-affective psychoses , and substance use disorders . Psychiatric disorders were found to be quite common . Some 41.2 % of the adult population under 65 had experienced at least one DSM-III-R disorder in their lifetime , among them 23.3 % within the preceding year . No gender differences were found in overall morbidity . Depression , anxiety , and alcohol abuse and dependence were most prevalent , and there was a high degree of comorbidity between them . The prevalence rate encountered for schizophrenia was lower ( 0.4 % lifetime ) than generally presumed . A comparison with findings from other countries is made . Relevant determinants of psychiatric morbidity were analysed In order to evaluate serotonin ( 5-HT ) function in panic disorder , a double blind placebo controlled study was conducted with ritanserin , a specific 5-HT2 receptor antagonist , and fluvoxamine , a selective 5-HT reuptake inhibitor , in 60 patients with panic disorder . Patients were treated for 8 weeks with 150 mg fluvoxamine , 20 mg ritanserin or placebo ; these dose levels were reached after 1 week . In addition , as an index of 5-HT function in panic disorder , plasma concentration of β-endorphin , cortisol and 5-hydroxyindolacetic-acid ( 5-HIAA ) were measured . Furthermore , 5-HT uptake in blood platelets was assessed . Noradrenergic function was assessed by measuring plasma MHPG concentration . In addition , plasma melatonin concentration was measured . Treatment with fluvoxamine result ed in a profound reduction in the number of panic attacks , followed by a decrease in avoidance behavior . Treatment with ritanserin appeared to be ineffective . During treatment no significant changes were observed in plasma concentrations of β-endorphin , cortisol , 5-HIAA and MHPG . With respect to 5-HT kinetics in blood platelets , a substantial increase in Km was observed after treatment with fluvoxamine , whereas Vmax decreased . After treatment with fluvoxamine , plasma concentration of melatonin was significantly increased , which suggests that melatonin synthesis is in part under serotonergic control . The findings of the present study do not support the hypothesis that 5-HT2 receptors are supersensitive in patients suffering from panic disorder , but allow no conclusions about the involvement of other 5-HT receptor subtypes BACKGROUND AND OBJECTIVE To conduct a pilot study to compare the frequency of errors that accompany single vs. double data extraction , compare the estimate of treatment effect derived from these methods , and compare the time requirements for these methods . METHODS Review ers were r and omized to the role of data extractor or data verifier , and were blind to the study hypothesis . The frequency of errors associated with each method of data extraction was compared using the McNemar test . The data set for each method was used to calculate an efficacy estimate by each method , using st and ard meta-analytic techniques . The time requirement for each method was compared using a paired t-test . RESULTS Single data extraction result ed in more errors than double data extraction ( relative difference : 21.7 % , P = .019 ) . There was no substantial difference between methods in effect estimates for most outcomes . The average time spent for single data extraction  was less than the average time for double data extraction ( relative difference : 36.1 % , P = .003 ) . CONCLUSION In the case that single data extraction is used in systematic review s , review ers and readers need to be mindful of the possibility for more errors and the potential impact these errors may have on effect estimates The objective of this double-blind , placebo-controlled r and omized withdrawal study was to evaluate the efficacy and safety of sertraline for 8 weeks in treating Japanese patients with DSM-IV panic disorder . Patients ( n=394 ) were initially treated with 8 weeks of open-label sertraline followed by 8 weeks of double-blind treatment with either sertraline ( 50–100 mg/day ) or placebo . Responders during the open-label phase were eligible to be entered into the double-blind phase . Two hundred and forty patients were entered to the double-blind phase and r and omly assigned to receive sertraline ( n=119 ) or placebo ( n=121 ) . On the primary efficacy measure ( relapse ) , there was no significant difference between the two treatment groups ( sertraline 10.1 % ; placebo 13.2 % ) . However , the frequency of panic attacks was significantly ( P=0.012 ) lower for sertraline compared to placebo . The proportion of sertraline-treated patients who met response criteria ( Clinical Global Impression – Improvement Scale score of 1 or 2 ) at the end of double-blind phase treatment was also significantly ( P=0.003 ) higher for sertraline ( 89.9 % ) compared to placebo ( 74.4 % ) . Panic Disorder Severity Scale total score was significantly ( P=0.012 ) lower in the sertraline group compared to the placebo group . Adverse events during acute treatment were consistent with the known adverse event profile of sertraline , and the incidence of adverse events during the double-blind phase treatment was not different between sertraline and placebo OBJECTIVE To assess the efficacy and tolerability of controlled-release paroxetine ( paroxetine CR ) in the treatment of adults with panic disorder . METHOD  Paroxetine CR ( 25 - 75 mg/day ; N = 444 ) was compared with  placebo ( N = 445 ) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical , double-blind , placebo-controlled , 10-week clinical trials that were pooled for analysis . RESULTS Paroxetine CR was statistically superior to placebo in the primary outcome measure , percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint . Of the total population that completed or prematurely terminated treatment , 63 % and 53 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free during the final 2 weeks ( p < .005 ; odds ratio [ OR ] = 1.63 ; 95 % CI = 1.21 to 2.19 ) . For week 10 completers ( 72 % of total ) , 73 % and 60 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free at week 10 ( p < .005 ; OR = 2.11 ; 95 % CI = 1.45 to 3.07 ) . Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale . Adverse events leading to study withdrawal were minimal and occurred in 11 % of the paroxetine CR group and 6 % of the placebo group . Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study . There were no unexpected adverse events , and serious adverse events were uncommon ( 10 [ 2.3 % ] of the 444 patients treated with paroxetine CR vs. 8 [ 1.8 % ] of the 445 patients treated with placebo ) . CONCLUSION Paroxetine CR is an effective and well-tolerated treatment for panic disorder . Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events Summary The Marks-Sheehan anxiety scales are the only scales where self-ratings and observer ratings are perfectly matched by the number , the content and the scaling of the items . Therefore these scales are an excellent tool to investigate the compatibility and to study different structures in self- and observer ratings . This was done by using the data material on the Marks-Sheehan scales of the Cross National Collaborative Panic Study . In this study 1168 out patients who met the DSM-III criteria for panic disorder were r and omly allocated either to alprazolam , imipramine or placebo treatment . Our results show that the Marks-Sheehan scales are highly comparable to other established rating scales . Both scales have a similar stable and consistent factor pattern for somatic symptoms but not for psychic symptoms of anxiety . Our results provide empirical evidence that the low consistencies between self- and observer ratings reported so far can be improved by using a rating scale which matches up item by item for self- and observer ratings . However , other sources of disagreement can only be solved by more elaborated item descriptions and training of patients as well as raters to obtain a better compatibility between self- and observer rating scales OBJECTIVE To examine the effects of long-term treatment with citalopram or clomipramine on subjective phobic symptoms in patients with panic disorder . DESIGN Double-blind , parallel-group , five-arm study . PATIENTS Patients aged 18 to 65 years with panic disorder ( DMS-III-R diagnosis ) and with no major depressive symptoms . INTERVENTIONS Four hundred and seventy-five patients were r and omized to 8 weeks of treatment with either citalopram ( 10 to 15 mg per day ; 20 to 30 mg per day ; or 40 to 60 mg per day ) , clomipramine ( 60 to 90 mg per day ) or placebo . Two hundred and seventy-nine patients continued treatment after the 8-week acute phase . OUTCOME MEASURES Phobic symptoms were assessed using the Phobia Scale and the Symptom Checklist 's ( SCL-90 ) phobia-related factors . RESULTS At all dosages , citalopram was more efficacious than placebo , with 20 to 30 mg generally being the most effective dosage . Citalopram ( 20 to 30 mg ) generally decreased phobic symptoms significantly more than placebo after Month 3 . Interpersonal sensitivity decreased when measured on the respective SCL-90 sub-scale . Alleviation of phobic symptoms generally continued to increase towards the end of the treatment . The effect of clomipramine was not as consistent . CONCLUSIONS All active treatment groups , especially the group receiving 20 to 30 mg per day of citalopram , effectively controlled phobic symptoms in patients with panic disorder . Long-term treatment with citalopram further decreased phobic symptoms Patients who meet DSM-III-R criteria for a diagnosis of panic disorder often show a complex mixture of psychopathological symptoms , including panic attacks ( spontaneous and situational ) , anxiety ( anticipatory and generalized ) , phobias ( fear and avoidance ) , depression/dysphoria , and social and occupational disability . Various theories about the pathogenesis of these symptoms have been advanced that focus on a given symptom ( e.g. , panic , phobia ) being primary in these disorders , with concurrent symptoms seen as epiphenomena or as secondary and reactive to a core symptom . This study , conducted on a large sample of panic disorder patients ( N = 1,168 ) , examines the temporal sequential pattern of symptom improvement in these patients , and explores how these relationships relate to various pathogenic theories . Our multiple analyses , when considered together , tend not to support any pathogenic theory that views a given symptom as being central to the overall disorder ; our findings have obvious implication s for theoreticians and clinicians interested in the study and treatment of panic and anxiety disorders OBJECTIVE The purpose of this study was to compare the therapeutic effect of exercise for patients with panic disorder to a drug treatment of proven efficacy and to placebo . METHOD Forty-six out patients suffering from moderate to severe panic disorder with or without agoraphobia ( DSM-III-R criteria ) were r and omly assigned to a 10-week treatment protocol of regular aerobic exercise ( running ) , clomipramine ( 112.5 mg/day ) , or placebo pills . RESULTS The dropout rate was 31 % for the exercise group , 27 % for the placebo group , and 0 % for the clomipramine group . In comparison with placebo , both exercise and clomipramine led to a significant decrease in symptoms according to all main efficacy measures ( analysis of variance , last-observation-carried-forward method and completer analysis ) . A direct comparison of exercise and clomipramine revealed that the drug treatment improved anxiety symptoms significantly earlier and more effectively . Depressive symptoms were also significantly improved by exercise and clomipramine treatment . CONCLUSIONS These results suggest that regular aerobic exercise alone , in comparison with placebo , is associated with significant clinical improvement in patients suffering from panic disorder , but that it is less effective than treatment with clomipramine Fluvoxamine and imipramine were compared to placebo in an 8-week doubleblind r and omized multicentre trial comprising of 148 out patients between 19 and 57 years of age ( mean : 35 ) with a DSM-III-R diagnosis of Panic Disorder . mean daily dose at endpoint was : fluvoxamine , 171.4 mg ; imipramine 164.7 mg . The mean number of panic attacks per week at baseline were 10.9 , 14.4 and 6.5 for fluvoxamine , imipramine and placebo , respectively . The intent-to-treat analysis of the change from baseline ( difference score ) of the number of panic attacks at endpoint revealed : a difference of 3.3 attacks ( 95 % CI : -0.3 , 6.8 ) between fluvoxamine and placebo and a difference of 6.0 attacks ( 95 % CI : 1.5 , 10.5 ) between imipramine and placebo . Treatment was stopped prematurely in 31 ( 62 % ) on fluvoxamine , 16 ( 33 % ) on imipramine and 29 ( 58 % ) on placebo . The number of patients withdrawing due to intolerance was 13 ( 26 % ) for fluvoxamine , 10 ( 21 % ) for imipramine and 4 ( 8 % ) for placebo . The number of patients withdrawing due to lack of efficacy was 10 ( 20 % ) for fluvoxamine , 4 ( 8 % ) for imipramine and 12 ( 24 % ) for placebo . Overall , this study demonstrated that fluvoxamine was not effective in the treatment of panic disorder but did show a strong effect for imipramine . A chance occurrence of significantly fewer number of panic attacks in the placebo group at baseline may limit the conclusions of this study At the end of a two-week single-blind placebo baseline , 43 patients with a diagnosis of panic disorder with agoraphobia without significant dysphoria-depression and with moderate to severe panic and phobic symptoms were assigned to , and 32 of them completed , a placebo-controlled ( n = 7 ) dose-response