title: Multicenter collaborative panic disorder severity scale. Absence of Neuropsychologic Deficits in Patients Receiving Long-Term Treatment With Alprazolam-XR for Panic Disorder Self-exposure therapy for panic disorder with agoraphobia: randomised controlled study of external v. interoceptive self-exposure. Pre-treatment predictors of treatment outcome in panic disorder and agoraphobia treated with alprazolam and exposure. Brief cognitive therapy for panic disorder: a randomized controlled trial. 12-month prevalence of panic disorder with or without agoraphobia in the Swedish general population Relationship of panic, anticipatory anxiety, agoraphobia and global improvement in panic disorder with agoraphobia treated with alprazolam and exposure. How study design affects outcomes in comparisons of therapy. I: Medical. Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study Cognitive and performance-based treatments for panic attacks in people with varying degrees of agoraphobic disability. Exposure in vivo of agoraphobics: contributions of diazepam, group exposure, and anxiety evocation. New evidence on benzodiazepine use and falls: the time factor. Bias in treatment assignment in controlled clinical trials. Group cognitive-behavioral treatment of panic disorder. Changes in “withdrawal symptoms” following discontinuation of low-dose diazepam Safety and side-effects of alprazolam. Controlled study in agoraphobia with panic disorder. Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? Suicidal ideation and suicide attempts in panic disorder and attacks. Effectiveness of cognitive--behavioral treatment for panic disorder versus treatment as usual in a managed care setting. A prospective naturalistic study of 326 panic-agoraphobic patients treated with antidepressants. Lactate-induced anxiety after imipramine and diazepam treatment. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Behavioural aggression in panic disorder after 8 weeks' treatment with alprazolam. Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind placebo-controlled study Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. Duration of Imipramine Therapy and Relapse in Panic Disorder With Agoraphobia Arousal levels and attribution effects in diazepam-assisted flooding. Does concurrent drug intake affect the long-term outcome of group cognitive behaviour therapy in panic disorder with or without agoraphobia? Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients. A crossover study of focused cognitive therapy for panic disorder. Diazepam versus alprazolam for the treatment of panic disorder. Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Impact of cognitive-behavioral treatment on quality of life in panic disorder patients. Effects of concurrent diazepam treatment on the outcome of exposure therapy in agoraphobia. A comparison of delivery methods of cognitive-behavioral therapy for panic disorder: an international multicenter trial. Double-blindness procedures, rater blindness, and ratings of outcome. Observations from a controlled trial. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. Diazepam and propranolol in panic disorder and agoraphobia. Alprazolam and exposure for panic disorder with agoraphobia. Attribution of improvement to medication predicts subsequent relapse.
abstract: OBJECTIVE To address the lack of a simple and st and ardized instrument to assess overall panic disorder severity , the authors developed a scale for the measurement of panic disorder severity . METHOD Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder ( with no or mild agoraphobia ) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder . In addition , 89 of these patients were reevaluated with the same scale after short-term treatment . A subset of 24 patients underwent two independent assessment s to establish interrater reliability . Internal consistency , convergent and discriminant validity , and sensitivity to change were also determined . RESULTS The Panic Disorder Severity Scale was associated with excellent interrater reliability , moderate internal consistency , and favorable levels of validity and sensitivity to change . Individual items showed good convergent and discriminant validity . Analysis suggested a two-factor model fit the data best . CONCLUSIONS The Panic Disorder Severity Scale is a simple , efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder . However , further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed Studies to date on the effects of benzodiazepines on neuropsychologic function have yielded conflicting data with respect to the type , severity , and duration of deficits that may be induced by these agents . As part of a placebo-controlled trial of alprazolam-XR ( extended release ) administered in combination with cognitive-behavioral therapy in patients with panic disorder , a battery of tests was used to measure neuropsychologic function .  Thirty-eight out patients were r and omly assigned to receive either alprazolam-XR or placebo . Dosages were titrated up so that the alprazolam group ( N = 18 ) received a mean dose of 4 mg/day ( reduced in two patients because of sedative side effects ) . Neuropsychologic function after 6 weeks of therapy at the target dosage was compared with baseline assessment s in each group . Both groups showed a statistically significant improvement from baseline to repeated assessment s on measures of attention , executive functioning , psychomotor speed , and visual memory ( p < 0.001 ) ; these gains were attributed to a practice effect . No significant changes were noted in measures of learning , verbal memory , or reaction time , and neither group showed any deterioration from baseline to retesting in any aspect of neuropsychologic function . These findings call into question the assumption that long-term benzodiazepine therapy produces significant neuropsychologic deficit in patients with diagnosed anxiety disorders BACKGROUND Exposure to external phobic cues is an effective therapy for  panic/agoraphobia  but the value of exposure to interoceptive cues is unclear . AIMS R and omised controlled comparison in panic/agoraphobia of the effects of ( a ) external , ( b ) interceptive or ( c ) combined external and interoceptive self-exposure to ( d ) control subjects . METHOD Eighty out- patients were r and omised to a control group or to one of three forms of self-exposure treatment ( external , interoceptive , or combined ) . Each treatment included