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 Psychopharmacological treatment of panic disorder and related states: A Placebo controlled study of alprazolam Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial. Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. Anxiety psychopathology predictive of outcome in patients with panic disorder and depression treated with imipramine, alprazolam and placebo. Response of panic disorder to fixed doses of alprazolam or imipramine. Predictors of response to alprazolam and placebo in patients with panic disorder. A Fixed‐Dose Study of Alprazolam 2 mg, Alprazolam 6 mg, and Placebo in Panic Disorder Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Adinazolam Sustained‐Release Treatment of Panic Disorder: A Double‐Blind Study Combined pharmacological and behavioral treatment for agoraphobia. Patients with panic disorder unaccompanied by depression improve with alprazolam and imipramine treatment. Reduction in urinary free cortisol during benzodiazepine treatment of panic disorder Long-term outcome after acute treatment with alprazolam or clonazepam for panic disorder. Relapse and rebound following discontinuation of benzodiazepine treatment of panic attacks: alprazolam versus diazepam. Anxiety in primary care: is short-term drug treatment appropriate? Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. The Relationship of Alprazolam Dose to Steady‐State Plasma Concentrations A multiple imputation strategy for clinical trials with truncation of patient data. The effects of clonazepam on quality of life and work productivity in panic disorder. Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Correlates of Therapeutic Response in Panic Disorder Presenting with Palpitations: Heart Rate Variability, Sleep, and Placebo Effect Differential response to placebo among patients with social phobia, panic disorder, and obsessive-compulsive disorder. A comparison of a β2-adrenoceptor antagonist (ICI 118,551), diazepam and placebo in the treatment of acute anxiety A double-blind, placebo-controlled, multicenter study with alprazolam and extended-release alprazolam in the treatment of panic disorder. Relationship of past depressive episodes to symptom severity and treatment response in panic disorder with agoraphobia. Physician prognosis in relationship to drug and placebo response in anxious and depressed psychiatric outpatients. Adverse effects associated with the short-term treatment of panic disorder with imipramine, alprazolam or placebo Guidelines for the pharmacological treatment of anxiety disorders, obsessive–compulsive disorder and posttraumatic stress disorder in primary care Double-blind clonazepam vs placebo in panic disorder treatment. How "blind" are double-blind studies? Double-blind, placebo-controlled study of a once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Sertraline and alprazolam in the treatment of panic desorder. Double-blind clinical assessment of alprazolam, a new benzodiazepine derivative, in the treatment of moderate to severe anxiety. Prevalence of psychiatric disorder in the general population: results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS) Patient Stage of Change predicts outcome in a panic disorder medication trial. Adinazolam-SR in panic disorder with agoraphobia: relationship of daily dose to efficacy. Pattern of placebo response in panic disorder. A comparison of alprazolam and behavior therapy in treatment of panic disorder. Safety and side-effects of alprazolam. Controlled study in agoraphobia with panic disorder. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Two Anti-anxiety Drugs: A Psychoneuroendocrine Study Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Changes in Appetite and Weight during the Pharmacological Treatment of Patients with Panic Disorder * Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety. A comparative study of suriclone, lorazepam and placebo in anxiety disorder. Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper. Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages. Behavioural aggression in panic disorder after 8 weeks' treatment with alprazolam. Imipramine and Buspirone in Patients With Panic Disorder Who Are Discontinuing Long-term Benzodiazepine Therapy Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder Dose-Response Study Group. Treatment of Panic Disorder in Older Adults: A Pilot Study Comparison of Alprazolam, Imipramine, and Placebo Etizolam versus placebo in the treatment of panic disorder with agoraphobia: a double-blind study. Alprazolam, Propranolol, and Placebo in the Treatment of Panic Disorder and Agoraphobia with Panic Attacks Studies with oral lorazepam in anxiety neurosis associated with depressive symptomatology. Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind placebo-controlled study Long-term comparison of alprazolam, lorazepam and placebo in patients with an anxiety disorder. Alprazolam in the treatment of neurotic anxiety. The changes of thyroid hormone during pharmacological treatment of panic disorder patients Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder. Nonspecific factors and side effect complaints: FACTORS AFFECTING THE INCIDENCE OF DROWSINESS IN DRUG AND PLACEBO TREATED ANXIOUS AND DEPRESSED OUTPATIENTS Overview of the Cross-National Collaborative Panic Study. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. A 15-year follow-up study of patients with panic disorder. Dementia and antipsychotic drugs. Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia. Surreptitious drug use by patients in a panic disorder study. Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder. Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder. Evidence that decreased function of lymphocyte beta adrenoreceptors reflects regulatory and adaptive processes in panic disorder with agoraphobia. Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Cross-National Collaborative Panic Study, Second Phase Investigators. Sequence of improvement in agoraphobia with panic attacks. Diazepam versus alprazolam for the treatment of panic disorder. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. 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]. Dehydroepiandrosterone-sulfate/cortisol ratio in panic disorder Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response. Controlled discontinuation of benzodiazepine treatment for patients with panic disorder. Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder? Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam. Effect size as a measure of symptom-specific drug change in clinical trials. Drug treatment of panic disorder: early response to treatment as a predictor of final outcome Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects. The use of low-dose intranasal midazolam to treat panic disorder: a pilot study. The significance of HPA axis disturbance in panic disorder Withdrawal syndrome with gradual tapering of alprazolam.