study with three weight-adjusted imipramine hydrochloride dosages : 0.5 mg/kg/d ( n = 10 ) , 1.5 mg/kg/d ( n = 9 ) , and 3 mg/kg/d ( n = 6 ) . Eleven patients , three from the medium-dose and eight from the high-dose conditions , dropped out owing to side effects . No instructions or encouragement for self-directed exposure to phobic situations or other coping strategies with panic or fear were given throughout the trial . Compliance , as assessed by pill counts and by plasma tricyclic levels , was high . Results provided strong evidence for a positive dose-response relationship on panic and phobic symptoms and confirmed earlier suggestions ( 1 ) that imipramine without concurrent exposure possesses a significant antipanic and antiphobic effect , ( 2 ) that improvement correlates primarily with imipramine but not N-desmethylimipramine plasma levels , and ( 3 ) that side effects prevent optimum dose buildup in a substantial proportion of patients with this disorder Summary Self-rating scales  are considered to be less useful for comparing different treatments in anxiety patients than observer-rating scales . However , the empirical evidence for this assumption is not adequate . A selfrating inventory of 35 items related to anxiety was perfectly parallel with an observer-rating inventory . Both instruments were used in the Cross National Collaborative Panic Study to compare the efficacy of imipramine , alprazolam and placebo in an 8-week drug trial in a sample of 1168 out patients . The variance of the self-rating assessment s was about two times higher . Both scales were equally sensitive to change ; however , the measurement of change by means of the self-rating scale was slightly less consistent . The discriminative power of the observer-rating scale between placebo and active treatment was two to three times higher than that of the selfrating scale ; consequently the observer-rating procedure provides a more valid instrument when the efficacies of different anxiolytic treatments are compared between different groups of patients BACKGROUND It has been argued that measurement of outcome in panic disorder should not be limited to monitoring the number of panic attacks , but should include all domains that affect patient quality of life . METHODS Data from a r and omized prospect i ve comparison of escitalopram , citalopram , and placebo in patients with DSM-IV panic disorder were analyzed with regard to measurements of impairment of quality of life . The subscales of the Panic and Agoraphobia Scale ( P&A ) ( Panic Attacks , Agoraphobic Avoidance , Anticipatory Anxiety , Functional and Social Disability , and Worries about Health ) and the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) were analyzed . RESULTS Treatment with escitalopram was associated with significant improvement on all 5 subscales of the P&A.  Citalopram was significantly different from placebo in 3 subscales . Escitalopram and citalopram were significantly better than placebo in improving quality of life ( measured by the total score of the Q-LES-Q Scale ) . Escitalopram was superior to placebo on 12 of 16 items of the Q-LES-Q , while citalopram was superior on 7 items . CONCLUSION The P&A scale was more robust than measurement of panic frequency in differentiating medication from placebo . Escitalopram treatment was associated with improvement on all assessed domains that impair quality of life in panic disorder . Measurement of clinical improvement should not be solely based on panic attack frequency , but should also include assessment of a broad range of domains that affect patient quality of life BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions OBJECTIVE Recent studies have suggested that most patients treated for panic disorder receive forms of psychotherapy other than cognitive behavior therapy , even though there is little information about the efficacy of such treatments or how they compare to proven active treatments . The authors compared one of these other forms , emotion-focused psychotherapy ( given to 30 patients with panic disorder ) , to results obtained with recommended st and ard treatment ( either cognitive behavior therapy [ N=36 ] or imipramine [ N=22 ] ) . The authors also compared emotion-focused psychotherapy to results obtained in subjects given pill placebo ( N=24 ) . METHOD Subjects met DSM-IV criteria for panic disorder with no more than mild agoraphobia . Treatment consisted of approximately 3 months of weekly visits followed by 6 monthly maintenance visits . Assessment s were conducted after each treatment phase and at a follow-up visit after 6 months of no treatment . RESULTS Emotion-focused psychotherapy  was less effective for symptoms of panic disorder than treatment with either cognitive behavior therapy or imipramine ; results obtained with emotion-focused psychotherapy after the acute and maintenance phases were similar to those seen with placebo .  Treatment expectations were not different among the different groups . Patients receiving emotion-focused psychotherapy had the highest completion rate . CONCLUSIONS The results suggest that emotion-focused psychotherapy ( a supportive form of psychotherapy ) has low efficacy for the treatment of panic disorder . However , emotion-focused psychotherapy may be superior to medical management in helping patients stay in treatment It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments ( interaction between treatment and baseline score ) . Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks , but not for the frequency of situational panic attacks or measures of agoraphobia . This report presents similar analyses of data from a study using moclobemide .  Patients ( N = 452 ) with panic disorder were r and omized to placebo  or a fixed dose of moclobemide ( 75 , 150 , 300 , 600 , or 900 mg/day ) . They were treated double-blindly and evaluated at baseline and 1 , 2 , 3 , 4 , 6 , and 8 weeks later . The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary , and fear and avoidance ratings based on the patient ’s main phobia using baseline ( pre ) and end-point ( post ) values for all r and omized patients . Adjoining dose groups were combined . Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes . Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms . This study replicates the authors ’ earlier findings , except for situational panic attacks , which probably were not reliably identified . Antidepressants selectively suppress panic attacks , especially unexpected attacks , but not agoraphobia . The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinical ly separable biologic and cognitive components that respond differentially to treatment . Antidepressants benefit primarily patients with many unexpected panic attacks . Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means ( analysis of covariance ) A double-blind placebo-controlled study of 5-HTP and clomipramine was carried out on 45 patients suffering from anxiety disorders ( DSM-III ) .  Clomipramine has shown to be effective in that it induced significant improvement on all rating scales as compared to placebo . 5-HTP showed a moderate reduction of the symptomatology on the 90-item symptoms checklist ( SCL-90 ) and the State Scale of the Spielberger State-Trait Anxiety Inventory .  Clomipramine and 5-HTP differed in their efficacy in that 5-HTP did not affect the associated depressive symptomatology . The results support the hypothesis that brain serotonergic pathways are involved in the pathogenesis of anxiety disorders , particularly in agoraphobia and panic disorders BACKGROUND This study investigates the naturalistic course of panic disorder over four years and attempts to identify predictors for outcome . METHOD 423 DSM-III-R panic disorder patients who had taken part in an international multicentre drug trial were selected for follow-up ; we were able to re-interview 367 ( 87 % ) . For panic attacks , phobic avoidance and disabilities the same rating scales were administered as had been used for the clinical trials . RESULTS While 61 % of all patients experienced at least occasional panic attacks at follow-up , few suffered from serious phobic avoidance ( 16.7 % ) or serious disabilities ( work 7.9 % ) ; family 8.7 % ; social 13.9 % ) . Panic attack frequency at baseline , original trial medication and continuous use of psychotropic medication during follow-up are not related to outcome , whereas longer duration of illness and more severe phobic avoidance at baseline are unfavourable . CONCLUSION The course of panic disorder is not uniform . Since long duration of illness and severe phobic avoidance at baseline are predictors for an unfavourable outcome , more rigorous efforts should be undertaken to detect and treat panic disorder at an early stage BACKGROUND A new 13-item scale has been developed for measuring severity of illness in patients with panic disorder and agoraphobia , the Panic and Agoraphobia Scale ( P & A ) . The scale has five subscales covering the main factors that reduce quality of life in panic disorder patients ( panic attacks , avoidance , anticipatory anxiety , disability and worries about health ) . The application of this scale in a double-blind placebo-controlled panic disorder trial is described . At the same time , the aim of the study was to compare the therapeutic effects of aerobic exercise with a treatment of well-documented efficacy . METHODS Patients with Panic disorder ( DSM-IV ) were r and omly assigned to three treatment modalities : running ( n=45 ) , clomipramine ( n=15 ) or placebo ( n=15 ) . Treatment efficacy was measured with the Panic and Agoraphobia Scale ( P & A ) and other rating scales . RESULTS According to the P & A and other scales , both exercise and clomipramine led to a significant decrease of symptoms in comparison to placebo treatment . Clomipramine was significantly more effective and improved anxiety symptoms significantly earlier than exercise . The evaluation of the P & A subscales revealed that exercise exerted its effect mainly reducing anticipatory anxiew and panic-related disability . CONCLUSIONS The new Panic and Agoraphobia Scale was shown to be sensitive to differences between different panic treatments . Analysis of the scales five subscores may help to underst and mechanisms of action of panic disorder treatments 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 prospect i ve study . Forty-four patients with panic disorder were r and omly 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 To date , no large-scale , controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported . This double-blind study compares the efficacy of venlafaxine extended-release ( ER ) and paroxetine with placebo . A total of 664 nondepressed adult out patients who met DSM-IV criteria for panic disorder ( with or without agoraphobia ) were r and omly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER ( 75 mg/day or 150 mg/day ) , or paroxetine 40 mg/day . The primary measure was the percentage of patients free from full-symptom panic attacks , assessed with the Panic and Anticipatory Anxiety Scale ( PAAS ) . Secondary measures included the Panic Disorder Severity Scale , Clinical Global Impressions -- Severity ( CGI-S ) and --Improvement ( CGI-I ) scales ; response ( CGI-I rating of very much improved or much improved ) , remission ( CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks ) ; and measures of depression , anxiety , phobic fear and avoidance , anticipatory anxiety , functioning , and quality of life . Intent-to-treat , last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo . No significant differences were observed between active treatment groups . Panic-free rates at end point with active treatment ranged from 54 % to 61 % , compared with 35 % for placebo . Approximately 75 % of patients given active treatment were responders , and nearly 45 % achieved remission . The placebo response rate was slightly above 55 % , with remission near 25 % . Adverse events were mild or moderate and similar between active treatment groups . Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder 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 % ) Factors that predicted the outcome of drug treatment ( alprazolam or imipramine ) of panic disorder were studied in a sample of 123 Sc and inavian patients participating in a multicenter placebo‐controlled 8‐week trial . The attrition rate was 95 % for alprazolam , 73 % for imipramine and 46 % for placebo . For the intention‐to‐treat and 3‐week‐completer sample s , drugs and anxiety symptoms at baseline were the best predictors of improvement on the Global Improvement Scale and on symptom scales focusing on panic attacks , phobic behavior and anticipatory anxiety . For completers of the 8‐week trial , only baseline scores predicted outcome . Generally , more severe symptoms at baseline predicted a worse outcome . A sub sample of patients had a marked placebo response . Avoidance , sex , age , childhood psychopathology and previous treatment experience had no or only a weak impact on the outcome . The relationship between panic disorder and mood disorder is presented elsewhere Objective : Several studies have documented that a variety of pharmacological compounds are quite effective in controlling acute symptomatology of panic disorder in the general population . However , there is a paucity of such studies in the management of  panic disorder in older adults ( ages 55 and above ) . The purpose of this study was to gather pilot data in older patients with panic disorder to begin to assess the efficacy of two commonly-used antipanic medications , imipramine and alprazolam . Method : Twenty-five ( n = 25 ( 23 females ; 2 males ) ; 18 completers , 7 dropouts ) older panic disorder ( DSM-III-R ) patients ( age range = 55–73 ; mean = 61.24 ) were studied in an eight-week r and omized , parallel-groups , double-blind , placebo-controlled , flexible dose design . Outcome was assessed weekly by global change ratings ( Hamilton Anxiety and Depression Scales ; Physicians ' Global Impression ratings ) and panic diaries . Because of small sample size , we present data descriptively . Results : Subjects in active medication groups evidence d reductions in panic attacks and in levels of overall anxiety and depression . Therapeutic dosages were approximately half those commonly used in younger panic disorder patients . Conclusion : Our data suggest the comparable efficacy of alprazolam and imipramine in the short-term treatment of older adults with panic disorder . There is clearly the need for a larger scale placebo-controlled study , preferably comparing imipramine and /or alprazolam with one of the SSRIs , to substantiate our findings Forty‐one panic disorder patients receiving placebo were investigated in a double‐blind comparison of alprazolam , imipramine and placebo in panic disorder . A significantly higher drop‐out rate was found in the placebo group than in the active treatment groups , but placebo response was found in 34 % of the patients , defined as reduction of panic attacks to zero , and in 23 % , defined as a score of > 8 on the Physician Global Improvement Scale ( 0 10 points ) . Several predictors of response to placebo were found . The responders had fewer panic attacks than the nonrcsponders at baseline . They also reported less psychopathology and were less help‐seeking than the nonresponders . The implication s for psychopathology and possible response to psychotherapy among responders and nonresponders are discussed . It is hypothesized that the responders show more signs of realistic processing of internal and external stimuli and fewer signs of subjective distress than the nonresponders . Responders will therefore probably be more responsive to psychotherapy than nonresponders This study was design ed to explore the dose‐response relationship for clomipramine in patients with panic disorder , with or without agoraphobia . After 1 week of single‐blind placebo pretreatment , 180 such patients were assigned to a multicentre  placebo‐controlled comparison of the effects of high and low doses of clomipramine , and were followed up for 8 weeks . In alleviating anxiety and panic disorder , both clomipramine doses were more efficacious than placebo for panic disorder and , to a lesser degree , for phobia . The lower dose was better tolerated and at least as effective as the higher dose , sometimes more so . These results indicate the clinical ly important possibility that low‐dose clomipramine is effective and well tolerated OBJECTIVE The authors assessed whether adding cognitive behavior therapy ( CBT ) to imipramine for patients with panic disorder decreased the severity of side effects and dropouts from side effects . METHOD Data were analyzed for 172 panic disorder patients who were r and omly assigned to receive imipramine alone , imipramine plus CBT , or placebo .  Mixed-effects models were used to assess longitudinal differences among the treatment groups with respect to side effect burden and dropout rates during the acute , maintenance , and follow-up phases of treatment . RESULTS Patients treated with imipramine plus CBT experienced less severe fatigue/weakness , dry mouth , and sweating and had a lower rate of dropout due to side effects compared with those treated with imipramine only . CONCLUSIONS The addition of CBT to medication treatment with imipramine was associated with less severe side effects and fewer dropouts due to perceived side effects than treatment with imipramine alone 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 clinical ly significant and lasting benefits in these patients BACKGROUND Citalopram is a serotonin reuptake inhibitor which has been demonstrated to be highly selective and with a superior tolerability profile to the classical tricyclic antidepressants . This study was design ed to test whether there was any difference in efficacy in the management of panic disorder ( PD ) between citalopram and placebo . METHOD This was a double-blind , placebo and clomipramine controlled , parallel group eight-week study . A total of 475 patients with PD , with or without agoraphobia , were r and omised to treatment with either placebo , clomipramine 60 or 90 mg/day , or citalopram 10 or 15 mg/day , or 20 or 30 mg/day , or 40 or 60 mg/day . Doses were increased over the first three weeks , stabilised during the fourth week and fixed between weeks five and eight . RESULTS Treatment with citalopram at 20 or 30 mg , 40 or 60 mg and clomipramine were significantly superior to placebo , judged by the number of patients free of panic attacks in the week prior to the final assessment . All rating scales examined suggested that citalopram 20 or 30 mg was more effective than citalopram 40 or 60 mg . CONCLUSION The most advantageous benefit/risk ratio for the treatment of PD was associated with citalopram 20 or 30 mg/day BACKGROUND Panic disorder ( PD ) is generally regarded as a chronic condition with considerable variation in severity of symptoms . AIMS To describe the long-term outcome of naturalistically treated PD . METHODS Fifty-five out patients with PD , who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study . RESULTS Complete recovery ( no panic attacks and no longer on medication during the last 10 years ) was seen in 18 % of patients , and an additional 13 % recovered but were still on medication . Fifty-one percent experienced recurrent anxiety attacks whereas 18 % still met diagnostic criteria for PD . The incidence of agoraphobia decreased from 69 % to 20 % . Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission , although both groups reported improved daily functioning at follow-up . Maintenance medication was common . No benzodiazepine abuse was reported . CONCLUSION PD has a favourable outcome in a substantial proportion of patients . However , the illness is chronic and needs treatment . The short-term treatment given in the drug trial had no influence on the long-term outcome 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 - BACKGROUND This 12-week , placebo-controlled study was carried out to compare the relative efficacy of paroxetine , clomipramine , and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia . METHOD After a 3-week single-blind , placebo run-in period , 131 patients were r and omly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark . Efficacy assessment s included the daily panic attack diary , the Clinical Global Impression scale , the Patient Global Evaluation , the Hamilton Rating Scale for Anxiety , the Marks-Sheehan Phobia Scale , the Montgomery-Asberg Depression Rating Scale , and the Sheehan Disability Scale . RESULTS Comparisons with placebo revealed significant superiority of paroxetine ( 20 - 60 mg/day ) and clomipramine ( 50 - 150 mg/day ) on nearly all outcome measures . On most measures , paroxetine also showed higher efficacy than cognitive therapy . With few exceptions , cognitive therapy did not differ significantly from placebo . The number of subjects becoming panic-free ( 66 % ) was higher and the onset of action was faster in the paroxetine-treated group . Treatment with cognitive therapy yielded the highest drop-out rate ( 26 % ) . CONCLUSION In this short-term study assessing treatment of panic disorder and agoraphobia , paroxetine and clomipramine were consistently superior to pill placebo , whereas cognitive therapy was superior on only a few measures 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 BACKGROUND Self-administered cognitive behavior therapy ( SCBT ) has been shown to be an effective alternative to therapist-delivered treatment for panic disorder ( PD ) . However , it is unknown whether combining SCBT and antidepressants can improve treatment . This trial evaluated the efficacy of SCBT and sertraline , alone or in combination , in PD . METHOD Patients ( n=251 ) were r and omized to 12 weeks of either placebo drug , placebo drug plus SCBT , sertraline , or sertraline plus SCBT . Those who improved after 12 weeks of acute treatment received treatment for an additional 12 weeks . Outcome measures included core PD symptoms ( panic attacks , anticipatory anxiety , agoraphobic avoidance ) , dysfunctional cognitions ( fear of bodily sensations , agoraphobic cognitions ) , disability , and clinical global impression of severity and improvement . Efficacy data were analyzed using general and generalized linear mixed models . RESULTS Primary analyses of trends over time revealed that sertraline/SCBT produced a significantly greater rate of decline in fear of bodily sensations compared to sertraline , placebo/SCBT and placebo . Trends in other outcomes were not significantly different over time . Secondary analyses of mean scores at week 12 revealed that sertraline/SCBT fared better on several outcomes than placebo , with improvement being maintained at the end of continuation treatment . Outcome did not differ between placebo and either sertraline monotherapy or placebo/SCBT . Moreover , few differences emerged between the active interventions . CONCLUSIONS This trial suggests that sertraline combined with SCBT may be an effective treatment for PD . The study could not confirm the efficacy of sertraline monotherapy or SCBT without concomitant medication or therapist assistance in the treatment of PD The Cross-National Collaborative Panic Study , Phase Two , compared alprazolam with imipramine and with placebo in a sample of 1168 r and omly 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 BACKGROUND Venlafaxine extended-release ( ER ) has proven efficacy in the treatment of anxiety symptoms in major depression , generalised anxiety disorder and social anxiety disorder . AIMS To evaluate the efficacy , safety and tolerability of venlafaxine ER in treating panic disorder . METHOD Adult out- patients ( n=361 ) with panic disorder were r and omly assigned to receive venlafaxine ER ( 75 - 225 mg/day ) or placebo for up to 10 weeks in a double-blind study . RESULTS Venlafaxine ER was not associated with a greater proportion of patients free from full-symptom panic attacks at the final on-therapy evaluation , but was associated with lower mean panic attack frequency and a higher proportion free from limited-symptom panic attacks , higher response and remission rates , and improvements in anticipatory anxiety , fear and avoidance . Adverse events were comparable with those of the drug in depression and anxiety disorders . CONCLUSIONS Venlafaxine ER seems to be effective and well tolerated in the short-term treatment of panic disorder Forty-seven patients meeting DSM-III-R criteria for panic disorder with agoraphobia ( PAG ) were assessed by the Minnesota Multiphasic Personality Inventory ( MMPI ) at baseline and after 8 weeks of treatment with imipramine , clomipramine and placebo . At pre-treatment patients had higher MMPI scores than the local normative data , the highest scores being for depression , hypochondria and hysteria . At week 8 the scores of most MMPI scales were significantly reduced . In addition , patients who showed clinical improvement had pre- and post-treatment scores lower than the unimproved patients . The results suggest that the abnormal MMPI profile found in PAG patients reflects the clinical state and that personality pathology relates to treatment outcome . The reduction in MMPI scores was associated with response to active treatment . We conclude that therapeutic interventions that successfully reduce PAG symptoms also modify personality scores Jitteriness appears to be a specific side effect of tricyclic antidepressant treatment in panic disorder patients . In addition , the patients with jitteriness have lower serum iron levels compared to those that do not develop jitteriness ( p = 0.01 ) A comparison of safety , and efficiency of Alprazolam , Imipramine , and placebo in the treatment of panic disorder shows that both active drugs are significantly superior to placebo as regards therapeutic effectiveness . On a 77 patient sample , 62 completed an 8-week treatment , and 66 were considered as " assessable " for efficiency results after completing a 3-week treatment . Significantly , more placebo-treated patients than either Alprazolam , or Imipramine-treated patients dropped out trial , while the number of panic attacks was significantly reduced in both Alprazolam- , and Imipramine-treated groups . When trial was over , 96 % of patients in Alprazolam group , and 95 % of patients in Imipramine group were free from panic attacks , if compared to 65 % in the placebo group . Generally speaking , drugs were well tolerated , and no serious adverse effects or life-threatening events were observed Serotonergic mechanisms have been implicated in panic disorder , and several preliminary studies suggest that fluvoxamine , a selective serotonin reuptake inhibitor ( SSRI ) , is helpful in its treatment . This 8-week double-blind parallel-group study compared fluvoxamine with a placebo in 188 patients with DSM-III-R defined panic disorder with or without agoraphobia . Efficacy assessment s included a Daily Panic Attack Inventory , the Sheehan Disability Scale , the Clinical Anxiety Scale and the Clinical Global Impression Scale . When compared with the placebo , fluvoxamine produced highly significant improvements in most measures of the frequency and severity of panic disorder and in the more