seven sessions over 10 weeks and daily self-exposure homework . Assessment s were at pre- and post-treatment and up to 1 year post-entry . Assessors remained blind during treatment . RESULTS The three self-exposure groups improved significantly and similarly at post-treatment and up to 1-year followup , and significantly more than did the control subjects . Rates of improvement on main outcome measures averaged 60 % at post-treatment and 77 % at follow-up . CONCLUSIONS The three methods of self-exposure were equally effective in reducing panic and agoraphobic symptoms in the short- and long-term Pre-treatment predictors of treatment outcome were examined in a group of 144 patients with panic disorder and agoraphobia r and omly allocated to alprazolam+exposure ( AE ) , placebo+exposure ( PE ) , alprazolam+relaxation ( AR ) , and placebo+relaxation ( PR ) . First-time psychotropic medication use , severity of agoraphobic disability , and longer duration of illness predicted less global improvement at post-treatment . Pre-treatment severity of agoraphobia predicted less improvement both in the short- and the long-term . Predictors of poorer outcome at 6-month follow-up were older age , past history of depression , severity of phobia targets , and longer duration of illness . Sex , source of referral , pre-treatment depression-anxiety-panic , and expectancy from treatment did not relate to outcome Cognitive therapy ( CT ) is a specific and highly effective treatment for panic disorder ( PD ) . Treatment normally involves 12 - 15 1-hr sessions . In an attempt to produce a more cost-effective version , a briefer treatment that made extensive use of between-sessions patient self- study modules was created . Forty-three PD patients were r and omly allocated to full CT ( FCT ) , brief CT ( BCT ) , or a 3-month wait list . FCT and BCT were superior to wait list on all measures , and the gains obtained in treatment were maintained at 12-month follow-up . There were no significant differences between FCT and BCT . Both treatments had large ( approximately 3.0 ) and essentially identical effect sizes . BCT required 6.5 hr of therapist time , including booster sessions . Patients ' initial expectation of therapy success was negatively correlated with posttreatment panic-anxiety . Cognitive measures at the end of treatment predicted panic-anxiety at 12-month follow-up Objective The present study examined the prevalence of  panic disorder  with or without agoraphobia according to DSM-IV criteria in the Swedish general population . Method Data were obtained by means of a postal survey administrated to 1000 r and omly selected adults . The panic disorder module of the World Health Organization 's Composite International Diagnostic Interview ( CIDI ) was included in the survey . Results 12-month prevalence was estimated at 2.2 % ( CI 95 % 1.02 % – 3.38 % ) . There was a significant sex difference , with a greater prevalence for women ( 5.6 % ) compared to men ( 1 % ) . Conclusion The Swedish panic disorder prevalence is relatively consistent with findings in most other parts of the western world In a controlled trial of alprazolam and exposure in 154 patients with panic disorder with agoraphobia , relations between panic , anticipatory anxiety , and phobic avoidance were examined . The three symptoms were independent of one another at baseline and improved largely independently during treatment ; only early improvement in avoidance predicted global improvement after treatment . Global improvement was more related to reduction of avoidance than a decrease in panics . Panic was not a valuable outcome measure in panic disorder with agoraphobia We analysed 113 reports published in 1980 in a sample of medical journals to relate features of study design to the magnitude of gains attributed to new therapies over old . Overall we rated 87 per cent of new therapies as improvements over st and ard therapies . The mean gain ( measured by the Mann-Whitney statistic ) was relatively constant across study design s , except for non-r and omized controlled trials with sequential assignment to therapy , which showed a significantly higher likelihood that a patient would do better on the innovation than on st and ard therapy ( p = 0.004 ) . R and omized controlled trials that did not use a double-blind design had a higher likelihood of showing a gain for the innovation than did double-blind trials ( p = 0.02 ) . Any evaluation of an innovation may include both bias and the true efficacy of the new therapy , therefore we may consider making adjustments for the average bias associated with a study design . When interpreting an evaluation of a new therapy , readers should consider the impact of the following average adjustments to the Mann-Whitney statistic : for trials with non-r and om sequential assignment a decrease of 0.15 , for non-double-blind r and omized controlled trials a decrease of 0.11 BACKGROUND Current recommendations suggest that pharmacotherapy for patients with panic disorder should be continued for at least 1 year [ Am . J. Psychiatry 155 ( 1998 ) 1 ] , despite a paucity of data systematic ally examining outcome for periods greater than 3 - 6 months . It is critically important to obtain more information on the effectiveness of medications over time for patients who initially responded to pharmacotherapy for panic disorder . METHODS Long-term outcome was examined for 78 patients who attained a 2-month period of sustained remission on medication and received maintenance pharmacotherapy for up to 24 months during the Massachusetts General Hospital Longitudinal Study of Panic Disorder , a prospect i ve , naturalistic study . Participants were categorized by their maintenance treatment condition at remission : benzodiazepine alone ( N = 45 , 58 % ) , antidepressant alone ( N = 12 , 16 % ) , and combined treatment with a benzodiazepine and an antidepressant ( N = 21 , 27 % ) . RESULTS Approximately half ( N = 36 , 46 % ) of the patients who had achieved remission relapsed at some time over the 2-year naturalistic study period , despite continued and adequate pharmacotherapy . There was no difference in timing or frequency of relapse by type of maintenance pharmacotherapy . LIMITATIONS Interpretation of the data is limited by the naturalistic nature of the study , and by the relatively low sample size . CONCLUSIONS This data suggests that patients with panic disorder have a high rate of relapse even after acute response to