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 The paper consists of two parts . A review of the relationship of panic disorder to the phobic states and the treatment of these disorders by means of tricyclic antidepressants , MAOIs , beta blocking drugs and benzodiazepines . A double blind study of alprazolam and placebo in 118 patients with agoraphobia and panic is presented . In an eight week study alprazolam was found to be significantly superior to placebo in the treatment of panic attacks , phobic avoidance , anticipatory anxiety and general anxiety 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 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 This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week , placebo-controlled trial of alprazolam and imipramine  ( n = 126 ) . Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment . Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4 . At endpoint , the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance . This relationship was not evident for completers , suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced 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 Date from a panic disorder treatment study with 506 patients , comparing alprazolam and placebo in a double-blind manner for 8 weeks , were analyzed to identify demographic and clinical characteristics of the patients that might predict response to treatment . The strongest predictors of response to alprazolam were age over 40 , and lower baseline levels of anxiety and phobic symptoms . Predictors of response to placebo were weaker and , in addition to lower levels anxiety and panic attacks , included a lack of previous psychiatric treatment A recently reported multinational , 8-week double-blind , placebo-controlled study assessing the efficacy of alprazolam versus placebo in the treatment of panic disorder indicated significant differences favoring alprazolam . We now report the results of a three-site , 6-week , double-blind , fixed-dose study comparing alprazolam 2 mg , alprazolam 6 mg , and placebo in 94 patients with panic disorder with or without agoraphobia . Both alprazolam treatment groups ( 6 mg and 2 mg ) improved significantly more than did the placebo treatment group on most outcome measures . Only a few statistically significant differences between the 6 mg and 2 mg alprazolam groups were discerned , although the pattern of treatment response across measures suggested a dose effect . Dropouts in the placebo group were primarily due to lack of efficacy and in the alprazolam 6 mg group were due to side effects , which may have contributed to the limited differences between groups at study end . The findings suggest that many patients may require less than 6 mg of alprazolam per day for effective treatment of panic disorder 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 Two hundred six out patients with panic disorder and agoraphobia were r and omly assigned to receive 4 weeks of treatment with placebo or sustained-release adinazolam under double-blind conditions . Eighty-eight percent of patients receiving drug and 85 % of patients receiving placebo remained in the study at week 4 . This report describes the “ intent-to-treat ” analysis of 202 patients who made at least one follow-up visit after r and omization at baseline . On the basis of the Clinical Global Impressions-Improvement Scale , 69.7 % of the adinazolam-treated patients were much or very much improved compared with 39.6 % of the placebo-treated patients at week 4 or end-point ( p = 0.0001 ) . At week 4 , panic attacks were completely blocked in 57.1 % of adinazolam-treated patients and in 39.2 % of the placebo-treated patients ( p = 0.009 ) . Adinazolam sustained-release treatment was statistically more effective than placebo treatment on measures of global improvement , number of panic attacks , SCL-90 phobia severity , main phobia severity , and anticipatory and general anxiety . No drug-placebo differences were found for overall self-rated phobia severity , unexpected or situational panic attacks , or for work , family , or social disability Thirty-seven severely-disabled agoraphobics were r and omly assigned to ( 1 ) Imipramine-no exposure . ( 2 ) Imipramine + exposure or ( 3 ) Placebo + exposure groups . To provide a more stringent test of the pharmacological effects of imipramine independent of exposure to phobic stimuli , Ss in the Imipramine-no exposure condition received antiexposure instructions during the first 8 weeks of therapy . Assessment s were conducted at 0 , 8 and 26 weeks . At 8 weeks , the group receiving imipramine combined with exposure therapy displayed more improvement than the other two groups , and was the only group to show a reduction in panic attacks . Ss receiving imipramine with antiexposure instructions showed little improvement on phobic indices , no reduction in panic , but significant improvement in anxiety and dysphoric mood . At 26 weeks Ss receiving the combined imipramine + exposure treatment exhibited further improvement result ing in a significant superiority of Imipramine + exposure over Placebo + exposure across a number of different outcome indices . Ss who had received imipramine with antiexposure instructions showed some improvement during the subsequent 18 weeks in which the antiexposure instructions were no longer in effect . However , neither this group nor the Placebo + exposure group showed a reduction in panic attacks . The results of the present trial provide support for the beneficial effects of combining intensive exposure with imipramine , but call into question the thesis that imipramine exerts its effect through a pharmacological blocking of panic attacks . Alternative hypotheses concerning the mode of action of imipramine are presented 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 Urinary free cortisol ( UFC ) levels were measured at baseline and at four and eight weeks after initiation of treatment in 66 patients who met DSM-III-R criteria for primary panic disorder ( PD ) . Thirty-seven normal control subjects also had UFC levels  measured three times at monthly intervals . Patients were r and omly assigned to treatment with alprazolam , diazepam , or placebo . At baseline , complicated PD patients ( those with agoraphobia and secondary depression ) had significantly higher UFC levels than did normal controls . At four and eight weeks , complicated PD patients receiving alprazolam and diazepam had significant reductions in UFC excretion compared to baseline . Patients with uncomplicated PD maintained UFC levels comparable to controls at each sampling period . Treatment with benzodiazepines did not lower UFC levels in this group . These findings suggest that patients with complicated PD demonstrate hyperactivity of the hypothalamo-pituitary-adrenal axis that is decreased by treatment with benzodiazepines The relative effectiveness of the available treatments for panic disorder may best be understood in the context of the longitudinal course of the disorder . This study examines a number of clinical ly relevant issues , including long-term outcome after acute treatment , the proportion of patients remaining on single-agent treatment or requiring multiple medications or nonpharmacologic interventions over time , evidence for dose escalation during maintenance high-potency benzodiazepine therapy , and predictors of acute and long-term response to treatment . Fifty-nine panic disorder patients originally r and omized to treatment in a controlled trial comparing alprazolam , clonazepam , and placebo  were reevaluated in a follow-up study . At a mean follow-up of 1.5 years , 78 % of patients remained on medication and the mean dosage of  alprazolam and clonazepam did not increase . Our data suggest that most patients maintain benefit with long-term pharmacotherapy but that residual symptomatology may require more intensive or additional treatment strategies . Response at the endpoint of the acute trial was significantly associated with pretrial baseline Clinical Global Impression Scale score and the presence of dysthymia . Poor outcome at follow-up was associated with total duration of the disorder , agoraphobic subtype , and the presence of comorbid social phobia . We underscore the potential importance of comorbid affective and anxiety disorders as well as phobic patterns in determining long-term response to treatment The authors assessed the effects of partial tapering followed by abrupt discontinuation of alprazolam , diazepam , and placebo in 40 patients with panic attacks .  