global aspects of disability and distress . Significant improvement was evident as early as week 1 for some panic variables . Fluvoxamine is a potent anti-panic agent with a relatively rapid onset of action OBJECTIVE To evaluate the efficacy , safety , and tolerability of venlafaxine extended release ( ER ) in short-term treatment of panic disorder . METHOD In this multicenter , double-blind study , conducted from April 2001 to December 2002 , 343 adult out patients who met criteria for panic disorder ( with and without agoraphobia ) according to the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , were r and omly assigned to flexible-dose venlafaxine ER ( 75 - 225 mg/d ) or placebo for 10 weeks ( N = 155 per group , intent-to-treat population ) . The primary outcome measure was the percentage of panic-free patients as assessed using the Sheehan Panic and Anticipatory Anxiety Scale . Key secondary measures included the Panic Disorder Severity Scale ( PDSS ) score and Clinical Global Impressions-Improvement ( CGI-I ) scale response ( score = 1 or 2 ) . Last-observation-carried-forward data were analyzed , and statistical significance was set at p < or= .05 . RESULTS At week 10 , the percentage of patients who were free from full-symptom panic attacks was 52 % in the venlafaxine ER group and 43 % in the placebo group ( p = .11 ) . Mean change from baseline in PDSS total score was significantly ( p = .006 ) greater for the venlafaxine ER group ( -9.3 ) than for the placebo group ( -7.5 ) , and significantly ( p = .03 ) more venlafaxine ER-treated patients achieved CGI-I response ( 71 % ) than did those receiving placebo ( 59 % ) at week 10 . Treatment with venlafaxine ER was generally safe and well tolerated . Adverse events were the primary or secondary cause for discontinuation for 7 placebo patients ( 4 % ) and 12 venlafaxine ER patients ( 7 % ) . CONCLUSIONS Venlafaxine ER appears to be effective , safe , and well tolerated in short-term treatment of panic disorder , although the results fell just short of significance on the primary outcome measure . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00038896 BACKGROUND Tricyclic antidepressants and selective serotonin reuptake inhibitors ( SSRIs ) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder . The introduction of SSRIs has enabled a greater underst and ing of the role of serotonin in the etiology of panic disorder ; however , the role of norepinephrine has been more challenging to ascertain . The aim of this study was to determine the efficacy and tolerability of reboxetine , a novel selective norepinephrine reuptake inhibitor , in patients with panic disorder with and without agoraphobia . METHOD Eighty-two patients ( aged 18 - 65 years ) with DSM-III-R panic disorder , with or without agoraphobia , were r and omly assigned to receive 6 to 8 mg/day of reboxetine ( 42 patients ) or placebo ( 40 patients ) for 8 weeks in this placebo-controlled , parallel-group , double-blind clinical trial . RESULTS Of the 82 patients enrolled in the trial , 75 were considered in the analysis ( 37 patients in the reboxetine group and 38 patients in the placebo group ) . At last assessment , there was a significant reduction in the mean number of panic attacks ( range , 9.3 - 1.2 ) and phobic symptoms ( range , 8.1 - 3.2 ) in the reboxetine group compared with the placebo group ( ranges , 8.5 - 5.8 and 7.7 - 5.2 , respectively ; p < .05 ) . Improvement in Hamilton Rating Scale for Depression , Hopkins Symptom Checklist-90 , and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group . Adverse events reported more frequently with reboxetine than placebo included dry mouth ( 36 % vs. 16 % ) , constipation ( 27 % vs. 22 % ) , and insomnia ( 26 % vs. 22 % ) . CONCLUSION Reboxetine was effective and well tolerated in the treatment of panic disorder 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 r and omized 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 Buspirone was compared with imipramine and placebo in the treatment of panic disorder in an 8-week , double-blind controlled study of 52 r and omly assigned patients . The side effect profile of buspirone was less disruptive than that of imipramine . Buspirone was not significantly superior to placebo in its antipanic or anxiolytic effects in panic disorder patients The aim of this 12‐week , double‐blind , parallel group , placebo‐controlled study was to compare paroxetine with clomipramine in 367 patients with DSM‐III‐R defined panic disorder . Efficacy assessment s included the daily panic attack diary , the Clinical Global Impression Scale , the Hamilton Anxiety Rating Scale , the Marks Sheehan Phobia Scale and the Sheehan Disability Scale .  Paroxetine produced significant improvements compared with placebo in various measurements of panic attack frequency , and was as effective as clomipramine . However , paroxetine appeared to have a more rapid onset of action than clomipramine in reducing the number of panic attacks to zero . There was an equivalent improvement with both paroxetine and clomipramine in the supportive efficacy variables which assessed associated aspects of therapeutic improvement . Significantly more adverse effects were reported in the clomipramine group compared with the paroxetine group , while there was no difference between the paroxetine and placebo groups BACKGROUND The objective of this study was to evaluate the efficacy and tolerability of citalopram in the long-term treatment of adult out patients with panic disorder with or without agoraphobia . METHOD Patients in this double-blind , parallel-group trial were assigned to 1 of 3 fixed dosage ranges of citalopram ( 10 or 15 mg/day , 20 or 30 mg/day , or 40 or 60 mg/day ) , 1 dosage range of clomipramine ( 60 or 90 mg/day ) , or placebo . After the completed 8-week acute treatment period , the eligible patients could continue the treatment for up to 1 year . Of the 475 patients who were r and omly assigned for the short-term trial , 279 agreed to continue double-blind treatment at their assigned doses . The primary efficacy measure used was the Clinical Anxiety Scale panic attack item , and the response was defined as no panic attacks ( score of 0 or 1 ) . The other key measures used were the Physician 's Global Improvement Scale , the Patient 's Global Improvement Scale , and the Hamilton Rating Scale for Anxiety ( HAM-A ) . RESULTS In all drug-treated groups , except the group receiving the lowest citalopram dose , the treatment outcome was generally better than with placebo . As determined by a life table analysis of response , the probability of response during the 12 months was significantly greater with all treatment regimens than with placebo ( p < .05 ) , with citalopram 20 or 30 mg/day demonstrating the best response . Panic attacks tended to disappear in all patients