pharmacotherapy , despite continued treatment . In addition , the use of combined pharmacotherapy with antidepressants and benzodiazepines does not appear to provide greater protection from relapse than monotherapy 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 Compared the effectiveness of cognitive therapy and performance-based exposure as treatments for panic attacks . Subjects were 48 panicky individuals selected without regard to agoraphobic disability , and who varied widely in that respect . Subjects were assigned r and omly to either cognitive treatment , performance-based exposure treatment , a combined cognitive/performance treatment , or a no-treatment control condition . All three treatments led to marked and enduring improvements in panic , and did not differ from one another in effectiveness , whereas the control condition produced little benefit . However , on several measures of phobia and panic-related cognitions , performance exposure was significantly more effective than cognitive therapy . Degree of agoraphobic disability had a significant bearing on panic treatment effectiveness . Whereas 94 % of the low agoraphobia Ss were free of panic after treatment , only 52 % of the high agoraphobia Ss became panic-free . The findings suggest that when panic treatment research excludes people with serious phobias , as it has routinely done in recent years , an overly positive estimate of panic treatment effectiveness can result Fifty-seven chronic agoraphobic out patients were treated by 12 hours of exposure in vivo on four days over two weeks to check the effects of oral diazepam versus placebo during group exposure , group versus individual exposure , and high versus medium anxiety arousal during individual exposure . The controlled parallel design allowed comparative evaluation of each treatment condition to six months follow-up . Assessment was blind with respect to drug and psychological treatment . Patients in all treatment conditions improved significantly in phobias and in related life areas . Outcome to group exposure on phobias and other measures was similar in all three drug conditions ( placebo , waning diazepam , peak diazepam ) with no significant differences between them . Diazepam patients had significantly less discomfort than placebo patients during group exposure treatment . Group exposure patients improved slightly but significantly more than individual exposure patients on non-phobic measures , though group exposure was accompanied by more panics during treatment yet was easier to run by the therapist . Individual exposure under high anxiety arousal was no more therapeutic than with lower anxiety .  Diazepam is a mild palliative during group exposure but does not facilitate outcome to treatment . Group exposure in vivo is mildly facilitatory for outcome compared with individual exposure . Anxiety evocation during treatment was not therapeutically helpful The objectives of this prospect i ve study were to calculate incidence rates for fall-related hospitalization , to compare the effect of risk factors among  benzodiazepine ( BZD ) users and unexposed controls , and to examine variations in risks according to length of time following a BZD prescription . Data were derived from Saskatchewan Health linked data bases , leading to information on 468 hospitalizations for injury due to falls among a study population of 321422 .  Incidence rates per 10000 within 28 days of the prescription fill date were 26.2 , 12.1 and 9.0 for BZD sedative users , BZD tranquillizer users and for unexposed controls , respectively . Incidence rates increased with age , and were higher for women than for men . Results from multivariate logistic regression models also showed a greater risk of falling for BZD users but the odds ratio was higher for men than for women . A history of treatment for alcohol abuse was a very strong risk factor for falls among both men ( odds ratio , 10.7 ) and women ( odds ratio , 4.3 ) . The highest risk of serious injury due to falls was within 15 days of filling the prescription , with an odds ratio of 3.6 for BZD sedatives and 2.6 for BZD tranquillizers . Risk decreased with further increase of time after the BZD fill date . For the individual BZD , flurazepam and triazolam showed the highest increase in risk with odds ratios of 3.4 and 2.7 , respectively , while oxazepam , lorazepam and diazepam showed odds ratios of 2.2 , 2.0 and 1.8 ( all odds ratios mentioned are statistically significant at p < 0.05 ) Controlled clinical trials of the treatment of acute myocardial infa rct ion offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment . A group of 145 papers was divided into those in which the r and omization process was blinded ( 57 papers ) , those in which it may have been unblinded ( 45 papers ) , and those in which the controls were selected by a nonr and om process ( 43 papers ) . At least one prognostic variable was maldistributed ( P less than 0.05 ) in 14.0 per cent of the blinded-r and omization studies , in 26.7 per cent of the unblinded-r and omization studies , and in 58.1 per cent of the nonr and omized studies . Differences in case-fatality rates between treatment and control groups ( P less than 0.05 ) were found in 8.8 per cent of the blinded-r and omization studies , 24.4 per cent of the unblinded-r and omization studies , and 58.1 per cent of the nonr and omized studies . These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration The present study examined the efficacy of an 8-wk , cognitive-behavioral group treatment for panic disorder . Patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia were r and omly assigned to treatment ( N = 34 ) or delayed treatment control ( N = 33 ) . The treatment consisted of : ( a ) education and corrective information ; ( b ) cognitive therapy ; ( c ) training in diaphragmatic breathing ; and ( d ) interoceptive exposure . At posttreatment , 85 % of treated Ss were panic free , compared to 30 % of controls . Treated Ss also showed clinical ly significant improvement on indices of anxiety , agoraphobia , depression and fear of fear . Recovery , as estimated conservatively by the attainment of normal levels of functioning on each of the major clinical dimensions of the disorder ( i.e. panic , anxiety and avoidance ) , was achieved in 64 % of the treated Ss and 9 % of the controls . At the 6 month follow-up , 63 % of the treated patients met criteria for recovery . These findings mirror those from recently-completed trials of individually-administered cognitive-behavioral treatment , and suggest that CBT is a viable alternative to pharmacotherapy in the treatment of panic disorder The intensity of putative benzodiazepine withdrawal symptoms was evaluated as part of a double blind placebo-controlled study of benzodiazepines and behaviour therapy in the management of agoraphobia . During the first phase of that study , some subjects were switched from low dose diazepam to placebo , and others remained on diazepam . Symptoms were evaluated in long-term benzodiazepine users ( n=30 ) and non-users ( n=32 ) when they first entered the study and 4 weeks later , after both groups had been r and omized to either diazepam or placebo , using eight analog rating scales measuring commonly reported withdrawal symptoms . At baseline , both users and non-users reported a substantial number of symptoms , with higher levels in the more anxious patients , but no differences between groups . After the transition to either diazepam or placebo , the users switched to placebo reported significantly higher levels of symptoms than users switched to diazepam and non-users combined . Multiple regression analysis suggested that the increase in symptoms was associated with the increase in anxiety , which was higher in the withdrawing group than the other three groups . These results raise questions concerning the extent to which withdrawal symptoms uniquely characterize benzodiazepine withdrawal . They confirm the common assumption that an increase in symptoms often accompanies withdrawal from benzodiazepines , but suggest that such symptoms are not so intense as to make withdrawal excessively difficult , at least in low-dose users BACKGROUND The widespread use of benzodiazepines has led to increasing recognition of their unwanted effects . The efficacy of alprazolam and placebo in panic disorder with agoraphobia , and the side-effect and adverse effect profiles of both drug groups were measured . METHOD In London and Toronto 154 patients who met DSM-III criteria for panic disorder with agoraphobia were r and omised to alprazolam or placebo .  Subjects in each drug group also received either exposure or relaxation . Treatment was from weeks 0 to 8 and was then tapered from weeks 8 to 16 . RESULTS Mean alprazolam dose was 5 mg daily . Compared with placebo subjects , alprazolam patients developed more adverse reactions ( 21 % v. 0 % ) of depression , enuresis , disinhibition and aggression ; and more side-effects , particularly sedation , irritability , impaired memory , weight loss and ataxia . Side-effects tended to diminish during treatment but remained significant at week 8 . Despite this , the drop-out rate was low . CONCLUSIONS Alprazolam caused side-effects and adverse effects during treatment but many patients were willing to accept these OBJECTIVE The authors investigated whether cognitive behavioral treatment could facilitate discontinuation of alprazolam therapy and maintenance of drug abstinence among panic disorder patients treated with alprazolam doses sufficient to suppress spontaneous panic attacks . METHOD Twenty-one out patients who met DSM-III-R criteria for panic disorder with mild to severe agoraphobia were made panic-free with alprazolam ( mean dose = 2.2 mg/day ) and were then r and omly assigned to receive either supportive drug maintenance and slow , flexible drug taper or an identical medication treatment plus 12 weeks of concurrent , individual cognitive behavioral treatment . Taper in the combined treatment group was sequenced to conclude before cognitive behavioral treatment ended . RESULTS Twenty subjects completed the study . There was no significant difference between groups in the rate of alprazolam discontinuation ( 80 % and 90 % , respectively , in the alprazolam-only group and the combined treatment group ) . However , during the 6-month follow-up period , half of the subjects who discontinued alprazolam without cognitive behavior therapy , but none of those who were given cognitive behavior therapy , relapsed and resumed alprazolam treatment . CONCLUSIONS Cognitive behavioral treatment administered in parallel with alprazolam maintenance and taper was effective in preventing relapse after drug discontinuation . The results warrant further research on the thoughtful integration of these two therapeutic modalities Panic disorder , which is found in about 1.5 percent of the population at some time in their lives , includes recurrent episodes of sudden , unpredictable , intense fear accompanied by symptoms such as palpitations , chest pain , and faintness . Panic attacks , which do not meet these diagnostic criteria fully , are two to three times more prevalent . Since panic symptoms can mimic those of other medical disorders , patients with these symptoms use medical services frequently . To determine the risk of suicidal ideation and suicide attempts in panic disorder and attacks , we studied a r and om sample of 18,011 adults drawn from five U.S. communities . Subjects who had panic disorder , as compared with other psychiatric disorders , had more suicidal ideation and suicide attempts , with an adjusted odds ratio for suicide attempts of 2.62 ( 95 percent confidence interval , 1.83 to 3.74 ) . The odds ratio was 17.99 ( 95 percent confidence interval , 12.18 to 26.58 ) when the group with panic disorder was compared with subjects who had no psychiatric disorder . Twenty percent of the subjects with panic disorder and 12 percent of those with panic attacks had made suicide attempts . These results could not be explained by the coexistence of major depression or of alcohol or drug abuse . We conclude that panic disorder and attacks are associated with an increased risk of suicidal ideation and suicide attempts . Physicians working in general medical setting s and emergency departments should be alert to this problem Eighty clients enrolled in a managed care health plan who identified panic disorder as their primary presenting problem were r and omly assigned to treatment by a therapist recently trained in a manual-based empirically supported psychotherapy or a therapist conducting treatment as usual ( TAU ) .  Participants in both conditions showed significant change from pre- to posttreatment on a number of measures . Those receiving  panic control therapy ( PCT ) showed greater levels of change than those receiving TAU . Among treatment completers , an average of 42.9 % of those in PCT and 18.8 % in TAU achieved clinical ly significant change across measures . The results are discussed with reference to the dissemination of PCT and other evidence -based psychotherapies to clinical practice setting OBJECTIVE How far the results of r and omized controlled studies apply to everyday care can not be judged without regular measurements of outcomes in daily practice . We report on systematic data from a 3-year naturalistic prospect i ve study on panic disorder-agoraphobic ( PDA ) patients treated with antidepressants in a setting of routine clinical practice . Our aim is to describe the evolution of PDA in relation to the treatments employed , and to explore demographic and clinical characteristics that might be predictive of outcome . METHODS 326 DSM-III-R PDA patients treated with antidepressants in a setting of routine clinical practice were included in a 3-year naturalistic prospect i ve study . We utilized structured and semi-structures instruments , including the Structured Clinical Interview for Diagnosis and the Longitudinal Interview Follow-up Examination . The main antidepressants used were imipramine ( 39 % ) , clomipramine ( 28.5 % ) and paroxetine ( 23.3 % ) ; only 9 % of patients received other antidepressants . RESULTS 147 patients ( 45.1 % ) stayed on medication throughout the entire period of the follow-up . Of those who interrupted the treatment , 38 % stayed in remission . The probability of achieving at least one remission during the 3-year follow-up period was 96.5 % for PD and 95.9 % for Agoraphobia . Relapses after a period of at least 2 months of complete remission were also common , and the probability of presenting at least one relapse during the 3-years follow-up period was 67.1 % for PD and 39 % for Agoraphobia . The longest period of remission of PD is associated with low severity , medium-lasting course in patients with an onset of the illness in young adulthood . Less severe agoraphobia associated with moderately severe panic attacks appears to confer a better control of phobic behavior . All three major drugs were reasonably well tolerated ( only 9 % dropped out because of side effects ) , with sexual dysfunction and increased appetite being the most common side effects at the last evaluation ; in the first phase of the treatment anticholinergic effects and jitteriness were more common with TCAs . CONCLUSION Both classical antidepressants and paroxetine emerge as a useful treatment in the long-term management of PDA ; paroxetine appears particularly useful in PDA patients because it was significantly less likely to induce jitteriness , thereby reducing barriers to compliance To examine the effect of treatment on lactate-induced anxiety in a controlled study , we infused 44 panic disorder patients with lactate and placebo before and after eight weeks of double-blind treatment with imipramine , diazepam , or placebo . During treatment , both imipramine and diazepam groups improved more than the placebo group . After treatment , patients in both the imipramine and diazepam groups had significantly less anxiety than the placebo patients when reinfused with lactate . In addition , imipramine decreased posttreatment panic attack frequency and diazepam decreased the perceived severity of posttreatment lactate-induced panic attacks . This study demonstrates that diazepam , like imipramine , is an effective treatment for panic disorder , and that both imipramine and diazepam blunt lactate-induced anxiety in a placebo controlled study OBJECTIVE The primary disadvantage of high-potency benzodiazepine treatment for panic disorder is the difficulty of discontinuing the treatment . During treatment discontinuation , new symptoms may emerge and anxiety may return , preventing many patients from successfully discontinuing their treatment . In this controlled , r and omized trial the authors investigated the efficacy of a cognitive-behavioral program for patients with panic disorder who were attempting to discontinue treatment with high-potency benzodiazepines .  METHOD Out patients treated for panic disorder with alprazolam or clonazepam for a minimum of 6 months and expressing a desire to stop taking the medication ( N = 33 ) were r and omly assigned to one of two taper conditions : a slow taper condition alone or a slow taper condition in conjunction with 10 weeks of group cognitive-behavioral therapy . RESULTS The rate of successful discontinuation of benzodiazepine treatment was significantly higher for the patients receiving the cognitive-behavioral program ( 13 of 17 ; 76 % ) than for the patients receiving the slow taper program alone ( four of 16 ; 25 % ) . There was no difference in the likelihood of discontinuation success between the patients treated with alprazolam and those who received clonazepam . At the 3-month follow-up evaluation , 77 % of the patients in the cognitive-behavioral program who successfully discontinued benzodiazepine treatment remained benzodiazepine free . CONCLUSIONS These findings support the efficacy of cognitive-behavioral interventions in aiding benzodiazepine discontinuation for patients with panic disorder A cross-national r and omised trial of alprazolam for chronic panic disorder with agoraphobia was run . Compared with previous trials it had three new features : an exposure therapy contrast group , a six-month treatment-free follow-up , and a low rate of early placebo drop-outs ( ' non-evaluables ' ) . The dose of alprazolam was high ( 5 mg/day ) . The 154 patients had eight weeks of : alprazolam and exposure ( combined treatment ) ; or alprazolam and relaxation ( a psychological placebo ) ; or placebo and exposure ; or placebo and relaxation ( double placebo ) . Drug taper was from weeks 8 to 16 . Follow-up was to week 43 . Results were similar at both sites . Treatment integrity was good . All four treatment groups , including double placebo , improved well on panic throughout . On non-panic measures , by the end of treatment , both alprazolam and exposure were effective , but exposure had twice the effect size of alprazolam . During taper and follow-up , gains after alprazolam were lost , while gains after exposure were maintained . Combining alprazolam with exposure marginally enhanced gains during treatment , but impaired improvement thereafter . The new features put previous trails in a fresh light . By the end of treatment , though gains on alprazolam were largely as in previous studies , on phobias and disability they were half those with exposure . Relapse was usual after alprazolam was stopped , whereas gains persisted to six-month follow-up after exposure ceased . Panic improved as much with placebo as with alprazolam or exposure 23 patients with a diagnosis of panic disorder with agoraphobia were r and omly assigned to 8 weeks ' treatment with alprazolam or placebo . They filled in self-ratings before and after treatment and competed on a competitive reaction time task , design ed to measure behavioural aggression , after 8 weeks ' treatment . Patients taking both alprazolam and placebo rated decreased anxiety after 8 weeks ' treatment but those on alprazolam also tended to report less hostility . On the behavioural task , patients on alprazolam behaved more aggressively in response to provocation . This is the first study to confirm clinical reports of benzodiazepine-induced dyscontrol on an objective laboratory measure . It is important that it is followed up in a larger group of patients In a double-blind controlled study lasting 8 weeks , 50 anxious psychoneurotic out patients with a primary diagnosis of generalized anxiety or panic disorder were r and omly assigned to alprazolam ( n=30 ) , a new benzodiazepine , or placebo ( n=20 ) , after a washout period of 1 week . Alprazolam at dosages between 0.25 and 3 mg/day was found to be significantly better than placebo in the treatment of either disorder . The finding that alprazolam was effective in the treatment of panic disorder is of interest as this diagnostic category is usually treated with tricyclic antidepressants or MAO inhibitors Forty-eight patients currently experiencing panic attacks were r and omly assigned to double-blind treatment with alprazolam , diazepam , or placebo .  Efficacy was assessed using the Hamilton Rating Scale for Anxiety and a panic attack frequency rating scale . Results indicate that the two active treatments appeared equally effective in reducing both the frequency of panic attacks and the severity of generalized anxiety when compared with placebo . Overall , these data support the use of benzodiazepines in the treatment of panic disorder It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse . This study further explores the relationship between relapse and duration of imipramine treatment in this population . Fifty-one patients , all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and r and omized to double-blind maintenance or placebo substitution , discontinued imipramine treatment eventually and were followed over a 12-month risk period : 27 during first year placebo substitution , 7 after 12 months of imipramine maintenance in placebo substitution , and 17 after variable duration s of imipramine maintenance in open discontinuation . There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation . Duration of imipramine treatment , the method of discontinuation ( open versus placebo substitution ) , or any of the 9 variables from the demographic , clinical , and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse . The rate of relapse after only 6 months of treatment ( 10 out of 27 , 37 % ) was identical to the rate of relapse after 12 to 30 months of treatment ( 9 out of 24 , 37.5 % ) . The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients . Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction Severely agoraphobic patients were treated with a combination of imaginal flooding and exposure to phobic situations in practice . This behavioural treatment was found to be more effective if given together with an anxiolytic drug ( diazepam ) . There was no indication that the therapeutic changes induced were smaller or more transient if the patient attributed them to the drug rather than to the behavioural treatment ; instead there appeared to be a placebo-like effect as well as the drug effect The present study investigated the impact of pre-existing pharmacotherapy regimes on the long-term outcome of brief intensive group cognitive-behavioural therapy ( BIGCBT ) in the treatment of panic disorder with or without agoraphobia in 106 patients ( 74 females ) . Forty patients were allocated to BIGCBT without medication , 40 to BIGCBT plus anti-anxiety medication , 10 to BIGCBT plus anti-depressant medication and 16 to BIGCBT plus combined anti-anxiety and anti-depressant medications . The mean follow-up period was 3.2 yr and ranged from 1.1 to 6.2 yr . The results demonstrated that patients who received BIGCBT concurrent with pre-existing medication regimes did not differ significantly ( P > 0.001 ) from each other or from patients who underwent BIGCBT without medication on any of the dependent measures either at pre-treatment assessment or long-term follow-up . However , BIGCBT ( with or without pharmacotherapy ) was associated with significant ( P < 0.001 ) long-term improvements in frequency of panic attacks , avoidance behaviour and question naire measures of anxiety , depression and agoraphobia . Furthermore , the large majority ( 80 % ) of patients in the BIGCBT without medication group remained medication-free at long-term follow-up . Of those patients who underwent BIGCBT concurrent with pre-existing pharmacotherapy , a large percentage ( 44 % ) reported no longer taking medication for their condition at long-term follow-up . Overall , it is concluded that pre-existing medication regimes ( anti-anxiety , anti-depressant or combinations of these ) do not significantly enhance or detract from the long-term outcome of a BIGCBT program used in the treatment of panic disorder and agoraphobia BACKGROUND Benzodiazepines ( BZs ) can impair explicit memory after a single dose and also when taken repeatedly for treatment of anxiety disorders . A previous study with agoraphobia/panic patients found that the BZ alprazolam impaired memory during an 8-week treatment and residual impairments were still manifest several weeks after drug withdrawal ( Curran et al. 1994 ) . The present study followed up the same group of patients 3.5 years after treatment to determine whether those memory impairments persisted . METHOD Thirty-one patients , 15 who had originally been treated with alprazolam and 16 with placebo  , were assessed on a battery of psychometric tests and self-rating scales .  RESULTS Ex-alprazolam patients performed at the same levels as ex-placebo patients on the memory task and on other objective tests . Performance levels of both groups were similar to pre-treatment baselines , however there were differences in subjective ratings whereby ex-alprazolam patients rated themselves as less attentive and clear headed and more incompetent and clumsy than ex-placebo patients . CONCLUSIONS Explicit memory impairments found while patients were taking alprazolam and weeks after drug withdrawal did not persist 3.5 years later . We suggest that the memory impairments observed in our previous study weeks after withdrawal of alprazolam were not residual effects of alprazolam but rather were due to the drug 's interference with practice effects on the tests and habituation of anxiety over repeated exposure to the test situation OBJECTIVE This study sought to determine the short- and long-term effects of focused cognitive therapy for  panic disorder . METHOD Thirty-three psychiatric out patients with the DSM-III diagnosis of panic disorder were r and omly assigned to either 12 weeks of individual , focused cognitive therapy or 8 weeks of brief supportive psychotherapy based on principles of client-centered therapy . The patients who received supportive psychotherapy were subsequently given the opportunity to cross over to cognitive therapy for 12 weeks . Patients were rated for panic and depression before therapy , after 4 and 8 weeks of therapy , and at 6-month and 1-year follow-up . RESULTS Clinician ratings and self-ratings of panic frequency and intensity indicated that the focused cognitive therapy group achieved significantly greater reductions in panic symptoms and general anxiety after 8 weeks of treatment than did the group that received brief supportive psychotherapy . At 8 weeks , 71 % of the cognitive therapy group were panic free , compared to 25 % of the psychotherapy group . Moreover , 94 % of the psychotherapy patients elected to cross over to 12 weeks of cognitive therapy . At 1-year follow-up , 87 % of the group that received cognitive therapy only and 79 % of the group that crossed over into cognitive therapy remained free of panic attacks . CONCLUSIONS Focused cognitive therapy offers a promising nonpharmacological alternative for the treatment of panic disorder BACKGROUND Alprazolam has proven efficacy as a treatment for panic disorder , but the place of other benzodiazepines is less well established . METHOD To compare the efficacy and tolerability of diazepam and alprazolam for the disorder , a placebo-controlled , double-blind trial was undertaken in two sites . Two hundred forty-one subjects with panic disorder or agoraphobia with panic attacks were r and omly assigned to flexible doses of diazepam , alprazolam , or placebo for 8 weeks . RESULTS At the end of the trial , over 60 % of subjects taking either diazepam or alprazolam were at least moderately improved compared with less than 30 % of those taking placebo . On all measures of efficacy , subjects taking diazepam and alprazolam showed an equally favorable response . Despite some sedation early in the trial , both drugs were tolerated well . More severely ill subjects responded less well to either benzodiazepine . CONCLUSION The results indicate that diazepam is an effective alternative to alprazolam for the treatment of panic disorder Benzodiazepines ( BZs ) produce transient antero grade amnesia when given to normal subjects . The present longitudinal study assessed whether BZs impair memory functions in a clinical ly anxious group . Eighty-two agoraphobics with panic disorder were r and omly allocated to one of four treatment groups result ing from a combination of two drug treatments ( alprazolam or placebo ) and two psychological treatments ( exposure or relaxation ) . Of these , 38 subjects were assessed on a range of objective and subjective indices of memory and mood at three time points : before treatment , after 8 weeks of treatment and again at 24 weeks when patients had been free of medication from 5 - 8 weeks . Alprazolam produced pronounced impairments on a word recall task . At the 24-week medication-free follow-up , alprazolam patients were still impaired on the task compared with placebo patients . Alprazolam did not impair performance on an implicit memory task and did not affect digit span . Differences between psychological treatments emerged mainly in subjective memory effects . Findings are discussed in terms of the specificity of BZ-induced amnesia and differential tolerance to the varying effects of BZs . Implication s are drawn out for the patient 's ability to function optimally in daily life while taking alprazolam Panic disorder ( PD ) is associated with significant social and health consequences . The present study examined the impact of treatment on PD patients '  quality of life . Patients ( N = 156 ) meeting DSM-III-R ( Diagnostic and Statistical Manual of Mental Disorders [ 3rd ed . , rev . ] ; American Psychiatric Association , 1987 ) criteria for PD with agoraphobia were r and omly assigned to group cognitive-behavioral treatment ( CBT ) or a delayed-treatment control . An assessment battery measuring the major clinical features of PD as well as quality of life was administered at baseline ( Week 0 ) , post-treatment ( Week 9 ) and 6-month follow-up ( Week 35 ) . Consistent with previous studies , PD patients displayed significant impairment in quality of life at intake . Compared with delayed-treatment control participants , CBT-treated participants showed significant reductions in impairment that were maintained at follow-up . Consistent with prediction , anxiety and phobic avoidance were significantly associated with quality of life , whereas frequency of panic attacks was not In a study design ed to evaluate the impact of benzodiazepine use on the outcome of behaviour  therapy , 91 , severe , chronic agoraphobics ( 46 BDZ users and 45 non-users ) were r and omly allocated on a double-blind basis to in vivo exposure with low-dose diazepam ( ED ) or placebo ( EP ) . Drug doses were adjusted on the basis of weekly psychiatric assessment s over weeks 1 - 4 . Patients had 8 x 2 hr exposure sessions ( weeks 5 - 12 ) and were then withdrawn from medication ( weeks 13 - 16 ) . Re- assessment s were completed at weeks 4 , 12 and 16 , and follow-up assessment s at approx 20 , 46 and 72 weeks . In the analysis of the results , the clinical outcome was evaluated in relation to the therapeutic regime ( ED vs EP ) and prior BDZ use ( users vs non-users ) . The results showed that the ED group had greater changes in anxiety than the EP group during the drug manipulation phases ( anxiety increasing during BDZ withdrawal ) . There were no group differences in agoraphobic symptoms and no evidence that the outcome of the behavior therapy was significantly affected by concurrent BDZ treatment . There were significant improvements in agoraphobic symptoms over the treatment period , with no evidence for relapse of treatment gains on withdrawal from BDZ , nor for differential responses over the one year follow-up . Initial differences between users and non-users were less marked than expected , although there was a trend for more drop-outs among users across both ED and EP groups Cognitive-behavioral therapy ( CBT ) is the psychological treatment of choice for panic disorder ( PD ) . However , given limited access to CBT , it must be delivered with maximal cost-effectiveness . Previous research ers have found that a brief computer-augmented CBT was as effective as extended therapist-delivered CBT . To test this finding , this study r and omly allocated 186 patients with PD across 2 sites in Scotl and and Australia to 12 sessions of therapist-delivered CBT ( CBT12 ) , 6 sessions of therapist-delivered ( CBT6 ) or computer-augmented CBT ( CBT6-CA ) , or a waitlist control . On a composite measure , at posttreatment , the outcome for CBT 12 was statistically better than the outcome for CBT6 . The outcome for CBT6-CA  fell between CBT12 and CBT6 , but could not be statistically distinguished from either treatment . The active treatments did not differ statistically at 6-month follow-up . The study provided some support for the use of computers as an innovative adjunctive-therapy tool and merits further investigation BACKGROUND We determined whether blindness in a double-blind r and omized controlled trial of alprazolam and exposure therapies in patients with panic disorder and agoraphobia was maintained in assessors and patients , what were the factors related to " unblinding , " and whether unblinding was associated with clinical outcome . METHOD In 129 patients with panic disorder and agoraphobia who were r and omized to alprazolam-exposure , placebo-exposure , alprazolam-relaxation , or placebo-relaxation conditions , blindness was tested at the end of treatment by the independent assessors ' and patients ' classification of the treatment condition . RESULTS Assessors ' classifications were correct in 82 % of the alprazolam group and 78 % of the placebo group ; corresponding figures for patients ' classifications were 73 % and 70 % , respectively . Factors associated with unblinding included drug side effects but not assessors ' ratings of treatment outcome . CONCLUSION Judgment of the validity of the outcome of a r and omized controlled trial is easier if the report notes not only the use of a double-blindness procedure but also details how blind the raters remained and how any unblinding affected their ratings of clinical outcome Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication . In this study , 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks . The medication was tapered over a period of four weeks , and patients were observed for another two weeks after all medication was discontinued . Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study . After improvement in the active treatment period , the alprazolam-treated group had significant relapse between the first and last week of taper . However , during the second postdiscontinuation week , outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper . Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13 % reported a rebound of anxiety on the Hamilton Anxiety Scale . No serious or life-threatening withdrawal symptoms were reported , but distinct , transient , mild to moderate withdrawal syndrome occurred in 35 % of the alprazolam-treated group and in none of the placebo-treated group . The coexistence of symptom rebound and a withdrawal syndrome occurred in 10 % of the alprazolam-treated group , but both subsided by the end of the second week without alprazolam . We recommend that patients with panic disorder be treated for a longer period , at least six months , and that medication be tapered over a more prolonged period , at least eight weeks , especially where high doses are employed The response to diazepam and propranolol hydrochloride was compared in 21 patients who ( with one exception ) met DSM-III criteria for panic disorder and agoraphobia . Each drug was administered for two weeks in double-blind fashion according to a crossover design . The response to diazepam was significantly superior on all measures . By observer rating , 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol .  Panic attacks and phobic symptoms responded to diazepam , but not to propranolol . The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders Patients with panic disorder plus agoraphobia had 8 weeks of drug treatment ( alprazolam or placebo ) plus psychological treatment ( exposure or relaxation ) . At the end of treatment at week 8 , 40 patients who had become much/very much improved rated how much their gains were attributable to medication or to their own efforts . During the tapering-off to week 16 , and treatment-free follow-up to week 43 , patients who at week 8 had attributed their gains to medication and felt less confident in coping without tablets had more severe withdrawal symptoms and greater loss of gains than did patients who at week 8 had attributed their gains to their own efforts during treatment . Baseline illness severity , greater age , higher expectations from drug treatment , and more side-effects of drugs during treatment all predicted more external attributions ( i.e. to the effect of drugs ) but did not independently predict relapse .  Patients on alprazolam compared with placebo  had more drug attributions . Though drug attributions predicted relapse in both alprazolam and placebo groups , predictions were stronger in the alprazolam group
target: The review established the paucity of high quality evidence investigating the efficacy of psychotherapy combined with benzodiazepines for panic disorder .
  Currently , there is inadequate evidence to assess the clinical effects of psychotherapy combined with benzodiazepines for patients who are diagnosed with panic disorder
background: BACKGROUND The efficacy of combining psychotherapy and benzodiazepines for panic disorder is unclear , despite widespread use .
  OBJECTIVES To examine the efficacy of the combination compared with either treatment alone .