The anxiety scores and frequency of panic attacks of the three groups did not differ at the end of the initial 2-week taper , but 1 week after abrupt discontinuation of the remaining medication , patients formerly taking alprazolam had greater increases in anxiety but no more panic attacks than did the other patients . Because of low statistical power , differences in benzodiazepine half-lives , absence of multiple ratings , and imbalances between groups in clinical characteristics , these findings must be viewed as preliminary Thirty-six patients with generalised anxiety disorder , panic disorder or agoraphobia with panic attacks , diagnosed by DSM-III criteria , were treated with a new non-benzodiazepine anti-anxiety drug , buspirone , and with diazepam and placebo , in a cross-over design . Each patient took buspirone , diazepam and placebo for one week each in flexible dosage and balanced order . Ratings of symptomatology using the Comprehensive Psychopathological Rating Scale were made after each week 's treatment and a sub-scale used for measuring anxiety change alone was used separately . There was no overall difference in efficacy between the drugs , but when the scores for individual symptoms were analysed , diazepam was significantly superior to the other treatments for the symptom of muscle tension only . The results suggest that the common practice of giving short-term therapy with tranquilising drugs for anxiety in primary care is pharmacologically suspect 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 Alprazolam is a widely used antianxiety agent , yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels . This study examines the relationship over a wide range of therapeutic doses . We conducted a parallel , double-blind , placebo-controlled study in 36 patients with agoraphobia with panic attacks , or panic disorder with limited phobic avoidance based on DSM- III criteria . Patients received alprazolam ( N = 25 ) or placebo ( N = 11 ) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved . Dosages were then gradually tapered according to a predetermined schedule . The entire study period lasted 14 weeks . Laboratory and clinical assessment s were conducted weekly . Doses up to 6 mg/day were tolerated by 80 % of patients on alprazolam and doses of 10 mg/day were tolerated by 40 % of patients . Twenty-seven percent of the placebo patients reached 10 tablets/day . In the alprazolam group , the principal cause of intolerance was sedation . Throughout the study no significant changes in vital signs or laboratory parameters were observed . Steady state alprazolam , 4-hydroxy alprazolam , and α-hydroxy alprazolam plasma levels were linearly related to dose . A 1 mg dosage increment produced , on the average , a corresponding 10 ng/ml increase in steady state level of the parent drug . Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml , with a maximum of 81 % of the sample s classified as re- sponders within the 60 ng/ml and above group . During taper , no severe withdrawal symptoms were noted ; 12 of 25 alprazolam patients , however , reported rebound anxiety ( anxiety rating scale scores higher than baseline ) , which occurred most commonly at the reduction from 1 mg to 0 mg 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 Although panic disorder has been associated with impaired quality of life ( QOL ) and financial dependence , no prior study has examined whether a clinical intervention will improve these outcomes . This study examines the effects of clinical ly titrated doses of clonazepam versus placebo on QOL and work productivity ( WP ) in patients with panic disorder .  QOL and WP were measured in conjunction with a r and omized , double-blind , placebo-controlled trial . The Medical Outcomes Study 36-Item Short Form Health Survey ( SF-36 ) and Work Productivity and Impairment question naire were used to assess QOL and WP , respectively . Baseline assessment s were obtained before r and omizing patients to receive clinical ly titrated doses of clonazepam or placebo . Follow-up assessment s were obtained after 6 weeks of therapy with the test drug or at premature termination from the study . Improvement on the SF-36 Mental Health Component Summary scale was more than twice as great with clonazepam than with placebo ( P = 0.03 ) . Clonazepam patients improved ( P < 0.05 ) on all five measures of mental health-related QOL , and both measures of physical health-related QOL , and both measures of WP .  Placebo patients improved on three of five measures of mental health-related QOL , but on no other measures . Patients with marked improvements on clinical measures of  panic disorder severity , especially avoidance and fear of the main phobia , showed the greatest gains on the SF-36 Mental Health Component Summary scale . Clinical ly titrated doses of clonazepam significantly improved mental health-related QOL and WP in panic disorder patients . Lesser improvements were obtained with placebo 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 Objective : To examine the correlates of therapeutic response of patients with panic disorder presenting with palpitations , we hypothesized that therapeutic response would correlate with heart rate variability ( HRV ) and sleep measures . Methods : After a 1-week placebo washout , 27 patients free of structural heart disease and not on cardioactive drugs were r and omized in a double-blinded fashion to 4 weeks of treatment with clonazepam ( a known antipanic agent ) or placebo . We performed st and ard sleep measures and recorded HRV from 24-hour Holter acquisitions at baseline and end of study . We defined response to therapy as a 50 % improvement in the Hamilton Anxiety Rating Scale ( HARS ) score , confirmed by question naires and reaction to sodium lactate infusion . Results : There were 12 responders and 15 nonresponders . Normalization of sleep pattern ( including less stage 1 and rapid eye movement [ REM ] sleep ) was observed in both drug and placebo responders ( P = 0.011 and P = 0.05 , respectively ) and in placebo responders alone , compared with nonresponders ( P = 0.006 and P = 0.013 , respectively ) . Placebo responders were more likely to show less depression , but even after we controlled for depression , main sleep effects remained . None of the HRV measures correlated with response , but compared with placebo , clonazepam led to a decrease in all the time and frequency domain measures of HRV ( all P < 0.05 ) . Conclusions : Central mechanisms are related to the therapeutic response of patients with panic disorder presenting with palpitations , but this does not directly correlate with HRV . Larger and longer studies may allow objective explanations of placebo response in panic disorder OBJECTIVE  Placebo effects in treatment of three anxiety disorders were compared . METHOD Treatment response and patients ' treatment expectancy were examined by using data from 70 patients with obsessive-compulsive disorder , social phobia , or panic disorder who received placebo in three r and omized , controlled trials comparing cognitive behavior therapy , medication , and their combination to placebo . RESULTS Patients with obsessive-compulsive disorder were less likely to respond to placebo than patients with generalized social phobia or panic disorder . Differential expectancy did not account for these findings . CONCLUSIONS Further examination of the placebo effect across the anxiety disorders may eluci date maintenance mechanisms of these disorders and have implication s for development of more effective treatments The effect of β 2-adrenoceptor antagonism in acute anxiety neurosis was investigated by comparing the effects of ICI 118,551 , a specific β2-adrenoceptor antagonist , diazepam and placebo in a double-blind , parallel group study . Sixty-three patients , who fulfilled criteria for Anxiety Disorder ( DSM III ) and were psychotropic drug- free ( apart from six using hypnotics ) , were entered . Anxiety symptoms were rated using the Hamilton Anxiety Scale ( HAS ) and Spielberger State Anxiety Scale . Assessment s were made at entry and following a 7-day single-blind placebo treatment phase , at the end of which only 51 wished to continue and had sufficient symptoms ( HAS score > 16 or reduction < 25 % on placebo ) for entry to the next phase . Following a double- blind , r and om allocation they then received ICI 118,551 ( 50 mg ) , diazepam ( 2 mg ) or placebo thrice daily for 4 weeks . Symptoms were assessed after 2 and 4 weeks in this active treatment phase ( i.e. at weeks 3 and 5 of the study ) . Thirty-five patients completed the study . A statistically significant improvement in HAS score was seen for all patients but there were no significant differences between treatments . Treatments did not differ in their effects on blood pressure or heart rate . β2-Adrenoceptor antagonism does not seem to have important effects on anxiety symptoms in anxiety neurosis This is a double-blind , placebo-controlled , flexible-dose , multicenter , 6-week study comparing regular alprazolam ( compressed tablet , CT ) , given four times per day , and extended release alprazolam ( XR ) , given once in the morning . The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety . Of the intent-to-treat group of 209 patients , 184 completed 3 weeks of medication and were evaluated according to protocol . There was a completer rate for the 6 weeks of 94 % ( CT ) , 97 % ( XR ) , and 87 % ( placebo ) . On global measures , Hamilton Rating Scale for Anxiety , phobia rating , and work disability measures , both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis . On analysis of the panic factor with endpoint data , both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group . Drowsiness occurred more frequently with CT alprazolam ( 86 % of patients ) than with the XR preparation ( 79 % ) or placebo ( 49 % ) BACKGROUND Many investigators have reported that panic disorder ( PD ) patients with comorbid major depression ( MD ) have more severe symptoms and a poorer response to treatment than patients with PD alone . It is not known if this is due to a distinct and more serious underlying disorder in these patients or simply a result of the simultaneous presence of the two disorders . METHOD Nondepressed patients presenting for treatment of panic disorder with agoraphobia ( PDA ) were studied before treatment ( N = 180 ) and after 4 weeks of treatment with adinazolam sustained release ( N = 89 ) or placebo ( N = 91 ) . Twenty-nine percent ( N = 53 ) of the patients had a past history of MD .  