remaining in the study until the end of follow-up . Analysis of the difference in the number of patients in different treatment groups remaining in the study ( perhaps the best measure of long-term efficacy ) also demonstrated that the patients treated with citalopram in dosage ranges of 20 or 30 mg/day and 40 or 60 mg/day had better response than placebo-treated patients ( p < .0002 and p < .004 , respectively ) . HAM-A and Global Improvement Scale scores also showed that patients treated with active drug showed greater improvement than placebo-treated patients . All treatment groups showed no new or exceptional adverse event clusters . CONCLUSION Citalopram in the dosage range of 20 to 60 mg/day is effective , well tolerated , and safe in the long-term treatment of patients who have panic disorder One of the core problems in clinical research is the detection of early changes in target symptoms that predict future therapeutic outcome . To analyze potential predictors of outcome , data of a multicenter study on patients with panic disorder were used . A total of 1010 patients were r and omly allocated either to alprazolam , imipramine or placebo treatment . Early improvement in the number of spontaneous panic attacks within the first week of treatment predicted outcome exclusively in the alprazolam group . In contrast , placebo responders and nonresponders were differentiated by early changes in anticipatory anxiety intensity . For tricyclic antidepressants such as imipramine an evaluation period of more than one week is required to allow conclusions about outcome BACKGROUND This study compared the efficacy and safety of sertraline to placebo in treating panic disorder . METHOD 178 out- patients with panic disorder who exhibited at least four panic attacks during the four weeks prior to screening and three during the two weeks of lead-in were r and omly assigned to 12 weeks of double-blind treatment with sertraline ( 50 , 100 or 200 mg ) or placebo . RESULTS Sertraline was superior to placebo in reducing the number of panic attacks , situational attacks , unexpected attacks , limited symptom attacks , and time spent worrying ( all P < 0.01 ) and the Hamilton Anxiety Scale ( P < 0.05 ) , although Clinical Global Impression ( Improvement ) did not significantly differentiate groups at 12 weeks and at end-point . No serious adverse events were associated with sertraline . No dose relationship was found for adverse events ; overall drop-out rates were not different for sertraline or placebo , although more sertraline-treated subjects discontinued for adverse events , typically early in the study . Only dry mouth and ejaculation failure ( primarily ejaculation delay ) were associated significantly with sertraline . CONCLUSIONS Sertraline was effective and safe in reducing panic attacks . Higher doses were no more effective than the 50 mg dose OBJECTIVE This study was design ed to determine the minimum paroxetine dose effective for treating panic disorder . METHOD Of 425 patients with DSM-III-R panic disorder with or without agoraphobia who underwent a 2-week drug-free screening period , 278 patients were r and omly assigned to double-blind treatment with a 10-week course of placebo or paroxetine at a dose of 10 , 20 , or 40 mg/day . RESULTS At 40 mg/day , paroxetine was superior to placebo across the majority of outcome measures . Despite a mean of 9.5 to 11.6 full panic attacks during the screening period , 86.0 % of the patients taking 40 mg of paroxetine , 65.2 % of those taking 20 mg , 67.4 % of those taking 10 mg , and 50.0 % of the placebo-treated patients were free of full panic attacks during the 2 weeks ending at week 10 . The 40-mg paroxetine group experienced significantly greater global improvement than the placebo group and significantly greater improvement in frequency of full and limited-symptom panic attacks , intensity of full panic attacks , phobic fear , anxiety , and depressive symptoms , usually evident by week 4 . All doses of paroxetine were well tolerated , and adverse effects were consistent with those associated with selective serotonin reuptake inhibitors . CONCLUSIONS Paroxetine is an effective and well-tolerated short-term treatment of panic disorder . The minimum dose demonstrated to be significantly superior to placebo was 40 mg/day , although some patients did respond at lower doses 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
target: We observed the same finding when classes of antidepressants were compared with placebo .
  When looking at dropouts due to adverse effects , which can be considered as a measure of tolerability , we found moderate- quality evidence showing that antidepressants as a whole are less well tolerated than placebo .
  The identified studies comprehensively address the objectives of the present review .Based on these results , antidepressants may be more effective than placebo in treating panic disorder .
  Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts , but a less favourable profile in terms of dropout due to adverse effects .
  However , the tolerability profile varied between different classes of antidepressants .
background: BACKGROUND Panic disorder is characterised by repeated , unexpected panic attacks , which represent a discrete period of fear or anxiety that has a rapid onset , reaches a peak within 10 minutes , and in which at least four of 13 characteristic symptoms are experienced , including racing heart , chest pain , sweating , shaking , dizziness , flushing , stomach churning , faintness and breathlessness .
  It is common in the general population with a lifetime prevalence of 1 % to 4 % .
  The treatment of panic disorder includes psychological and pharmacological interventions .
  Amongst pharmacological agents , the National Institute for Health and Care Excellence ( NICE ) and the British Association for Psychopharmacology consider antidepressants , mainly selective serotonin reuptake inhibitors ( SSRIs ) , as the first-line treatment for panic disorder , due to their more favourable adverse effect profile over monoamine oxidase inhibitors ( MAOIs ) and tricyclic antidepressants ( TCAs ) .
  Several classes of antidepressants have been studied and compared , but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition .
  OBJECTIVES To assess the effects of antidepressants for panic disorder in adults , specifically:1 .
  to determine the efficacy of antidepressants in alleviating symptoms of panic disorder , with or without agoraphobia , in comparison to placebo;2 .
  to review the acceptability of antidepressants  in panic disorder , with or without agoraphobia , in comparison with placebo ; and 3 .
  to investigate the adverse effects of antidepressants  in panic disorder , with or without agoraphobia , including the general prevalence of adverse effects , compared to placebo .