Symptom severity and treatment outcome were compared in patients with primary , secondary , single , recurrent , or no past MD . RESULTS There were no consistent differences in symptom severity or treatment outcome in patients with a past history of primary , secondary , or single episode MD compared with patients with no history of MD . However , a small number of patients with history of recurrent MD exhibited consistently greater symptom severity and poorer response to treatment than patients with no history of MD . CONCLUSION The greater severity and worse outcome of comorbid PD and MD observed in earlier studies are more likely due to the simultaneous presence of the two disorders than to a more serious and enduring underlying disorder . However , our results suggest that recurrent MD may indicate a more serious condition in patients with PDA . This possibility warrants further study The relationship between treating physician 's prognosis and treatment response to active drug or placebo in sample s of 517 anxious and 569 depressed out patients who had participated in 4-week double-blind drug trials was examined . Log-linear analyses employing diagnosis , prognosis , treatment ( active drug or placebo ) , and treatment response were conducted . Anxious patients had been treated with either chlordiazepoxide or placebo , and depressed patients had received either amitriptyline or placebo . Significant differences were found , suggesting that physician prognosis is related to pharmacologically induced symptom relief in anxious but not in depressed patients . In the depressed patient sample , prognosis and improvement were found to be significantly related in placebo but not drug-treated patients 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 Abstract Objective . Anxiety disorders are frequently under-diagnosed conditions in primary care , although they can be managed effectively by general practitioners . Methods . This paper is a short and practical summary of the World Federation of Biological Psychiatry ( WFSBP ) guidelines for the pharmacological treatment of anxiety disorders , obsessive – compulsive disorder ( OCD ) and posttraumatic stress disorder ( PTSD ) for the treatment in primary care . The recommendations were developed by a task force of 30 international experts in the field and are based on r and omized controlled studies . Results . First-line pharmacological treatments for these disorders are  selective serotonin reuptake inhibitors  ( for all disorders ) ,  serotonin-norepinephrine reuptake inhibitors  ( for some ) and  pregabalin  ( for generalized anxiety disorder only ) . A combination of  medication and cognitive behavior/exposure therapy  was shown to be a clinical ly desired treatment strategy . Conclusions . This short version of an evidence -based guideline may improve treatment of anxiety disorders , OCD , and PTSD in primary care OBJECTIVE To assess the effectiveness of clonazepam , in a fixed dose ( 2 mg/day ) , compared with placebo in the treatment of panic disorder patients . METHOD 24 panic disorder patients with agoraphobia were r and omly selected . The diagnosis was obtained using the structured clinical interview for DSM-IV . All twenty-four subjects were r and omly assigned to either treatment with clonazepam ( 2 mg/day ) or placebo , during 6 weeks . Efficacy assessment s included : change from baseline in the number of panic attacks ; CGI scores for panic disorder ; Hamilton rating scale for anxiety ; and panic associated symptoms scale . RESULTS At the therapeutic endpoint , only one of 9 placebo patients ( 11.1 % ) were free of panic attacks , compared with 8 of 13 ( 61.5 % ) clonazepam patients ( Fisher exact test ; p=0,031 ) . CONCLUSION the results provide evidence for the efficacy of clonazepam in panic disorder patients 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 OBJECTIVE The goals of this study were to assess the antipanic efficacy of a new , sustained-release formulation of alprazolam and to assess the safety and tolerability of once-a-day administration of 1 - 10 mg of sustained-release alprazolam . METHOD One hundred ninety-four patients with diagnosis of agoraphobia with panic attacks or panic disorder with limited phobic avoidance underwent a 1-week placebo washout before being r and omly assigned to groups receiving 8 weeks of double-blind treatment with either sustained-release alprazolam or placebo . RESULTS There was a significant treatment effect favoring sustained-release alprazolam ( highest mean dose = 4.7 mg/day ) across almost all measures of anxiety , panic , and phobic avoidance , despite a significantly higher dropout rate in patients receiving placebo . Eighty-five percent of the patients treated with sustained-release alprazolam , compared with 61 % of the patients given placebo , reported complete blockade of panic attacks by the end of 6 weeks of treatment . Sedation was the most commonly reported adverse effect . Discontinuation of sustained-release alprazolam was associated with moderate but transient levels of distress in 48 % of the patients ; discontinuation of placebo led to distress in only 10 % of the patients . Nonetheless , there was no difference in the proportion of patients who were able to remain off the study drug for at least 2 weeks . CONCLUSIONS These results suggest that sustained-release alprazolam is highly effective in the acute treatment of panic disorder at doses comparable to those in the originally marketed compressed tablet of alprazolam . The medication was well tolerated but showed rebound effects during a rapid drug taper after 6 weeks of treatment A compared , 12 week , placebo controlled study , with fixed dose , outpatient study of patients diagnosed with panic disorder with and without agoraphobia according to ICD-10 , was conducted to evaluate the efficacy and safety of sertraline and alprazolam . The study included 40 patients , divided in two groups . We evaluated number of ICD-10-defined panic attacks , agoraphobia and anticipatory anxiety .  All patients were aged 18 year and older and were r and omized to either sertraline or alprazolam . Sertraline applied in fixed doses of 20 mg/day and alprazolam in doses 1 - 1,5 mg/day significantly reduced the frequency of panic attacks in panic disorder patients , reduced symptoms of agoraphobia and anticipatory anxiety This four-week , double-blind , placebo-controlled clinical trial assessed the new benzodiazepine derivative alprazolam ( Xanax ) treatment of moderate to severe anxiety characteristic of anxiety neurosis . Sixty-two out patients participated ; 8 per cent of those taking drug and 52 per cent of those taking placebo discontinued participation due to side effects or lack of efficacy . The mean total daily alprazolam dose was 1.35 mg taken in divided doses . Alprazolam significantly improved scores on five anxiety rating scales -- Hamilton Anxiety Rating Scale , Physician 's Global Impressions , Target Symptoms Record , Self-Rating Symptom Scale , and Patient 's Global Impressions .  Alprazolam patients experienced no clinical ly significant changes in vital signs and laboratory values ; they reported drowsiness as the most frequent side effect . We conclude that alprazolam is an effective and safe anxiolytic agent 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 OBJECTIVE The authors test the hypothesis that patient readiness to change predicts outcome in a placebo-controlled medication trial . METHOD Out- patients with panic disorder and agoraphobia completed the Stages of Change ( SOC ) question naire , a measure of readiness to change , before being r and omly assigned either sustained release ( SR ) adinazolam or placebo in a 4 week double-blind trial . RESULTS In the " intent to treat " analysis , for the 202 subjects who made at least one visit after baseline , adinazolam SR was significantly more effective than placebo on most major outcome measures . Of the 126 subjects who completed the SOC question naire , regression analyses showed significant correlations between SOC scores and all 5 outcome measures . In a second analysis , cluster membership based on SOC scores was predictive of outcome on 3 of 5 measures . In each statistical analysis , subjects who were not predisposed to change as measured by the SOC were significantly less likely to change . CONCLUSIONS Patient readiness to change was strongly correlated with outcome in a placebo-controlled panic disorder trial with an effective medication . In this study , the SOC category , Precontemplation ( i.e. , those subjects who reported the belief that they had no problem ) were less likely to change compared to those who believed that they had a problem BACKGROUND We report the results from a multicenter , double-blind , r and omized , fixed-dose study design ed to evaluate the relationship between daily dose and efficacy of adinazolam-SR in patients with panic disorder with agoraphobia . METHOD Patients ( N = 315 ) were r and omized to one of four treatment groups ( placebo , N = 83 ; 30-mg group , N = 79 ; 60-mg group , N = 81 ; and 90-mg group , N = 72 ) and then treated twice daily for 4 weeks . All treatment groups were comparable demographically . Primary efficacy measures included total number of panic attacks , global improvement score using the Clinical Global Impressions ( CGI ) scale , phobic anxiety dimension of the Symptom Checklist-90 phobic cluster , overall phobia state using the Phobia Scale , and severity of illness on the CGI . RESULTS The 60- and 90-mg/day adinazolam-SR treatment groups showed superior results when compared with the placebo group at Week 4 while the 30-mg group did not . Treatment with adinazolam-SR was well tolerated , with sedation the only treatment-emergent symptom that occurred more frequently in patients treated with adinazolam-SR than placebo . CONCLUSION These results suggest that adinazolam-SR at doses of 60-mg/day or greater administered twice daily is a safe and effective treatment in selected patients with panic disorder with agoraphobia This study characterizes the pattern of placebo response in depressed panic disorder patients who participated in a r and omized clinical trial . We compared  placebo-treated subjects whose panic attacks remitted , with those whose attacks did not remit , and with remitting and nonremitting subjects treated with active medication . Seventy-one subjects who met criteria for panic disorder and for a concurrent depressive diagnosis ( major depression , dysthymia , or depressive disorder not otherwise specified [ NOS ] ) were treated with either imipramine ( n = 36 ) or alprazolam ( n = 35 ) , and 28 patients were treated with placebo . Sixteen placebo-treated and 40 medication-treated patients were panic free at Week 8 . Placebo panic remitters were significantly more ill than active-medication remitters on all measures . In contrast , subjects who achieved panic remission on placebo showed no difference on other clinical measures from active medication nonremitters , and little difference from placebo nonremitters . Results support the need for assessment of all core panic disorder symptoms in determining treatment efficacy and in considerations of response and remission The results of a clinical outcome study ( N = 57 ) comparing  behavior therapy directed at panic disorder ( panic control treatment [ PCT ] ) with alprazolam were reported . These conditions were compared with a medication placebo and a waiting-list control group . Patterns of results on measures of panic attacks , generalized anxiety , and global clinical ratings reveal that PCT was significantly more effective than placebo and waiting-list conditions on most measures . The alprazolam group differed significantly from neither PCT nor placebo . The percentage of clients completing the study who were free of panic attacks  following PCT was 87 % , compared with 50 % for alprazolam , 36 % for placebo , and 33 % for the waiting-list group . Since alprazolam may work more quickly than PCT but may also interfere with the effects of behavioral treatment , these data suggest a series of studies on the feasibility of integrating these treatments and on the precise patterns and mechanisms of action of various successful treatment approaches to panic disorder 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 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 Eight males were studied during 27 weeks , including two periods of five weeks during which they received clinical doses of sodium amylobarbitone and benzoctamine . Substitution of placebo for either drug caused raised anxiety and impairment of mental concentration . The drugs reduced restlessness during sleep and reduced paradoxical sleep . By the fifth week of sodium amylobarbitone , although sleep was still less restless in the early night it was more restless than normal in the late night . Blood sample s were taken half-hourly during sleep by indwelling venous catheter . Plasma growth hormone concentration was little affected during drug administration but rose temporarily after withdrawal . There was a reduction of plasma corticosteroid concentration during sleep throughout administration of the drugs and a rebound above normal during the first withdrawal week 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 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 In a multicenter placebo-controlled study , the safety , side effects , and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined . A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were r and omly assigned to receive alprazolam or placebo , which they took for eight weeks . The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily . Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug . These included acute intoxication ( three ) , hepatitis ( two ) , mania ( two ) , amnesia ( one ) , aggressive behavior ( one ) , and depression ( one ) . Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation , fatigue , ataxia , slurred speech , and amnesia . Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug . Patient acceptance of alprazolam , as measured by the rate of completion for study participants , was high . Eighty-four percent of patients receiving active drug completed the study compared with 50 % receiving placebo In a four-week double-blind r and omized trial preceded by a one-week single-blind placebo treatment , the efficacy and the side-effects of suriclone ( 1.50 - 2.25 mg/d ) ( n = 24 ) , lorazepam ( 5.0 - 7.5 mg/d ) ( n = 19 ) and placebo ( n = 21 ) were compared in 64 out patients with a DSM-III diagnosis of generalized anxiety disorder ( n = 56 ) or panic disorder ( n = 8) .  Efficacy was measured weekly by means of a global clinical impression scale , the Hamilton Anxiety Rating Scale , the Zung Anxiety Self- Assessment Scale and a target symptom scale . Side-effects were evaluated weekly by an adverse events scale , which recorded the spontaneous complaints and the complaints elicited by an extensive somatic inventory question naire . The three groups showed a statistically significant and clinical ly relevant improvement early on in the treatment : this improvement was maintained during the remaining period . Early on in the treatment there was some indication of a better response , but also of more side-effects , in the suriclone and the lorazepam groups . After four weeks of treatment no difference was found between the three groups either in efficacy or in side-effects . The effect size achieved in the placebo group was not inferior to that of benzodiazepines in general 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 % ) BACKGROUND The purpose of this multicenter , double-blind , placebo-controlled study was to evaluate the efficacy and safety of optimized dosages of clonazepam for the treatment of panic disorder and assess the tolerability of a schedule for gradual discontinuation . METHOD Adult patients with panic disorder with or without agoraphobia ( DSM-III-R criteria ) were r and omly assigned to receive either placebo or clonazepam in individually adjusted doses over 3 weeks to approximate an optimal dosage , which was then maintained for an additional 3 weeks , amounting to a 6-week therapeutic phase . The daily dose range was 0.25 to 4.0 mg administered in 2 divided doses . In the following 7-week discontinuance phase , the doses were tapered gradually to cessation . RESULTS At the therapeutic endpoint , clonazepam ( N = 222 ) proved clinical ly and statistically superior to placebo ( N = 216 ) in change in the number of panic attacks and in Clinical Global Impressions-Severity of Illness ( CGI-S ) and CGI-Change scores , Patient 's Global Impression of Change scores , amount of fear and avoidance associated with phobic symptoms , and duration of anticipatory anxiety . The gradual tapering of clonazepam was not associated with symptoms suggestive of withdrawal syndrome . Although patients taking clonazepam experienced some clinical worsening compared with the status achieved at endpoint , particularly in terms of number of panic attacks , no deterioration was observed using their condition at baseline as point of reference . No overall evidence of rebound was found . All regimens were generally well tolerated . Somnolence was the main adverse event associated with clonazepam therapy . The percentage of patients who reported adverse events was higher in the clonazepam group than in the placebo group , as was the mean number of adverse events per patient . CONCLUSION In this placebo-controlled trial , clonazepam was an efficacious and safe shortterm treatment of the symptoms of panic disorder . Discontinuance during and after slow tapering was well tolerated 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 Pretreatment with imipramine , buspirone , or placebo was compared in 40 patients meeting the Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition criteria for panic disorder and in patients who were discontinuing long-term benzodiazepine use . The average duration of benzodiazepine use was 75 ± 64 months , and the average benzodiazepine intake expressed as diazepam equivalents was 25.7 ± 19 mg/d . We hypothesized that pretreatment with either imipramine or buspirone , in contrast to pretreatment with placebo , would lead to a significant decrease of symptoms of anxiety and depression before tapering benzodiazepines , thus making the taper process easier to complete . All 3 treatments ( imipramine , buspirone , and placebo ) caused a reduction in anxiety and depression symptoms as measured by changes in the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale . Neither discontinuation severity nor taper-free status 12 weeks posttaper differed between the 3 treatment groups In this multicenter , parallel-group , placebo-controlled , fixed-dose study , the efficacy , safety , dosing characteristics , and discontinuation of clonazepam  were analyzed in patients with panic disorder . Four hundred thirteen patients were r and omly assigned to receive placebo or one of five fixed daily doses of clonazepam ( 0.5 mg , 1.0 mg , 2.0 mg , 3.0 mg , and 4.0 mg ) . After 3 weeks of dose escalation , the fixed dose was given for 6 weeks ( the dose-maintenance phase ) and then was tapered during a 7-week discontinuance phase . The completion rates for the dose-maintenance phase ranged from 59 to 85 % for the clonazepam groups ( 74 % for the placebo group ) . Efficacy measurements at the end of the dose-maintenance phase indicated clinical improvement in all treatment groups but with a clear differentiation of the four higher doses of clonazepam from the 0.5-mg dose and placebo . The minimum effective dosage , as determined by the Williams ' test , was 1.0 mg daily . Dose-response analysis showed that daily dosages of 1.0 mg and higher were equally efficacious in reducing the number of panic attacks . All treatments were well tolerated . Somnolence and ataxia were reported more often by patients in the 3.0- and 4.0-mg groups ; depression , dizziness , fatigue , and irritability , although not showing dose-relatedness , were reported by more patients taking clonazepam than placebo . During the discontinuance phase , most patients worsened from their condition at the end of the dose-maintenance phase but did not revert to that at baseline . In addition , with the tapering schedule chosen for this study , patients in all treatment groups tolerated the discontinuance of clonazepam . Daily doses of 1.0 to 2.0 mg of clonazepam offered the best balance of therapeutic benefit and tolerability 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 Thirty out- patients suffering from panic disorders associated with agoraphobia were enrolled in a double-blind , controlled trial to compare the effectiveness and tolerability of etizolam and placebo . After a 1-week washout period on placebo , patients were allocated at r and om to receive twice daily doses of either 0.5 mg etizolam or placebo over a period of 4 weeks . Assessment s , made at baseline and after 2 and 4 weeks of treatment , used the Hamilton Rating Scales for Anxiety and for Depression , the Covi Anxiety Scale , and determination of the weekly panic crises frequency . The results showed that etizolam produced significant improvements in chronic anxiety , phobic ideas , associated depressive symptoms and episodic anxiety , and was significantly more effective than placebo . Etizolam treatment was generally well tolerated and was not significantly different from placebo in this respect Fifty-five patients completed a 5-week double-blind study comparing alprazolam , propranolol , and placebo in the treatment of panic disorder and agoraphobia with panic attacks . There was no concomitant behavioral treatment . Patient and therapist rating scales included Sheehan 's Panic and Anxiety Attack Scales , the Marks-Sheehan Phobia Scale , the Hamilton Anxiety Scale , the Hamilton Depression Scale , and the Side Effects Checklist . The results generally support the efficacy of alprazolam , but not propranolol , in the treatment of panic disorder and agoraphobia with panic attacks . The significance of the results are discussed , as well as a number of the unique aspects of our procedures and patient population Twelve studies were undertaken under a common four-week protocol to investigate the efficacy of lorazepam compared with placebo in reducing the severity of moderate to severe anxiety in 264 patients also having significant depressive symptomatology . Analysis of the results indicated that lorazepam gave generally better anxiety relief than placebo  ; in the majority of comparisons the differences were substantial enough to be both statistically and clinical ly significant . No data were obtained evidencing significant toxicity in either treatment group 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 In a double-blind , placebo-controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam . Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam . The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg . Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale , with a trend toward more improvement in the alprazolam group in the later weeks of the study . Target Symptoms , Physician 's and Patient 's Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo . The major side effects were sedation and drowsiness ; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo . An overall rating of side effect severity was not significantly different among the three groups A double-blind study was carried out in 30 hospital out- patients suffering from moderate to severe neurotic anxiety to compare the efficacy and tolerance of alprazolam and placebo . Patients were allocated at r and om to receive alprazolam , in a dosage of 0.5 to 1 mg 3-times daily , or placebo over a 4-week period . The results of assessment s using the Hamilton Anxiety Rating Scale and global impressions of response to treatment by both physician and patients showed alprazolam to be superior to placebo in the relief of symptoms . Side-effects were infrequent : only 3 of the 15 patients in the alprazolam group reported mild or moderate drowsiness 1 . Because imipramine has lowered T4 in uncontrolled studies we examined the effect of imipramine on serum thyroid levels in panic disorder patients in a double-blind placebo and diazepam treatment controlled study . 2 . Treatment with imipramine  ( 10 subjects ) was associated with a significant decrease of T4 and FTI and treatment with diazepam  ( 8 subject ) was associated with a significant decrease of T4 . However , there was no significant difference across treatment groups . 3 . This finding suggests that previously reported decreases in thyroid hormones during antidepressant therapy may be due to nonspecific effects of treatment rather than to the drug itself BACKGROUND Etizolam is an anxiolytic drug with a pharmacologic profile similar to that of the classic benzodiazepines . Neurochemical research suggests that etizolam may have selectivity for the sub population of Y-aminobutyric acid type A receptors associated with anxiety ( ie , alpha1 , beta2 , gamma2 ) . This property , plus its characterization as a lig and with fewer of the adverse events typical of full agonists ( impaired cognitive function , tolerance , and dependence ) , led to its selection for this study . OBJECTIVES The primary aim of this study was to test for the noninferiority of etizolam 0.5 mg BID versus placebo in affecting cognitive function in patients with mild to moderate anxiety disorder of recent onset ( < 1 month ) .  Anxiety measures and tolerability were also assessed . METHODS Patients between the ages of 18 and 65 years were eligible for enrollment . This double-blind , placebo-controlled study was performed in 5 centers in Italy using a 2-treatment , 3-period crossover design . Patients were r and omized to 3-week sequences of either etizolam-placebo-placebo or placebo-etizolam-etizolam . They were evaluated at 4 scheduled visits ( screening and days 7 , 14 , and 21 ) . Cognitive function was assessed using scores from the Wechsler Adult Intelligence Scale ( WAIS ) Digit Span test ( total forward and backward scores and the time required to perform the test ) . Anxiety was measured using the Hamilton Anxiety Rating Scale ( HAM-A ) and the State-Trait Anxiety Inventory ( STAI ) for screening and to monitor adequacy of therapy . Blood pressure , heart rate , weight , and adverse events were also recorded . RESULTS A total of 77 white patients were enrolled ( mean age , 33.3 years [ range , 22 - 60 years ] ; 62.3 % female ; mean weight , 65.2 kg ) . With a power of 0.80 , the difference between the effects of etizolam and placebo on WAIS Digit Span performance was not significant for total score ( 0.102 [ 90 % CI , -0.130 to 0.335 ] ) or time required for completion ( 0.029 second [ 90 % CI , -0.574 to 0.632 ] ) . Anxiety , as measured using the HAM-A and STAI instruments , did not differ significantly between groups . No significant differences were found between etizolam 0.5 mg BID and placebo for cardiovascular events , weight changes , or adverse events . Mild or moderate somnolence was reported by 7 of 77 patients ( 9.1 % [ 3 patients while receiving etizolam and 4 patients while receiving etizolam and placebo ] ) . CONCLUSIONS No significant differences between etizolam 0.5 mg BID and placebo were found for cognitive function or anxiety measures in these patients with anxiety . Etizolam was well tolerated Discriminant function analyses were applied to data obtained from anxious psychiatric out patients treated with either chlordiazepoxide ( n = 353 ) or placebo ( n = 259 ) and depressed out patients treated with either amitriptyline ( n = 310 ) or placebo ( n = 328 ) , who had participated in controlled drug trials of 4 weeks ’ duration , in an attempt to identify factors associated with complaints of drowsiness made by these patients . Although the magnitude of the relationships between individual predictors and drowsiness was small , several factors emerged which had consistent impact across treatment groups . Predictors of complaints of drowsiness attributed to active drugs arose primarily from demographic attributes probably reflective of life style , and from illness and treatment history . In contrast , predictors of drowsiness attributed to placebo were almost exclusively confined to indices of the severity of several aspects of presenting symptomatology . In particular , more frequent complaints of drug‐induced drowsiness were found among better educated individuals with an illness of long duration . Complaints of placebeinduced drowsiness were more common among patients with more severe emotional ( phobic‐obsessive ) symptomatology and more frequent headaches and among those individuals in whom hypochondriasis was less severe The Cross-National Collaborative Panic Study is a two-phase multinational , multicenter controlled trial for the evaluation of drug treatment of  panic disorder and associated agoraphobia .  The First Phase compared alprazolam with placebo in a large sample of more than 600 subjects at eight centers -- five in the United States , two in Canada , and one in Australia . The Second Phase compared alprazolam , imipramine hydrochloride , placebo  in more than 1100 patients in 14 countries . The scientific background , aims and purpose s , governance , and policies regarding statistical analyses and scientific presentations and publications are review ed as background for the series of individual articles reporting detailed findings from the First Phase 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 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 Introduced in the 1950s , antipsychotic agents have been found to improve symptomatology and function in young and middle-aged psychotic schizophrenics . Three decades of research , however , have not made clear these agents ' usefulness in demented elderly patients . A review of placebo-controlled studies suggests a definite but limited role for antipsychotic medication in behaviorally disturbed elderly dementia patients with agitated behavior . Studies also suggest that cognitive function needs careful monitoring when these drugs are prescribed to treat behavioral symptoms of dementia OBJECTIVE The authors ' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia . METHOD Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week , fixed-dose , double-blind , placebo-controlled , dose-response study of 2 mg/day or 6 mg/day of alprazolam . Assessment s were made of panic attacks , avoidance behavior , generalized anxiety , and global response . Blood sample s were collected throughout the study and analyzed for alprazolam and other benzodiazepines . RESULTS Patient compliance with the protocol was judged to be good on the basis of plasma concentrations . According to logistic regression analysis , the relationships between plasma alprazolam concentration and response , as reflected by number of panic attacks reported , phobia ratings , physicians ' and patients ' ratings of global improvement , and the emergence of side effects , were significant . However , there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms . CONCLUSIONS The authors conclude that plasma concentration of alprazolam  is related to treatment response , particularly in panic attacks . The  alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals , highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects 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 A series of 237 patients with DSM-III-diagnosed panic disorder , or agoraphobia with panic attacks , received alprazolam as part of the placebo-controlled Cross-National Collaborative Panic Study . After a 1-week drug-free period , alprazolam dosage was titrated upward with the objective of reaching 6.0 mg/d in all patients . At week 3 of treatment , alprazolam  plasma levels were significantly correlated with daily dosage ( regression slope : 11.7 ng/mL per milligram per day ) but with considerable individual variation . Among patients with spontaneous panic attacks , 70 % of those with plasma alprazolam levels greater than 20 ng/mL achieved complete remission vs 31 % of those with levels less than 20 ng/mL. Situational panic attack remission increased in frequency with increasing plasma levels , but the relationship was not significant . Patient- and physician-rated global improvement and Hamilton Anxiety and Depression Scale score reductions were maximal at 20 to 39 ng/mL , with no further benefit at higher levels . Central nervous system-depressant side effects increased in frequency with higher plasma levels . Between weeks 3 and 8 of treatment , physicians were permitted to adjust dosage ( maximum : 10 mg/d ) to optimize response . At week 8 , the dose-concentration relationship was essentially identical ( regression slope : 10.8 ng/mL per milligram per day ) , but plasma levels were no longer related to efficacy or side effects . Thus , monitoring of plasma alprazolam concentrations may have a clinical ly useful role during short-term treatment of panic disorder To test the reported antipanic efficacy of clonazepam , the authors r and omized 72 subjects with panic disorder to 6 weeks of treatment with either alprazolam , clonazepam , or placebo . Endpoint analysis demonstrated a significant beneficial effect of both active treatments , but not placebo treatment , on the frequency of panic attacks , overall phobia ratings , and the extent of disability . Comparison of the two active treatments revealed no significant differences and no consistent tendency for one agent to be favored over another , although power to detect small differences was limited . Sedation and ataxia were the most common side effects reported , but these effects were mild and transient and did not interfere with treatment outcome . The results of this double-blind , placebo-controlled trial are consistent with previous reports of clonazepam 's antipanic efficacy OBJECTIVE This study was design ed to clarify the nature of the reduced function of the peripheral beta adrenoceptor system observed in panic disorder with agoraphobia . The authors hypothesized that this phenomenon reflected a regulatory and adaptive process . METHODS Lymphocyte beta adrenoreceptor density and affinity , basal lymphocyte cAMP level , and isoproterenol-stimulated cAMP generation were measured in 27 untreated out patients with panic disorder with agoraphobia and 24 healthy comparison subjects .  Lymphocyte beta receptor attributes were again assessed in patients after 4 weeks of double-blind treatment with adinazolam ( slow-release form ) or placebo .  Panic frequency , agoraphobic symptoms , overall anxiety , and improvement with treatment were assessed with st and ard rating instruments . RESULTS Multivariate statistics revealed significantly lower beta receptor density and isoproterenol-stimulated cAMP generation in patients than in comparison subjects . beta receptor density tended to normalize after adinazolam but not after placebo . Pretreatment beta receptor density was lower in treatment responders than nonresponders . Patients with mild agoraphobia had lower cAMP responsivity than patients with moderate or severe agoraphobia . CONCLUSIONS Decreased function of lymphocyte beta receptors in panic disorder with agoraphobia is expressed as both decreased density and decreased cAMP responsivity . This pattern of changes , and the tendency for receptor density to normalize with treatment , is consistent with an active , regulatory process rather than a structural deficit in the beta receptor system . Preliminary clinical findings suggest that these changes may reflect adaptive processes associated with a favorable clinical course in panic disorder with agoraphobia 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 In a multi-center comparison of alprazolam to placebo in the treatment of agoraphobia with panic attacks , the sequence of sustained remission in both treatment groups , was panic attacks before phobias . This may suggest that phobias are secondary to panic attacks in the pathogenesis of the disorder , although other explanations may account for these data and are discussed 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 Following promising preliminary evidence , the benzodiazepine-derivative alprazolam was studied in a large , placebo-controlled , eight-week , flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder . Of 526 patients , 481 completed three weeks of treatment ; however , significantly more placebo ( 102/234 ) than alprazolam ( 21/247 ) recipients subsequently dropped out of the trial , primarily citing ineffectiveness ( of placebo ) as the reason . Alprazolam was found to be effective and well tolerated . There were significant alprazolam-placebo differences in improvement for ( 1 ) spontaneous and situational panic attacks , ( 2 ) phobic fears , ( 3 ) avoidance behavior , ( 4 ) anxiety , and ( 5 ) secondary disability , all significant by the end of week 1 . At the primary comparison point ( week 4 ) , 82 % of the patients receiving alprazolam were rated moderately improved or better vs 43 % of the placebo group . At that point , 50 % of the alprazolam recipients vs 28 % of placebo recipients were free of panic attacks 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 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 We hypothesized that the dehydroepi and rosterone-sulfate (DHEA-S)/cortisol ratio , which has been used as an index of adrenocortical function , would be altered in panic disorder patients and would change after treatment . We evaluated 10 male and 14 female out patients meeting DSM-III-R criteria for panic disorder . Of these 24 subjects , 13 were treated with clonazepam  , 8 were treated with alprazolam , and 3 were treated with placebo as part of a double-blind study . The DHEA-S/cortisol ratio values in the 24 patients with panic disorder ( mean = 20.5 , SD = 11.6 ) were significantly higher than those of a group of 60 normal controls ( mean = 11.5 , SD = 6.01 ) and were also significantly higher than those of a group of 22 depressed patients ( mean = 10.6 , SD = 6.33 ) . Although there was no significant difference in the pretreatment DHEA-S/cortisol ratio values between male ( mean = 23.6 , SD = 11.8 ) and female ( mean = 18.2 , SD = 11.3 ) panic disorder patients , the effects of treatment on this ratio differed between the two sexes . In fact , in the female patients there was a significant decrease in the DHEA-S/cortisol ratio at the end of the study ( mean = 15.1 , SD = 7.9 ) , while in the male patients there was no significant change in this ratio at the end of the study ( mean = 30.2 , SD = 21.4 ) . No significant differences were noted between pretreatment and posttreatment DHEA-S/cortisol ratio values in patients treated with alprazolam ( n = 8) , in patients treated with clonazepam ( n = 13 ) , or in patients treated with placebo ( n = 3 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Thirty-two out patients with a DSM-III diagnosis of panic disorder or agoraphobia with panic attacks were r and omly assigned to 4 weeks of treatment with clonazepam or placebo , after a 1-week placebo washout period . Twenty-nine patients entered the double-blind phase of the study and were eligible for intent-to-treat analysis . Clonazepam-treated patients experienced significantly fewer panic attacks , and these were of lesser intensity and short duration than those in placebo-treated patients ( p < 0.001 ) . Clonazepam was also superior to placebo with respect to symptoms of anxiety and depression ( p < 0.001 ) . The mean dose of clonazepam at week 4 was 2.2 mg ( st and ard deviation , 0.7 mg ) . There was significant ( p < 0.05 ) correlation between drug concentration in plasma and decrease in the global measure of the severity of panic disorder ( r = 0.68 ) ; similar trends were seen for the decreases in frequency ( r = 0.60 ) and severity ( r = 0.55 ) of panic attacks , but not between concentration in plasma and decline in generalized anxiety . The most common adverse event was drowsiness , which occurred in 9 of 13 clonazepam-treated patients OBJECTIVE The purpose of this study was to compare the effects of discontinuing treatment with intermediate- and long-acting benzodiazepines . METHOD Fifty patients with panic disorder who had taken part in a double-blind treatment study and had responded to alprazolam , diazepam , or placebo for 8 months were asked to stop taking these medications gradually . RESULTS After a relatively rapid dose reduction , the majority of patients relapsed . Rebound anxiety and withdrawal symptoms were identified in a substantial minority of patients . Those who were taking alprazolam showed earlier and more intense rebound anxiety and withdrawal symptoms than did the patients who received diazepam . Both the level of pretreatment anxiety and the drug the patient was taking predicted the level of anxiety when drug treatment was discontinued . CONCLUSIONS The findings indicate that withdrawal phenomena commonly occur after patients stop taking benzodiazepines and that they are more frequent after discontinuation of treatment with shorter-acting drugs 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 The pharmacokinetics and pharmacodynamics of the benzodiazepine alprazolam ( 1 mg , administered orally ) were compared between eight patients with panic disorder and eight age- and sex-matched healthy volunteers . Subjects received orally administered placebo and alprazolam in a r and omized , double-blind , single-dose crossover study . The elimination half-life , time of maximum plasma concentration , maximum concentration , volume of distribution , and clearance of alprazolam were similar for both groups . For each cohort , alprazolam treatment ( vs. placebo ) produced significant changes in typical benzodiazepine agonist effects , such as increased sedation and impaired cognitive performance on the digit-symbol substitution test . For the panic disorder group only , there was a significant increase in the subjective rating of"contented " and a reduction in the rating of " easily irritated . " For the healthy volunteer group , alprazolam produced increases in ratings of " fatigued " and " slowed thinking , " but also increases in ratings of " relaxed . " In each group , alprazolam significantly increased the electroencephalographic ( EEG ) measure of relative beta amplitude ( range , 13 - 30 Hz ) compared with placebo .  Concentration-EEG response curves fit a sigmoid E(max ) model , and there was greater sensitivity to EEG effects , as measured by a 28 % reduction in the EC50 value , in the panic disorder group compared with healthy control subjects . After alprazolam treatment , there was increased sensitivity to EEG and mood effects and fewer aversive effects in the panic disorder group compared with healthy subjects . There were no differences in the pharmacodynamic measures of sedation and cognition or differences in pharmacokinetics between the two groups A data -analytic strategy is proposed for identifying the symptom-specific effects of each medication in a clinical trial . The within-group effect size is a st and ardized ratio of the pre-post change relative to the stability of change for each treatment group . Advantages of using this descriptive approach are illustrated by examining antidepressant effects of alprazolam , imipramine , and placebo in a clinical trial for patients meeting criteria for both panic disorder and depression . There was a significant difference between active medication and placebo on the Hamilton Rating Scale for Depression ( HAM-D ) total , but no difference between the anti-depressant effects of the active medications despite their diverse psychopharmacologic properties . Examination of effect sizes for each HAM-D item revealed distinct symptom-specific effects of each active medication in this study sample . Although these descriptive findings can not be used for inferential conclusions , they can be used to guide the design of future trials 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 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 BACKGROUND Drug therapy of panic disorder , despite the intermittent nature of the panic attack , requires daily administration of antidepressants , which are often not tolerated , or benzodiazepines , which can result in physical dependence and withdrawal . The use of rapidly acting , low-dose intranasal midazolam to prevent incipient panic suggested itself to us as a novel alternative treatment strategy . METHOD We conducted a 6-week double-blind , placebo-controlled , crossover- design pilot study of the safety and efficacy of p.r.n . low-dose intranasal midazolam in five patients diagnosed with DSM-III-R panic disorder . RESULTS One to two drops of midazolam ( approximately 0.25 to 0.5 mg ) was well tolerated and highly effective in preventing incipient panic attacks and in reducing the overall weekly frequency of attacks . CONCLUSION Intermittent intranasal midazolam shows promise as a novel alternative treatment for panic , but a controlled study of its efficacy and safety ( including abuse potential ) must be conducted Agoraphobic and panic disorder patients underwent 1-mg Dexamethasone Suppression Tests ( DST ) before , during , and after an 8-week trial of diazepam , alprazolam , or placebo . Previously described , never-ill controls underwent similar testing . At baseline , 21 of 82 ( 25.6 % ) panic disorder and 5 of 38 ( 13.2 % ) controls were nonsuppressors . This difference grew more marked with multiple testing over a 2-month period ; 18 of 44 ( 40.9 % ) panic disorder patients were nonsuppressors on at least 1 of 3 tests compared with only 5 of 35 ( 14.3 % ) controls ( p = 0.006 ) .  DST results were related to severity , but not to the presence or absence , of depressive syndromes . Control for plasma dexamethasone levels left highly significant differences in postdexamethasone cortisol across diagnostic groups . Neither  DST results nor plasma dexamethasone levels changed in concert with clinical change , and type of treatment had little differential effect on these measures . Nor did  DST results predict subsequent course when active treatment was extended by 6 months . However ,  DST results during the initial 8 weeks of treatment were strongly related to relapse when medications were tapered , even though this occurred 6 months after the last DST The clinical and biological correlates of gradual alprazolam withdrawal were investigated in 10 patients in a double-blind , placebo-controlled trial . During gradual alprazolam withdrawal , anxiety and plasma cortisol levels were higher than during a postwithdrawal medication-free period
target: Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo .
  Low- quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders .
  Due to these limitations , our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice .
background: BACKGROUND Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes .
  Panic disorder is a common disorder , with an estimated lifetime prevalence of 1 % to 5 % in the general population and a 7 % to 10 % prevalence in primary care setting s. Its aetiology is not fully understood and is probably heterogeneous .
  Panic disorder is treated with psychological and pharmacological interventions , often used in combination .
  Although benzodiazepines are frequently used in the treatment of panic disorder , guidelines recommend antidepressants , mainly selective serotonin reuptake inhibitors ( SSRIs ) , as first-line treatment for panic disorder , particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines .
  Despite these recommendations , benzodiazepines are widely used in the treatment of panic disorder , probably because of their rapid onset of action .
  OBJECTIVES To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults .