title: Maintenance drug therapy of panic disorder. Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators. Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial. The acute antipanic and anxiolytic activity of aerobic exercise in patients with panic disorder and healthy control subjects. Effect of fluvoxamine on panic disorder. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study. Reboxetine and citalopram in panic disorder: a single-blind, cross-over, flexible-dose pilot study Medical utilisation and costs in panic disorder: a comparison with social phobia. Open‐Label Support for Duloxetine for the Treatment of Panic Disorder Early coadministration of clonazepam with sertraline for panic disorder. Sertraline treatment of panic disorder: results of a long‐term study Placebo-controlled study of gabapentin treatment of panic disorder. Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study. Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. A bibliotherapy approach to relapse prevention in individuals with panic attacks. Safety and efficacy of levetiracetam for patients with panic disorder: results of an open-label, fixed-flexible dose study. The efficacy of reboxetine in the treatment-refractory patients with panic disorder: an open label study. Long-term maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Antidepressant discontinuation in the context of cognitive behavioral treatment for panic disorder. Olanzapine Augmentation in Treatment-Resistant Panic Disorder: A 12-Week, Fixed-Dose, Open-Label Trial Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. Comparison of aerobic exercise, clomipramine, and placebo in the treatment of panic disorder. Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Cognitive-behavioral therapy helps prevent relapse and recurrence of panic disorder following alprazolam discontinuation: a long-term follow-up of the Peoria and Dartmouth studies. Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? Combined Paroxetine and Clonazepam Treatment Strategies Compared to Paroxetine Monotherapy for Panic Disorder Interactive Model of Therapeutic Response in Panic Disorder: Moclobemide, a Case in Point Next-step strategies for panic disorder refractory to initial pharmacotherapy: a 3-phase randomized clinical trial. Acute exercise reduces the effects of a 35% CO2 challenge in patients with panic disorder. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Increased Risk of Acute Myocardial Infarction for Patients With Panic Disorder: A Nationwide Population-Based Study A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Clomipramine treatment of panic disorder: pros and cons. The efficacy of milnacipran in panic disorder: an open trial A study of the clinical effects of phenelzine and placebo in the treatment of phobic anxiety The effect of citalopram in panic disorder. Efficacy of D-Cycloserine for Enhancing Response to Cognitive-Behavior Therapy for Panic Disorder Duration of Imipramine Therapy and Relapse in Panic Disorder With Agoraphobia Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group. Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release. Aripiprazole as augmentation treatment of refractory generalized anxiety disorder and panic disorder. A randomized, controlled trial of aerobic exercise in combination with paroxetine in the treatment of panic disorder A dose-finding and discontinuation study of clomipramine in panic disorder An open-label trial of risperidone augmentation for refractory anxiety disorders. Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder. Effects of the GABA-reuptake inhibitor tiagabine on panic and anxiety in patients with panic disorder. Panic attacks in the community. Social morbidity and health care utilization. Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision A double-blind, placebo-controlled, parallel-group, flexible-dose study of venlafaxine extended release capsules in adult outpatients with panic disorder. A Naturalistic Long-Term Comparison Study of Selective Serotonin Reuptake Inhibitors in the Treatment of Panic Disorder Controlled discontinuation of benzodiazepine treatment for patients with panic disorder. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. Moclobemide and fluoxetine for panic disorder. International Panic Disorder Study Group. A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder. Randomised placebo-controlled trial of moclobemide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? Potential effectiveness and safety of olanzapine in refractory panic disorder. Mortality of anxiety syndromes in a normal population. The Lundby Study. Evidence why paroxetine dose escalation is not effective in major depressive disorder: a randomized controlled trial with assessment of serotonin transporter occupancy.
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 Paroxetine has been shown to be effective in panic disorder in three 10- to 12-week studies . This trial studied the longer term effects of paroxetine in patients with DSM-III-R defined panic disorder . Patients who satisfactorily completed a 12-week , double-blind , placebo-controlled study of paroxetine and clomipramine  could choose to continue receiving their r and omized treatment for a further 36 weeks . Efficacy assessment s included the daily panic attack diary , the Clinical Global Impression Scale , the Hamilton Anxiety Rating Scale , the Marks Sheehan Phobia Scale and the Sheehan Disability Scale . In total , 176 patients were included in the intention-to-treat population . The number of full panic attacks decreased in all three groups during the 12-week study , and improvements continued with long-term therapy . Paroxetine was statistically significantly more effective than placebo throughout the long-term study with respect to reduction from baseline of full panic attacks , and at the end of treatment with respect to the proportion of patients who eventually experienced no panic attacks . There were no significant differences between paroxetine and clomipramine . The proportion of patients who withdrew from the study due to adverse effects  was greater in the clomipramine group ( 19 % ) than in either the paroxetine group ( 7 % ) or the placebo group ( 9 % ) . Paroxetine was significantly more effective than placebo and as effective as ( but better tolerated than ) clomipramine in the long-term treatment of panic disorder . Not only was efficacy maintained , but continued improvement was also seen , indicating the importance of long-term treatment in patients with panic disorder 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 Regular physical activity is anxiolytic in both healthy subjects and patients with panic disorder . In contrast , acute exercise may induce acute panic attacks or increase subjective anxiety in patients with panic disorder more than in other people . The effects of quiet rest or an aerobic treadmill exercise ( 30 min at an intensity of 70 % of the maximal oxygen uptake , VO2max ) on cholecystokinin tetrapeptide ( CCK-4 ) induced panic attacks were studied in a crossover design in 12 patients with panic disorder and 12 matched healthy subjects . The effects of CCK-4 ( 25 microg in patients and 50 microg in control subjects ) were measured with the Acute Panic Inventory ( API ) score , comparing panic attack frequencies , total score , and subscores for anxiety and somatic symptoms . CCK-4-induced panic attacks were less frequent after prior exercise : they occurred in 15 ( 62.5 % ) subjects after rest ( 9 patients and 6 control subjects ) , but only 5 ( 20.8 % ) subjects after exercise ( 4 patients and 1 control subject ) . In both conditions , CCK-4 administration induced a significant increase in the total API score and the anxiety and somatic symptoms subsores . However , compared to prior rest , exercise result ed in a significantly reduced CCK-4-induced increase of the total API score and the anxiety subscore . In patients with panic disorder exercise increased the total API score and the somatic symptoms subscale but not the anxiety subscore .  Patients with panic disorder showed increased somatic but not anxiety symptoms after an acute bout of exercise .  Severity of CCK-4-induced panic and anxiety , on the other h and was reduced by exercise . These findings suggest that in addition to exercise training an acute bout of exercise may be used to reduce anxiety and panic attack frequency and intensity in panic disorder patients Several reports suggest that selective serotonin reuptake blockers are helpful in the treatment of panic disorder . The aim of the study was to compare fluvoxamine with placebo in 50 panic disorder patients by using an 8-week , double-blind , parallel-groups design . Weekly assessment included a panic attack diary ( frequency and severity ) , the Montgomery-Asberg Depression Scale , the Clinical Anxiety Scale , and the Sheehan Disability Scale . Although both groups improved on all measures , the fluvoxamine group experienced significantly less frequent major panic attacks from the third week on and significantly lower ratings on anxiety , depression , and disability from the sixth week on . Mean ratings of the severity of major and the severity and frequency of minor attacks were not affected differently by fluvoxamine and placebo . At the end of the study , significantly more patients on fluvoxamine were free of major and minor panic attacks . The results indicate that : ( 1 ) the administration of fluvoxamine , as compared with placebo , led to a significant reduction in the number of panic attacks . ( 2 ) The severity of panic attacks was not affected by fluvoxamine . ( 3 ) The effect of fluvoxamine on anxiety , depressive mood , and disability differed from placebo only after 6 weeks of treatment , after which the placebo group showed either no further improvement or a reversal of symptoms . ( 4 ) Participation in a drug study , even without additional psychotherapy , led to significant improvement in all patients BACKGROUND Escitalopram , the therapeutically active isomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram , has shown significant anxiolytic effects in placebo-controlled clinical trials of social anxiety disorder , generalized anxiety disorder , and anxiety symptoms associated with major depression . This study evaluated the safety and efficacy of escitalopram in out patients diagnosed with panic disorder . METHOD Male and female out patients between 18 and 80 years of age meeting DSM-IV criteria for panic disorder , with or without agoraphobia , were r and omly assigned to 10 weeks of double-blind treatment with escitalopram , citalopram , or placebo in a study conducted from September 1999 to July 2001 . The primary measure of efficacy was panic attack frequency at week 10 relative to baseline , as assessed by the Modified Sheehan Panic and Anticipatory Anxiety Scale . RESULTS A total of 366 subjects ( 128 escitalopram patients , 119 citalopram patients , and 119 placebo patients ) received at least 1 dose of double-blind treatment . The frequency of panic attacks was statistically significantly improved ( p = .04 ) , and the increase in percentage of patients with zero panic attacks reached borderline significance ( p = .051 ) , in the escitalopram-treated group relative to the placebo-treated group . Both escitalopram and citalopram statistically significantly reduced panic disorder symptoms and severity versus placebo at endpoint ( p < /=.05 ) , as measured by the Panic and Agoraphobia Scale total score , the Clinical Global Impressions scale , the Patient Global Evaluation , and the Quality of Life Enjoyment and Satisfaction Question naire . Treatment with escitalopram was safe and well tolerated , with a similar incidence of the most common adverse events for the escitalopram and placebo groups . The rate of discontinuation for adverse events was 6.3 % for escitalopram , 8.4 % for citalopram , and 7.6 % for placebo . CONCLUSION Escitalopram is efficacious , safe , and well tolerated in the treatment of panic disorder RATIONALE Few r and omized , placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder . OBJECTIVES The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release ( ER ) with placebo in treating panic disorder . Secondary objectives included comparing paroxetine with venlafaxine ER and placebo . METHODS Out patients aged > or = 18 years ( placebo , n = 157 ; venlafaxine ER 75 mg , n = 156 ; venlafaxine ER 225 mg , n = 160 ; paroxetine , n = 151 ) , with a primary diagnosis of panic disorder ( + /-agoraphobia ) based on the Diagnostic and Statistical Manual of Mental Disorders ( Fourth Edition ) criteria for > or =3 months were r and omly assigned to receive venlafaxine ER ( titrated to 75 mg/day or 225 mg/day ) , paroxetine ( titrated to 40 mg/day ) , or placebo for 12 weeks . The primary efficacy measure was the percentage of patients free of full-symptom panic attacks ( > or = four symptoms ) at endpoint . Key secondary outcomes included the Panic Disorder Severity Scale ( PDSS ) mean score change and response . RESULTS At endpoint , all active treatment groups showed a significantly ( P < 0.01 ) greater proportion of patients free of full-symptom panic attacks , compared with placebo , and were superior ( P < 0.05 ) on most secondary measures . The venlafaxine ER 225 mg group had significantly ( P < 0.05 ) greater mean PDSS score improvement than the paroxetine group ( -12.58 vs -11.87 ) and a significantly higher proportion of patients free of full symptom panic attacks ( 70.0 vs 58.3 % ) . Both drugs were generally well tolerated . CONCLUSION Venlafaxine ER 75 mg/days and 225 mg/days and paroxetine 40 mg/day were both well tolerated and effective for short-term 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 CONTEXT Previous studies have documented an association of depression and phobic anxiety with cardiovascular morbidity and mortality , but little is known about the cardiovascular sequelae of panic anxiety . OBJECTIVE To determine whether panic attacks are associated with risk of cardiovascular morbidity and mortality in postmenopausal women . DESIGN Prospect i ve cohort survey . SETTING Ten clinical centers of the 40-center Women 's Health Initiative . PARTICIPANTS A total of 3369 community-dwelling , generally healthy postmenopausal women ( aged 51 - 83 years ) enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study who completed a question naire about occurrence of panic attacks in the previous 6 months .  MAIN OUTCOME MEASURES Cardiovascular/cerebrovascular outcomes ( fatal and nonfatal myocardial infa rct ion and stroke ) and all-cause mortality were ascertained after a mean of 5.3 years of follow-up . RESULTS A 6-month history of full-blown panic attacks , endorsed by 10 % of postmenopausal women in this cohort , was associated with both coronary heart disease ( hazard ratio , 4.20 ; 95 % confidence interval , 1.76 - 9.99 ) and the combined end point of coronary heart disease or stroke ( hazard ratio , 3.08 ; 95 % confidence interval , 1.60 - 5.94 ) after controlling for multiple potential confounders . The hazard ratio for all-cause mortality , excluding those with a history of cardiovascular/cerebrovascular events , was 1.75 ( 95 % confidence interval , 1.04 - 2.94 ) . CONCLUSION Panic attacks are relatively common among postmenopausal women and appear to be an independent risk factor for cardiovascular morbidity and mortality in older women Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder . The advent of selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) ( e.g. citalopram ) and , more recently , selective noradrenergic ( NA ) reuptake inhibitors ( NRIs ) ( e.g. reboxetine ) has provided potentially important avenues of treatment for the disorder . To date , the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved . Nineteen patients with panic disorder were r and omized in a single-blind , cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug . At week 18 , seven of 13 patients ( 54 % ) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram ( 82 % ) . Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy . However , citalopram demonstrated superior efficacy in treating depressive symptoms . One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram . Although SSRIs are viewed as a first-line treatment for panic disorder , these results suggest that a NA agent such as reboxetine may also have a role . These data also suggest an advantage for citalopram in treating comorbid depressive symptoms , although some patients may respond preferentially to an SSRI and other patients to an NRI There is considerable evidence that people with panic disorder utilise the physical health care system more frequently than people in the general community and so incur for themselves , and impose on the public health care system , considerably greater costs . Although this is probably because of specific characteristics to do with panic disorder , it may also be a function of having any anxiety disorder where panic is prominent . This study represents one of the few comparisons of medical utilisation and costs incurred by people with panic disorder to those incurred by people with another anxiety disorder , in this case , social phobia . Before treatment , 41 people with panic disorder , 15 with social phobia and 43 nonanxious controls  were interviewed about their use of the medical care system over the previous 12 months . As expected , people with panic disorder had significantly higher utilisation rates than either the nonanxious controls or the socially phobic subjects , and incurred substantially higher costs . Adequate screening for panic disorder at the primary medical care level together with appropriate treatment referral therefore have the potential to substantially reduce the personal and community costs incurred by people with panic disorder Panic disorder with or without agoraphobia is a common , often chronic and refractory anxiety disorder . Although a number of pharmacotherapies are now indicated for panic disorder , many patients do not respond to available interventions . We hypothesized that duloxetine , a serotonin‐norepinephrine reuptake inhibitor ( SNRI ) that has greater initial noradrenergic effects than venlafaxine , would have broad efficacy for individuals with panic disorder . Fifteen individuals with panic disorder with or without agoraphobia received 8 weeks of open label duloxetine flexibly dosed from 60 to 120 mg per day . Duloxetine treatment result ed in significant anxiolysis as measured by the primary outcome measure , the Panic Disorder Severity Scale ( PDSS ) ( paired t(df ) = 4.02(14 ) , P= 0.0013 ) , as well as measures of generalized anxiety , depression and quality of life ( all P < 0.05 ) . Although definitive conclusions are limited due to its small open‐label nature , this first prospect i ve study provides preliminary support for the efficacy of duloxetine for panic disorder and suggests larger r and omized controlled study is warranted BACKGROUND There is debate about combining benzodiazepines with selective serotonin reuptake inhibitors in the acute treatment of panic disorder . Although this medication combination is widely used in clinical practice , there is no well-tested , optimal method of coadministering these medications for the treatment of panic disorder . The purpose of this study was to test the efficacy of early coadministration of clonazepam with sertraline in the treatment of panic disorder . METHODS Fifty patients with panic disorder were r and omized into a double-blind clinical trial . Patients received open-label sertraline for 12 weeks ( target dose , 100 mg/d ) , and in addition were r and omized to groups receiving either 0.5 mg of active clonazepam 3 times daily or placebo clonazepam for the first 4 weeks of the trial . The clonazepam dose was then tapered during 3 weeks and discontinued . RESULTS Thirty-four ( 68 % ) of 50 patients completed the trial .  Drop-out rates were similar in the sertraline/placebo vs the sertraline/clonazepam group ( 38 % vs 25 % ) ( P = .5 ) . An intent-to-treat analysis ( on last observation carried forward data ) revealed a much greater proportion of responders in the sertraline/clonazepam compared with the sertraline/placebo group at the end of week 1 of the trial ( 41 % vs 4 % ) ( P = .003 ) . There was also a significant between-group difference at the end of week 3 with 14 ( 63 % ) of 22 of the sertraline/clonazepam group responding to treatment vs 8 ( 32 % ) of 25 of the sertraline/placebo group ( P = .05 ) . This difference was not observed at other times during the trial . CONCLUSION These data indicate that rapid stabilization of panic symptoms can be safely achieved with a sertraline/clonazepam combination , supporting the clinical utility of this type of regimen for facilitating early improvement of panic symptoms relative to sertraline alone Objective : To investigate the long‐term efficacy , prevention of relapse and safety of sertraline in the treatment of panic disorder A r and omized , double-blind , placebo-controlled , parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of  panic disorder . One hundred three patients were r and omly assigned to receive double-blind treatment with either gabapentin ( dosed flexibly between 600 and 3,600 mg/day ) or placebo for 8 weeks . No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale ( PAS ) ( p = 0.606 ) . A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure ( PAS score > or = 20 ) . In this population , the gabapentin-treated patients showed significant improvement in the PAS change score ( p = 0.04 ) . In patients with a PAS score of 20 or greater , women showed a greater response than men regardless of treatment . Adverse events were consistent with the known side effect profile of gabapentin and included somnolence , headache , and dizziness . One patient experienced a serious adverse event during the study . No deaths were reported . The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder INTRODUCTION Serotonergic agents have greater effectiveness than noradrenergic ones in the treatment of Panic Disorder ( PD ) . However preliminary studies suggested that reboxetine might be effective in the treatment of PD . We compared the effectiveness and tolerability of reboxetine and paroxetine in the treatment of PD . METHODS Sixty-eight patients with PD were assigned to treatment groups in a single-blind , r and omized design . Each patient was assessed at day 0 and 90 by the Panic Associated Symptoms Scale ( PASS ) , the Sheehan Disability Scale ( SDS ) and the Fear Question naire ( FQ ) . Side effects were also recorded . RESULTS Reduction of PASS scores was significantly greater in the paroxetine group than in the reboxetine one . Vice versa we did not find any significant differences for other outcome measures . Sexual dysfunction and weight gain were significantly less frequent in the reboxetine group . CONCLUSIONS The results showed a greater effect of paroxetine on panic attacks than reboxetine , while no differences for anticipatory anxiety and avoidance were found , suggesting a different role of noradrenaline and serotonin in the treatment of PD Several issues remain to be ascertained beyond the acute response to imipramine hydrochloride in patients with panic disorder . Study 1 consisted of a prospect i ve , systematic characterization of half-dose 12-month maintenance in patients with panic disorder with agoraphobia who had shown marked and stable response to 6 months of acute-phase treatment with imipramine .  Study 2 assessed the 6-month cumulative relapse rate following discontinuation of acute-phase imipramine treatment in a comparable sample of patients . The same assessment battery was used in both studies , and the integrity of experimental drug conditions was verified by plasma drug level determinations . In contrast to the high relapse rate following discontinuation of acute-phase treatment , none of the patients showed relapse or had sustained worsening in panic or phobia measures during the half-dose maintenance period . The results underscore the importance of pharmacological prophylaxis and provide empirical guidelines for a successful low-dose maintenance regimen for patients with panic disorder and agoraphobia who respond markedly to imipramine The present study examined a relapse prevention ( RP ) program delivered via bibliotherapy in the treatment of individuals with panic attacks . Compared with a wait list control group , individuals receiving RP exhibited significant reductions on measures of frequency of panic attacks , panic cognitions , anticipatory anxiety , avoidance , and depression . In addition , individuals in the RP group were more likely to attain a " clinical ly significant change " in status on both panic-free status and level of avoidance more frequently than individuals in the control group . When compared with treatment effects evaluated in two prior phases of the study , the obtained results appear to be the product of a synchronous effect of bibliotherapy and minimal phone contact during the 6-month follow-up period . The results reflect the importance of brief therapist contact in increasing motivation for active participation in bibliotherapy interventions OBJECTIVE To examine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of patients with panic disorder . METHOD In an open-label , fixed-flexible dose study , 18 patients with panic disorder with or without agoraphobia ( DSM-IV diagnostic criteria ) were treated with levetiracetam for 12 weeks . Outcome was assessed with st and ard rating instruments ( Clinical Global Impressions-Severity of Illness scale [ CGI-S ] , Clinical Global Impressions-Improvement scale [ CGI-I ] , and the 14-item Hamilton Rating Scale for Anxiety [ HAM-A ] ) and by the number of panic attacks during the previous week . The study was conducted in 2 outpatient clinics in New York City from January 2004 through July 2005 . RESULTS Of the 13 patients completing the study , 11 were rated " very much " or " much " improved on the CGI-I. Panic attack frequency , anxiety ( HAM-A ) , and global severity ( CGI-S ) ratings also demonstrated significant improvement ( all p < .00 ) . For most patients , clinical benefits were apparent after only 1 to 2 weeks of treatment . Levetiracetam was well tolerated with minimal side effects . CONCLUSION Given its favorable pharmacokinetics , side effect profile , and , if confirmed , early onset of action and efficacy , levetiracetam might represent significant progress in the pharmacologic management of panic disorder BACKGROUND AND OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are currently the first-line treatment for panic disorder , although up to 30 % of patients either do not respond to SSRIs or withdraw due to adverse events . Reboxetine , a selective norepinephrine reuptake inhibitor ( selective NRI ) , is effective in treating depression and may alleviate depression-related anxiety . This study aim ed to investigate the efficacy of reboxetine in the treatment of patients with panic disorder who did not respond to SSRIs . METHOD In this 6-week , open-label study , 29 adult out patients with panic disorder who had previously failed to respond to SSRI treatment received reboxetine 2 mg/day , titrated to a maximum of 8 mg/day over the first 10 days .  Efficacy was assessed using the Panic Self- Question naire ( PSQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the 17-item Hamilton Rating Scale for Depression ( HRSD ) and the Global Assessment of Functioning ( GAF ) Scale . RESULTS The 24 patients who completed the study responded well to reboxetine treatment . Significant improvement ( p < 0.001 ) was observed in the number of daily panic attacks , and on the scales measuring anxiety , depression and functioning . Reboxetine was generally well tolerated . Five patients withdrew due to  adverse events . CONCLUSIONS Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients and warrants further clinical investigation BACKGROUND There has been little systematic work done regarding the long-term treatment of panic disorders . The aim of the present study was to assess the 12-month cumulative risk of relapse specifically due to discontinuation of imipramine and to test the hypothesis that maintenance treatment with imipramine protects patients with panic disorder and agoraphobia from such reversals . METHOD Following an acute-phase open trial with imipramine ( 2.25 mg/kg per day ) involving 110 patients for 6 months , the 56 patients who were in stable remission , did not require additional treatment , and consented to be r and omly assigned to double-blind maintenance ( n = 29 ) or discontinuation ( n = 27 ) conditions were followed up with planned assessment s every 2 months during a 1-year period . There were no behaviorally oriented interventions or instructions at any time during the 18 months of the study . RESULTS Maintenance treatment ( 1 relapse ) and discontinuation ( 10 relapses ) conditions had significantly different survival curves ( Mantel-Cox statistic chi(2)1 = 10.47 , P = .001 ) . None of the additional 10 variables from demographic , clinical , and open-treatment domains considered in the proportional hazard model disrupted the significant relationship between experimental drug condition and relapse ; other things being equal , a patient receiving imipramine maintenance was 92.5 % lower in the hazard rate of relapse than a patient receiving placebo . CONCLUSION The results confirm the very high degree of prophylactic effectiveness of maintenance imipramine treatment and demonstrate that relapse , although substantial , occurs in a minority of patients with panic disorder and agoraphobia who are in stable remission prior to treatment discontinuation Cognitive behavioral treatment ( CBT ) has been shown to reduce risk for adverse reactions ( e.g. , rebound panic ) following benzodiazepine taper for patients with panic disorder ( PD ) . This study evaluated the effects of antidepressant discontinuation for patients with PD in the context of CBT .  Patients with PD ( n=21 ) on a stable dose of antidepressants completed a 12-week group CBT treatment and were r and omly assigned to discontinue antidepressants during week 8 of the treatment . There were no statistically significant differences between groups at posttreatment or 6-month follow-up . Data indicate no apparent immediate or long-term adverse effects for antidepressant discontinuation for patients with PD receiving CBT The purpose of our study was to evaluate the efficacy and tolerability of low-dose olanzapine augmentation in selective serotonin reuptake inhibitor (SSRI)-resistant panic disorder ( PD ) with or without agoraphobia . In this 12-week , open-label study , 31 adult out patients with treatment-resistant PD who had previously failed to respond to SSRI treatment were treated with fixed dose of olanzapine ( 5 mg/d ) in addition to SSRI .  Efficacy was assessed using the Panic Attack and Anticipatory Anxiety Scale ( PAAAS ) , the Agoraphobic Cognitions Question naire ( ACQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the Hamilton Rating Scale for Depression ( HAM-D ) , the Global Assessment of Functioning Scale ( GAF ) , and the Clinical Global Impression of Improvement ( CGI-I ) . Twenty-six patients completed the trial period with a dropout rate of 16.1 % . At week 12 , 21 patients were responders ( 81.8 % ) , and an overall improvement on all rating scales was observed in all patients both with or without agoraphobia . Fifteen patients ( 57.7 % ) achieved remission . Olanzapine was well tolerated and the most frequent adverse effects were mild-to-moderate weight gain and drowsiness . No extrapyramidal symptoms were reported . Olanzapine appears to be effective as augmentation strategy in the treatment of SSRI-resistant PD , but study limitations must be considered and placebo-controlled studies are needed OBJECTIVE To assess the efficacy and tolerability of controlled-release paroxetine ( paroxetine CR ) in the treatment of adults with panic disorder . METHOD  Paroxetine CR ( 25 - 75 mg/day ; N = 444 ) was compared with  placebo ( N = 445 ) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical , double-blind , placebo-controlled , 10-week clinical trials that were pooled for analysis . RESULTS Paroxetine CR was statistically superior to placebo in the primary outcome measure , percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint . Of the total population that completed or prematurely terminated treatment , 63 % and 53 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free during the final 2 weeks ( p < .005 ; odds ratio [ OR ] = 1.63 ; 95 % CI = 1.21 to 2.19 ) . For week 10 completers ( 72 % of total ) , 73 % and 60 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free at week 10 ( p < .005 ; OR = 2.11 ; 95 % CI = 1.45 to 3.07 ) . Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale . Adverse events leading to study withdrawal were minimal and occurred in 11 % of the paroxetine CR group and 6 % of the placebo group . Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study . There were no unexpected adverse events , and serious adverse events were uncommon ( 10 [ 2.3 % ] of the 444 patients treated with paroxetine CR vs. 8 [ 1.8 % ] of the 445 patients treated with placebo ) . CONCLUSION Paroxetine CR is an effective and well-tolerated treatment for panic disorder . Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events OBJECTIVE The purpose of this study was to compare the therapeutic effect of exercise for patients with panic disorder to a drug treatment of proven efficacy and to placebo . METHOD Forty-six out patients suffering from moderate to severe panic disorder with or without agoraphobia ( DSM-III-R criteria ) were r and omly assigned to a 10-week treatment protocol of regular aerobic exercise ( running ) , clomipramine ( 112.5 mg/day ) , or placebo pills . RESULTS The dropout rate was 31 % for the exercise group , 27 % for the placebo group , and 0 % for the clomipramine group . In comparison with placebo , both exercise and clomipramine led to a significant decrease in symptoms according to all main efficacy measures ( analysis of variance , last-observation-carried-forward method and completer analysis ) . A direct comparison of exercise and clomipramine revealed that the drug treatment improved anxiety symptoms significantly earlier and more effectively . Depressive symptoms were also significantly improved by exercise and clomipramine treatment . CONCLUSIONS These results suggest that regular aerobic exercise alone , in comparison with placebo , is associated with significant clinical improvement in patients suffering from panic disorder , but that it is less effective than treatment with clomipramine BACKGROUND As part of a longitudinal study , prevalence findings of DSM-IV disorders are presented for a r and om sample of 3021 respondents aged 14 to 24 , with response rate 71 % . METHOD Assessment included various subtypes of disorders , subthreshold conditions and disorders that have only rarely been studied in other epidemiological surveys . The computer-assisted Munich-Composite International Diagnostic Interview ( M-CIDI ) was used to derive DSM-IV diagnoses . RESULTS Substance disorders were the most frequent ( lifetime 17.7 % ; 12-month 11.4 % ) , with abuse being considerably more frequent than dependence . Other mental disorders had a lifetime prevalence of 27.5 % ( 12-month , 17.5 % ) with depressive disorders ( 16.8 % ) being more frequent than anxiety disorders ( 14.4 % ) . Eating disorders ( 3.0 % ) and threshold somatoform disorders ( 1.2 % ) were rare disorders . Subthreshold anxiety and somatoform disorders , however , were more frequent than threshold disorders . Prevalence of disorders was equally high for males and females , although specific disorder prevalence varied significantly by gender . The co-occurrence of disorders ( co-morbidity ) was substantial and was significantly related to greater reductions in work productivity and increased rates of professional helpseeking behaviour . CONCLUSIONS Findings underline that mental disorders in young adults are frequent and impairing , limiting work and education ability and social interaction . Given the fact that adolescents and young adults are in a key phase of socialization in terms of professional career and interpersonal relationships , our findings indicate a considerable risk potential for an accumulation of complicating factors and future chronicity . This paper is the first report of this ongoing longitudinal study about early developmental conditions of mental disorders The present research evaluated patients from 2 previous studies ( 1 conducted in Peoria , the other at Dartmouth ) during a 2- to 5-year posttreatment period . Results showed that 75 % of the Peoria sample and 76 % of the Dartmouth sample were able to discontinue alprazolam therapy , remain abstinent of any type of treatment for panic disorder , and maintain their acute-treatment clinical gains over this follow-up period . The degree to which patients ' anxiety sensitivity declined during treatment predicted relapse versus survival during the 1st 6 months of follow-up , when most relapses occurred . Implication s of these findings for benzodiazepine discontinuation , combined pharmacotherapy and psychotherapy , and relapse prevention in panic disorder are discussed OBJECTIVE The authors investigated whether cognitive behavioral treatment could facilitate discontinuation of alprazolam therapy and maintenance of drug abstinence among panic disorder patients treated with alprazolam doses sufficient to suppress spontaneous panic attacks . METHOD Twenty-one out patients who met DSM-III-R criteria for panic disorder with mild to severe agoraphobia were made panic-free with alprazolam ( mean dose = 2.2 mg/day ) and were then r and omly assigned to receive either supportive drug maintenance and slow , flexible drug taper or an identical medication treatment plus 12 weeks of concurrent , individual cognitive behavioral treatment . Taper in the combined treatment group was sequenced to conclude before cognitive behavioral treatment ended . RESULTS Twenty subjects completed the study . There was no significant difference between groups in the rate of alprazolam discontinuation ( 80 % and 90 % , respectively , in the alprazolam-only group and the combined treatment group ) . However , during the 6-month follow-up period , half of the subjects who discontinued alprazolam without cognitive behavior therapy , but none of those who were given cognitive behavior therapy , relapsed and resumed alprazolam treatment . CONCLUSIONS Cognitive behavioral treatment administered in parallel with alprazolam maintenance and taper was effective in preventing relapse after drug discontinuation . The results warrant further research on the thoughtful integration of these two therapeutic modalities Despite the widespread application of combined selective serotonin reuptake inhibitors ( SSRI ) and benzodiazepine treatment for panic disorder , there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy . Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment , this study is the first to address the critical question of whether continued combined treatment confers superior efficacy . This study is a r and omized , double-blind , three-arm study in patients with panic disorder ( n = 60 ) , comparing the efficacy and safety of paroxetine and placebo ( PP ) , paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase ( PC-D ) , and ongoing combination treatment ( PC-M ) . All treatment groups demonstrated significant improvement by endpoint . There was a significant advantage for the combined treatment groups early in treatment but , subsequently , outcome in all three groups was similar . A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered . The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout . Combined treatment with paroxetine and clonazepam result ed in more rapid response than with the SSRI alone , but there was no differential benefit beyond the initial few weeks of therapy . Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments ( interaction between treatment and baseline score ) . Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks , but not for the frequency of situational panic attacks or measures of agoraphobia . This report presents similar analyses of data from a study using moclobemide .  Patients ( N = 452 ) with panic disorder were r and omized to placebo  or a fixed dose of moclobemide ( 75 , 150 , 300 , 600 , or 900 mg/day ) . They were treated double-blindly and evaluated at baseline and 1 , 2 , 3 , 4 , 6 , and 8 weeks later . The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary , and fear and avoidance ratings based on the patient ’s main phobia using baseline ( pre ) and end-point ( post ) values for all r and omized patients . Adjoining dose groups were combined . Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes . Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms . This study replicates the authors ’ earlier findings , except for situational panic attacks , which probably were not reliably identified . Antidepressants selectively suppress panic attacks , especially unexpected attacks , but not agoraphobia . The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinical ly separable biologic and cognitive components that respond differentially to treatment . Antidepressants benefit primarily patients with many unexpected panic attacks . Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means ( analysis of covariance ) BACKGROUND More data are needed to guide next-step interventions for panic disorder refractory to initial intervention . METHOD This 24-week r and omized clinical trial ( RCT ) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases . Patients who failed to meet remission criteria were eligible for r and omization in the next treatment phase . Phase 1 was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg ( or escitalopram equivalent ) to prospect ively define treatment refractoriness ( lack of remission ) . Phase 2 was a 6-week double-blind RCT of ( 1 ) increased-dose selective serotonin reuptake inhibitor ( SSRI ) versus ( 2 ) continued SSRI plus placebo . Phase 3 was a 12-week RCT of added cognitive-behavioral therapy ( CBT ) compared to " medication optimization " with SSRI plus clonazepam . Primary endpoints were remission and change in Panic Disorder Severity Scale ( PDSS ) score in the intent-to-treat sample in each phase . RESULTS In phase 1 , 20.5 % ( 8/39 ) of the patients achieved remission , and only baseline severity predicted endpoint PDSS score ( beta [ SE ] = 1.04 [ 0.15 ] , t = 6.76 , P < .001 ) . In phase 2 , increasing the SSRI dose did not result in greater improvement or remission rates  ( placebo 15 % [ n = 2 ] vs increased dose 9 % [ n = 1 ] : Fisher exact test P = NS ) . In phase 3 , remission was minimal ( medication optimization = 11 % [ n = 1 ] ; CBT = 10 % [ n = 1 ] ) , with a lack of group difference in PDSS score reduction ( t(17 ) = 0.51 , P > .60 ) consistent with a small effect size ( d = 0.24 ) . CONCLUSIONS Although power was limited and larger studies are needed , we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose . Further , augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ , suggesting that both are reasonable next-step options . However , low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00118417 BACKGROUND Chronic exercise has been shown to have therapeutic effects in panic disorder ( PD ) . The mechanism of these effects is unknown . Acute exercise reduces the effect of a panic challenge in healthy volunteers . Such an effect has not yet been demonstrated in PD patients . The present study aim ed at exploring the antipanic effects of acute exercise on a 35 % CO2 panic provocation in treatment-naïve PD patients to further eluci date the mechanisms of the beneficial effects of exercise on panic . METHODS Eighteen PD patients performed either moderate/hard exercise or very-light exercise before a 35 % CO2 challenge in a r and omized , between-group design . The reactivity to CO2 was assessed with the Visual Analogue Anxiety Scale and the DSM-IV Panic Symptom List . RESULTS Panic reactions to CO2 were smaller in patients that performed moderate/hard exercise in contrast to those that performed very-light exercise . Increments in both measurements and panic rates were consistently reduced by intense exercise . LIMITATIONS Since this study focuses on the acute effects of exercise on CO2 sensitivity in patients with PD , the results of repetitive exercise sessions on the rate of spontaneous panic attacks and overall symptoms are warranted . The small sample size and other limitations are addressed . CONCLUSIONS Exercise reduced the panicogenic effects of a CO2 challenge . In addition to its therapeutic potential , exercise may also be useful as a laboratory maneuver with heuristic value in experimental research into the mechanisms of antipanic treatment 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 Endogenous anxiety ( anxiety hysteria , agoraphobia with panic attacks ) is characterized by sudden , spontaneous panic attacks accompanied by multiple autonomic symptoms , overwhelming fear , a flight response , and polyphobic behavior . Psychotherapy , behavior therapy , and tranquillizers have been of limited success in treating this syndrome . Fifty-seven patients severely disabled by the syndrome for a mean period of 13 years completed the three-month study . R and omly assigned in a double-blind , placebo-controlled design to imipramine hydrochloride , pheneizine sulfate , or placebo , they were seen in supportive group therapy every two weeks . Patients in the pheneizine and imipramine cells showed significant improvement ovehe persistent trend for pheneizine to be superior to imipramine achieved significance only on the Work and Social Disability Scale and the Sympton Severity and Phobic Avoidance Scale . The implication s for classification and theory are discussed Objective : To examine prospect ively the relationship between a diagnosis of panic disorder and the risk of acute myocardial infa rct ion within 1 year of follow-up . Panic disorder is associated prospect ively with coronary artery disease , but the risk of acute myocardial infa rct ion associated with panic disorder has not been specifically investigated . Method : This nationwide population -based study used data from the Taiwan National Health Insurance Research Data base covering the years 2000 to 2005 . A total of 9641 patients diagnosed with panic disorder in 2004 were included , together with 28,923 matched nonpanic disorder enrollees as a comparison cohort . Cox proportional hazard regressions were conducted to compute hazard ratios , after adjustment for comorbid medical disorders and sociodemographic characteristics . Results : Results indicated that 4.77 % of patients with panic disorder ( approximately one in 21 ) experienced an acute myocardial infa rct ion episode within a year , compared with 2.73 % of patients in the comparison cohort . The adjusted hazard of acute myocardial infa rct ion was significantly higher ( 1.75 times , 95 % Confidence Interval = 1.55 - 1.97 ) for patients with panic disorder , relative to the comparison cohort . The association persisted in further analyses stratified by hypertension , coronary heart diseases , and age . Conclusion : Panic disorder was identified as an independent risk factor for subsequent acute myocardial infa rct ion . Comprehensive multidisciplinary approaches are needed to optimize primary and secondary prevention of acute myocardial infa rct ion among patients with panic disorder . PD = panic disorder ; CHD = coronary heart disease ; AMI = acute myocardial infa rct ion ; MI = myocardial infa rct ion ; NHIRD = National Health Insurance Research Data base ; NHI = National Health Insurance program ; HR = hazard ratio ; CI = Confidence Interval ; HRV = heart rate variability To date , no large-scale , controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported . This double-blind study compares the efficacy of venlafaxine extended-release ( ER ) and paroxetine with placebo . A total of 664 nondepressed adult out patients who met DSM-IV criteria for panic disorder ( with or without agoraphobia ) were r and omly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER ( 75 mg/day or 150 mg/day ) , or paroxetine 40 mg/day . The primary measure was the percentage of patients free from full-symptom panic attacks , assessed with the Panic and Anticipatory Anxiety Scale ( PAAS ) . Secondary measures included the Panic Disorder Severity Scale , Clinical Global Impressions -- Severity ( CGI-S ) and --Improvement ( CGI-I ) scales ; response ( CGI-I rating of very much improved or much improved ) , remission ( CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks ) ; and measures of depression , anxiety , phobic fear and avoidance , anticipatory anxiety , functioning , and quality of life . Intent-to-treat , last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo . No significant differences were observed between active treatment groups . Panic-free rates at end point with active treatment ranged from 54 % to 61 % , compared with 35 % for placebo . Approximately 75 % of patients given active treatment were responders , and nearly 45 % achieved remission . The placebo response rate was slightly above 55 % , with remission near 25 % . Adverse events were mild or moderate and similar between active treatment groups . Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder BACKGROUND Controlled trials suggest that clomipramine may be a highly effective antipanic drug . Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance . METHOD Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment . Starting at 10 mg/day , the dose was gradually increased to a mean dose of 97 mg/day . RESULTS While completers showed highly significant improvement , the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment . CONCLUSION Given the alternatives , clomipramine should not be used as a first-line antipanic medication The aim of this study is to evaluate the efficacy of milnacipran in the acute treatment of patients with panic disorder . Thirty-one patients who met Diagnostic and statistical manual of mental disorders-IV criteria for panic disorder with or without agoraphobia were included in the study . Patients were initially treated with milnacipran 25 mg twice daily and then 50 mg twice daily until the 10th week . The treatment outcome and panic disorder severity were determined by the Panic Disorder Severity Scale , Panic Inventory , Clinical Global Impression and Hamilton Anxiety Scale , all of which were applied during every evaluation interview . Quality of life ( WHOQOL-bref ) was evaluated at baseline and at the end of the study . Missing data were h and led by using the last observation carried forward for all participants who had taken at least one dose of study medication . Intention-to-treat was used in the analyses . Pharmacological treatment result ed in a clinical ly and statistically significant mean reduction in all severity measures . Remission ( Clinical Global Impression≤2 ) was obtained in 58.1 % of the sample . Regarding WHOQOL , we found a significant improvement ( P<0.05 ) across treatment in all the domains studied . Although results may be influenced by the open design of this pilot study and by the small sample size , our findings suggest that milnacipran may be effective for the treatment of panic disorder and justify further research The detailed results are presented of a double-blind controlled trial of phenelzine and placebo in chronic agoraphobic and socially phobic psychiatric out- patients . Forty patients entered the trial and thirty-two of these completed the 8 weeks period of treatment , in which phenelzine or placebo were taken in flexible dosage , 30–90 mg daily . Patients were prospect ively matched in pairs so that clinical response could be assessed in detail . Phenelzine was significantly superior to placebo on a number of measures , particularly for overall assessment ( P<0.01 ) . The treatment differences were not significant after 4 weeks treatment but were so at 8 weeks . The correlates of response and the results of the clinical ratings suggest that phenelzine is not acting as an antidepressant in this population BACKGROUND Citalopram is a serotonin reuptake inhibitor which has been demonstrated to be highly selective and with a superior tolerability profile to the classical tricyclic antidepressants . This study was design ed to test whether there was any difference in efficacy in the management of panic disorder ( PD ) between citalopram and placebo . METHOD This was a double-blind , placebo and clomipramine controlled , parallel group eight-week study . A total of 475 patients with PD , with or without agoraphobia , were r and omised to treatment with either placebo , clomipramine 60 or 90 mg/day , or citalopram 10 or 15 mg/day , or 20 or 30 mg/day , or 40 or 60 mg/day . Doses were increased over the first three weeks , stabilised during the fourth week and fixed between weeks five and eight . RESULTS Treatment with citalopram at 20 or 30 mg , 40 or 60 mg and clomipramine were significantly superior to placebo , judged by the number of patients free of panic attacks in the week prior to the final assessment . All rating scales examined suggested that citalopram 20 or 30 mg was more effective than citalopram 40 or 60 mg . CONCLUSION The most advantageous benefit/risk ratio for the treatment of PD was associated with citalopram 20 or 30 mg/day BACKGROUND Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders . Enhancement of cognitive-behavior therapy with d-cycloserine ( DCS ) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder . METHOD This is a r and omized , double-blind , placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg d-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy .  R and omized participants were 31 out patients meeting DSM-IV criteria for panic disorder with or without agoraphobia , who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations ( interoceptive exposure ) but also including informational , cognitive , and situational exposure interventions . Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5 . The primary outcome measures were the Panic Disorder Severity Scale ( PDSS ) and Clinicians ' Global Impressions of Severity . RESULTS Results indicated large effect sizes for the additive benefit of d-cycloserine augmentation of cognitive-behavior therapy for panic disorder . At posttreatment and 1 month follow-up , participants who received d-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinical ly significant change status ( 77 % vs. 33 % ) . There were no significant adverse effects associated with DCS administration . CONCLUSIONS This pilot study extends support for the role of d-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse . This study further explores the relationship between relapse and duration of imipramine treatment in this population . Fifty-one patients , all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and r and omized to double-blind maintenance or placebo substitution , discontinued imipramine treatment eventually and were followed over a 12-month risk period : 27 during first year placebo substitution , 7 after 12 months of imipramine maintenance in placebo substitution , and 17 after variable duration s of imipramine maintenance in open discontinuation . There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation . Duration of imipramine treatment , the method of discontinuation ( open versus placebo substitution ) , or any of the 9 variables from the demographic , clinical , and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse . The rate of relapse after only 6 months of treatment ( 10 out of 27 , 37 % ) was identical to the rate of relapse after 12 to 30 months of treatment ( 9 out of 24 , 37.5 % ) . The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients . Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction OBJECTIVE Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessment s are unreliable , studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement . The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement . METHOD Patients with a diagnosis of panic disorder ( N = 243 ) were r and omly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo . Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores . Other assessment s included a panic attack inventory , clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale , a phobia rating scale , the Hamilton Anxiety Rating Scale , the 21-item Hamilton Depression Rating Scale , and the Sheehan Disability Scale . Correlations were determined between outcomes in individual symptom domains and overall clinical outcome . RESULTS Fluoxetine , particularly the 20-mg/day dose , was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures , including global improvement , total panic attack frequency , phobic symptoms , and functional impairment . Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks .  Fluoxetine treatment for panic disorder was well tolerated , with a safety profile consistent with that observed for fluoxetine in other disorders . CONCLUSIONS These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks , phobic symptoms , anxiety , and depressive symptoms in patients with panic disorder . Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance , anxiety , depressive symptoms , and functional impairment , suggesting that outcome measures in this disorder should be more broadly based OBJECTIVE To compare the long-term efficacy of venlafaxine extended release ( ER ) with placebo in preventing panic disorder relapse in out-patient treatment responders . METHOD Out patients aged > or = 18 years who met Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , criteria for panic disorder with or without agoraphobia for at least the previous 3 months , with > or = 6 full symptom panic attacks in the 2 weeks prior to screening and > or = 3 in the 2 weeks before baseline and a Clinical Global Impressions-Severity of Illness rating > or = 4 at screen were eligible to participate . Out patients received flexible-dose ( 75 - 225 mg/day ) venla-faxine ER for 12 weeks . Treatment responders were r and omly assigned to venlafaxine ER or placebo for 26 weeks . Criteria for response were < or = 1 panic attack per week during the last 2 weeks of open-label treatment and a Clinical Global Impressions-Improvement score of 1 or 2 . The primary endpoint , time to relapse during double-blind treatment , defined as > or = 2 full symptom panic attacks per week for 2 consecutive weeks or discontinuation due to loss of effectiveness , was evaluated using Kaplan-Meier survival analysis . The study was conducted between December 2001 and August 2003 . RESULTS The intent-to-treat population had 291 patients in the open-label phase and 169 in the double-blind phase  ( placebo , N = 80 ; venlafaxine ER , N = 89 ; mean daily dose 165 - 171 mg ) . Time to relapse was significantly longer with venlafaxine ER than placebo ( p < .001 ) . All secondary measures of panic attack treatment efficacy , quality of life , and disability were significantly better with venlafaxine ER than placebo ( p < or = .005 ) . CONCLUSION Venlafaxine ER was safe , well tolerated , and effective in preventing relapse in out patients with panic disorder INTRODUCTION Individuals with anxiety disorders often remain symptomatic despite treatment with a first-line pharmacologic agent . More research examining pharmacotherapy augmentation strategies to improve outcomes is needed . METHODS In an 8-week , open-label , prospect i ve augmentation study , we examined the efficacy and tolerability of the novel antipsychotic agent aripiprazole for adult out patients with generalized anxiety disorder ( n=13 ) or panic disorder ( n=10 ) who remained symptomatic despite treatment for at least 8 weeks with an adequate ( or maximally tolerated ) dose of typical pharmacotherapy . RESULTS Aripiprazole augmentation was associated with a significant reduction in Clinical Global Impressions-Severity scores ( paired t=4.41 , df=22 , P<.001 ) in the intent-to-treat sample of 23 individuals . Three subjects ( 13 % ) discontinued due to sedation , chest discomfort , and restlessness , respectively . CONCLUSION These data provide preliminary evidence that aripiprazole may be a useful augmentation strategy for individuals with generalized anxiety disorder or panic disorder who show a limited response to initial pharmacotherapy Abstract Objectives . Regular aerobic exercise ( running ) has been shown to be superior to a pill placebo in the treatment of panic disorder . Combined drug and exercise treatment has not been investigated in r and omized controlled studies to date . Methods . This is a r and omized , 10-week , controlled , parallel group , pilot study . A total of 75 out patients with panic disorder with or without agoraphobia ( DSM-IV and ICD-10 ) received either ( 1 ) exercise plus paroxetine 40 mg/day ( n=21 ) , ( 2 ) relaxation plus paroxetine ( n=17 ) , ( 3 ) exercise plus pill placebo ( n=20 ) , or ( 4 ) relaxation plus pill placebo ( n=17 ) . Changes in the Panic and Agoraphobia Scale ( P&A ) , and the Clinical Global Impression Scale ( CGI ) underwent repeated measure analysis . Results . Effects sizes were large for all groups ( d=1.53–3.87 ) , however not significantly different . Paroxetine-treated patients were significantly more improved than placebo-treated patients . On the CGI , patients in the exercise groups ( plus paroxetine or placebo ) had a trend toward better improvement compared to relaxation ( P=0.06 ) . Response and remission rates were higher in the paroxetine compared to pill placebo groups . Conclusions . While paroxetine was superior to placebo , aerobic exercise did not differ from relaxation training in most efficacy measures Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions . Fifty-seven ( 70.3 % ) reached operational criteria for full remission in 16.2 ± 6.5 weeks , with a mean dose of 89.1 ± 8.2 mg/day . Fifty-four ( 81 % ) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4–6 months . No patient relapsed during the clomipramine maintenance phase . Their medication was then tappered and discontinued with placebo substitution under double-blind conditions . Fifty-one ( 63 % ) patients were followed-up until relapse or recurrence for up to 3 years , with periodic assessment s. Three different outcome groups were identified : the first ( n = 19 , 19 ; 37.2 % ) experienced an early/immediate relapse ( 5.2 ± 4.9 weeks after drug discontinuation ) ; the second group ( n= 22 , 22 ; 43.1 % ) experienced recurrence after 42.9 ± 35 weeks following discontinuation ; and the third group ( n = 10 , 10 ; 19.6 % ) remained assymptomatic and functionally well throughout the follow-up . Predictors of early relapse were : ( 1 ) higher baseline score in the Beck Depression Inventory ; ( 2 ) higher global score on the phobic avoidance scale after the full remission criteria ; and ( 3 ) the need for  higher clomipramine  doses to reach full remission . The need for long-term or intermittent maintenance for most patients is emphasized BACKGROUND There is a paucity of data to support " next-step " treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy . METHOD Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder ( PD ) , social anxiety disorder ( SAD ) , or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate ( or maximally tolerated ) antidepressant and /or benzodiazepine trial of at least 8 weeks ' duration prior to study initiation received open-label augmentation with  flexibly dosed risperidone for 8 weeks . Participants were diagnosed using the Structured Clinical Interview for DSM-IV . RESULTS Risperidone augmentation at a mean + /- SD dose of 1.12 + /- 0.68 mg/day ( range , 0.25 - 3.00 mg/day ) result ed in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety ( HAM-A ) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale , the Liebowitz Social Anxiety Scale , and HAM-A-in the intent-to-treat sample . Seventy percent ( 21/30 ) of participants completed the 8-week trial , with premature discontinuation due primarily to sedation and weight gain . CONCLUSIONS Although conclusions are limited by the open-label , relatively brief nature of this trial , our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD , SAD , or GAD refractory to adequate initial intervention with antidepressants and /or benzodiazepines . Longer-term , controlled safety and efficacy data are needed to underst and the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders BACKGROUND This 12-week , placebo-controlled study was carried out to compare the relative efficacy of paroxetine , clomipramine , and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia . METHOD After a 3-week single-blind , placebo run-in period , 131 patients were r and omly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark . Efficacy assessment s included the daily panic attack diary , the Clinical Global Impression scale , the Patient Global Evaluation , the Hamilton Rating Scale for Anxiety , the Marks-Sheehan Phobia Scale , the Montgomery-Asberg Depression Rating Scale , and the Sheehan Disability Scale . RESULTS Comparisons with placebo revealed significant superiority of paroxetine ( 20 - 60 mg/day ) and clomipramine ( 50 - 150 mg/day ) on nearly all outcome measures . On most measures , paroxetine also showed higher efficacy than cognitive therapy . With few exceptions , cognitive therapy did not differ significantly from placebo . The number of subjects becoming panic-free ( 66 % ) was higher and the onset of action was faster in the paroxetine-treated group . Treatment with cognitive therapy yielded the highest drop-out rate ( 26 % ) . CONCLUSION In this short-term study assessing treatment of panic disorder and agoraphobia , paroxetine and clomipramine were consistently superior to pill placebo , whereas cognitive therapy was superior on only a few measures INTRODUCTION There is evidence that a decreased GABAergic tone plays a role in the pathophysiology of panic disorder ( PD ) . Selective GABAergic treatment has been suggested as a new therapeutic strategy in PD . In this pilot- study anxiolytic effects of the GABA reuptake inhibitor tiagabine ( TGB ) were investigated in PD . METHODS A total of 19 patients were treated with TGB ( n=10 ) or placebo ( n=9 ) for 4 weeks . PAS , HAM-A , and CGI ratings were administered every week . To further assess specific antipanic activity , panic challenges with CCK-4 were carried out in single subjects . RESULTS Although there was a significant reduction of clinical rating scores over time , no differences were detected between the groups . However , during challenge experiments TGB treated subjects showed decreased sensitivity to CCK-4 . DISCUSSION Whereas tiagabine did not show beneficial effects on clinical symptoms in PD compared to placebo , results of challenge experiments suggest effects of TGB on sensitivity to experimentally induced panic This article focuses on social morbidity and health care utilization in persons with panic attacks not meeting full diagnostic criteria for panic disorder . The findings are based on data from a r and om sample of over 18,000 adults drawn from five US communities . Panic attacks not meeting full criteria for panic disorder have a relatively high lifetime prevalence ( 3.6 % of the adult population ) . Persons with panic attacks had impairment in perceived physical and emotional health , and in occupational and financial functioning , increased use of health care facilities , emergency departments , and psychoactive drugs . Persons with panic attacks were intermediate in severity between those with panic disorder and those with other psychiatric disorders . The findings could not be explained by comorbidity with other psychiatric disorders . We conclude that panic attacks have clinical significance and are associated with substantial morbidity BACKGROUND Venlafaxine extended-release ( ER ) has proven efficacy in the treatment of anxiety symptoms in major depression , generalised anxiety disorder and social anxiety disorder . AIMS To evaluate the efficacy , safety and tolerability of venlafaxine ER in treating panic disorder . METHOD Adult out- patients ( n=361 ) with panic disorder were r and omly assigned to receive venlafaxine ER ( 75 - 225 mg/day ) or placebo for up to 10 weeks in a double-blind study . RESULTS Venlafaxine ER was not associated with a greater proportion of patients free from full-symptom panic attacks at the final on-therapy evaluation , but was associated with lower mean panic attack frequency and a higher proportion free from limited-symptom panic attacks , higher response and remission rates , and improvements in anticipatory anxiety , fear and avoidance . Adverse events were comparable with those of the drug in depression and anxiety disorders . CONCLUSIONS Venlafaxine ER seems to be effective and well tolerated in the short-term treatment of panic disorder In this report , which is an up date of a guideline published in 2002 ( B and elow et al. 2002 , World J Biol Psychiatry 3:171 ) , recommendations for the pharmacological treatment of anxiety disorder , obsessive-compulsive disorder ( OCD ) and post-traumatic stress disorder ( PTSD ) are presented . Since the publication of the first version of this guideline , a substantial number of new r and omized controlled studies of anxiolytics have been published . In particular , more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs . The recommendations , developed by the World Federation of Societies of Biological Psychiatry ( WFSBP ) Task Force for the Pharmacological Treatment of Anxiety , Obsessive-Compulsive and Post-traumatic Stress Disorders , a consensus panel of 30 international experts , are now based on 510 published r and omized , placebo- or comparator-controlled clinical studies ( RCTs ) and 130 open studies and case reports . First-line treatments for these disorders are selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-noradrenaline reuptake inhibitors ( SNRIs ) and the calcium channel modulator pregabalin . Tricyclic antidepressants ( TCAs ) are equally effective for some disorders , but many are less well tolerated than the SSRIs/SNRIs . In treatment-resistant cases , benzodiazepines may be used when the patient does not have a history of substance abuse disorders . Potential treatment options for patients unresponsive to st and ard treatments are described in this overview . Although these guidelines focus on medications , non-pharmacological were also considered . Cognitive behavioural therapy ( CBT ) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders , OCD , and PTSD to support them being recommended either alone or in combination with the above medicines OBJECTIVE To evaluate the efficacy , safety , and tolerability of venlafaxine extended release ( ER ) in short-term treatment of panic disorder . METHOD In this multicenter , double-blind study , conducted from April 2001 to December 2002 , 343 adult out patients who met criteria for panic disorder ( with and without agoraphobia ) according to the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , were r and omly assigned to flexible-dose venlafaxine ER ( 75 - 225 mg/d ) or placebo for 10 weeks ( N = 155 per group , intent-to-treat population ) . The primary outcome measure was the percentage of panic-free patients as assessed using the Sheehan Panic and Anticipatory Anxiety Scale . Key secondary measures included the Panic Disorder Severity Scale ( PDSS ) score and Clinical Global Impressions-Improvement ( CGI-I ) scale response ( score = 1 or 2 ) . Last-observation-carried-forward data were analyzed , and statistical significance was set at p < or= .05 . RESULTS At week 10 , the percentage of patients who were free from full-symptom panic attacks was 52 % in the venlafaxine ER group and 43 % in the placebo group ( p = .11 ) . Mean change from baseline in PDSS total score was significantly ( p = .006 ) greater for the venlafaxine ER group ( -9.3 ) than for the placebo group ( -7.5 ) , and significantly ( p = .03 ) more venlafaxine ER-treated patients achieved CGI-I response ( 71 % ) than did those receiving placebo ( 59 % ) at week 10 . Treatment with venlafaxine ER was generally safe and well tolerated . Adverse events were the primary or secondary cause for discontinuation for 7 placebo patients ( 4 % ) and 12 venlafaxine ER patients ( 7 % ) . CONCLUSIONS Venlafaxine ER appears to be effective , safe , and well tolerated in short-term treatment of panic disorder , although the results fell just short of significance on the primary outcome measure . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00038896 Objectives : Selective serotonin reuptake inhibitors ( SSRIs ) are currently considered as the first drug of choice in the treatment of panic disorder ( PD ) . The aim of this long-term , naturalistic comparison study was to compare 4 SSRIs with respect to tolerability and treatment outcome of PD . Outcome measures included relapse rates and adverse effects . Methods : Two hundred patients with PD were enrolled in our study . All subjects met DSM-IV criteria for PD or PD with agoraphobia ( PDA ) . All patients were assigned to receive SSRI monotherapy for 12 months with either citalopram ( n = 50 ) , fluoxetine ( n = 50 ) , fluvoxamine ( n = 50 ) , or paroxetine ( n = 50 ) in a r and omized , nonblinded fashion . Both the treating psychiatrist and the patients were not blind to the assigned treatment , but the clinician raters were blind to the study medication . The study design allowed for assignment of a particular SSRI as indicated according to the clinical judgment of the study psychiatrists . The Panic Self- Question naire , which is a self-report scale , was administered at baseline and then once per month during the duration of the 12-month study . The visual analog scale and the Clinical Global Impression Scale were administered at baseline and then once per month during the period of the study . Reports of sexual dysfunction were assessed using a nonstructured clinical interview at monthly visits . The body weight of study subjects was measured at baseline , and then at the 12th month visit end point . Results : Of 200 patients who entered the study , 127 patients ( 63.5 % ) completed the full 12-month protocol . Retention rates were highest for paroxetine ( 76 % [ 38/50 ] ) , intermediate for citalopram ( 68 % [ 34/50 ] ) and fluvoxamine ( 60 % [ 30/50 ] ) , and lowest for fluoxetine ( 50 % [ 25/50 ] ) . Patients who completed the 12-month protocol responded favorably to the study treatment . The paroxetine and the citalopram groups had significantly lower rates of panic symptoms as measured at visits on weeks 4 and 8 . At visits on months 3 , 6 , 9 , and 12 , however , there were no statistically significant differences between the 4 groups in relapse rates ( defined as the occurrence of 1 or more panic attacks during the previous week of treatment ) ( F1,127 = 0.17 ; P = 0.13 [ not statistically significant ] ) . At the 12th month end point , patients in all 4 treatment groups had a statistically significant increase in body weight . Body weight among the study population increased by 6.1 + 4.9 kg from a mean weight of 72.4 + 7.3 kg at the onset of treatment . Reports of sexual adverse effects at the 12th month visit were similar in the citalopram , fluoxetine , and paroxetine groups , but the fluvoxamine patient group reported fewer sexual adverse effects at the 12th month visit . Conclusions : Most of our PD patients responded well to 12-month treatment with either citalopram , fluoxetine , fluvoxamine , or paroxetine , and the overall response rate was equal after the first 4 weeks of treatment . Although patients treated with paroxetine had the lowest dropout rates during the initiation phase , they had the highest rate of adverse effects as measured at the 12th month visit . Conversely , patients in the fluvoxamine group had the highest dropout rate ( which was primarily caused by adverse effects in the initiation phase of treatment . ) ; however , patients who were able to tolerate fluvoxamine throughout the full course of the study were observed to have lower rates of sexual dysfunction and weight gain compared with patients treated with the other agents . Overall , when measured at the 12th month visit , monotherapy with paroxetine and citalopram was associated with a higher rate of sexual adverse effects than was treatment with fluoxetine or fluvoxamine . In addition , monotherapy with paroxetine , citalopram , and fluoxetine seemed to cause more weight gain than did treatment with fluvoxamine 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 BACKGROUND Tricyclic antidepressants and selective serotonin reuptake inhibitors ( SSRIs ) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder . The introduction of SSRIs has enabled a greater underst and ing of the role of serotonin in the etiology of panic disorder ; however , the role of norepinephrine has been more challenging to ascertain . The aim of this study was to determine the efficacy and tolerability of reboxetine , a novel selective norepinephrine reuptake inhibitor , in patients with panic disorder with and without agoraphobia . METHOD Eighty-two patients ( aged 18 - 65 years ) with DSM-III-R panic disorder , with or without agoraphobia , were r and omly assigned to receive 6 to 8 mg/day of reboxetine ( 42 patients ) or placebo ( 40 patients ) for 8 weeks in this placebo-controlled , parallel-group , double-blind clinical trial . RESULTS Of the 82 patients enrolled in the trial , 75 were considered in the analysis ( 37 patients in the reboxetine group and 38 patients in the placebo group ) . At last assessment , there was a significant reduction in the mean number of panic attacks ( range , 9.3 - 1.2 ) and phobic symptoms ( range , 8.1 - 3.2 ) in the reboxetine group compared with the placebo group ( ranges , 8.5 - 5.8 and 7.7 - 5.2 , respectively ; p < .05 ) . Improvement in Hamilton Rating Scale for Depression , Hopkins Symptom Checklist-90 , and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group . Adverse events reported more frequently with reboxetine than placebo included dry mouth ( 36 % vs. 16 % ) , constipation ( 27 % vs. 22 % ) , and insomnia ( 26 % vs. 22 % ) . CONCLUSION Reboxetine was effective and well tolerated in the treatment of panic disorder An international , multicentre , double blind parallel group study compared the tolerability and efficacy of moclobemide with the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine for panic disorder . SSRIs have been shown effective for panic . The target dose of moclobemide was 450 mg and of fluoxetine was 20 mg . There were two consecutive studies . An eight week study of acute adverse events , tolerability and efficacy was followed by a long-term extension study to 1 year . The efficacy data showed no significant difference between moclobemide and fluoxetine . Both had acute efficacy , with 63 % moclobemide and 70 % fluoxetine patients ( ns ) panic free at 8 weeks . Both agents were well tolerated to 8 weeks , but moclobemide had fewer severe adverse events ( 5 ) than fluoxetine ( 9 ) . There were no severe adverse events in the extension phase with either drug , and almost all patients completing 1 year extension treatment ( moclobemide 61 patients , fluoxetine 65 ) were much or very much improved . These data suggest moclobemide and fluoxetine are tolerated and effective for both acute panic treatment and maintenance therapy The aim of this 12‐week , double‐blind , parallel group , placebo‐controlled study was to compare paroxetine with clomipramine in 367 patients with DSM‐III‐R defined panic disorder . Efficacy assessment s included the daily panic attack diary , the Clinical Global Impression Scale , the Hamilton Anxiety Rating Scale , the Marks Sheehan Phobia Scale and the Sheehan Disability Scale .  Paroxetine produced significant improvements compared with placebo in various measurements of panic attack frequency , and was as effective as clomipramine . However , paroxetine appeared to have a more rapid onset of action than clomipramine in reducing the number of panic attacks to zero . There was an equivalent improvement with both paroxetine and clomipramine in the supportive efficacy variables which assessed associated aspects of therapeutic improvement . Significantly more adverse effects were reported in the clomipramine group compared with the paroxetine group , while there was no difference between the paroxetine and placebo groups BACKGROUND The objective of this study was to evaluate the efficacy and tolerability of citalopram in the long-term treatment of adult out patients with panic disorder with or without agoraphobia . METHOD Patients in this double-blind , parallel-group trial were assigned to 1 of 3 fixed dosage ranges of citalopram ( 10 or 15 mg/day , 20 or 30 mg/day , or 40 or 60 mg/day ) , 1 dosage range of clomipramine ( 60 or 90 mg/day ) , or placebo . After the completed 8-week acute treatment period , the eligible patients could continue the treatment for up to 1 year . Of the 475 patients who were r and omly assigned for the short-term trial , 279 agreed to continue double-blind treatment at their assigned doses . The primary efficacy measure used was the Clinical Anxiety Scale panic attack item , and the response was defined as no panic attacks ( score of 0 or 1 ) . The other key measures used were the Physician 's Global Improvement Scale , the Patient 's Global Improvement Scale , and the Hamilton Rating Scale for Anxiety ( HAM-A ) . RESULTS In all drug-treated groups , except the group receiving the lowest citalopram dose , the treatment outcome was generally better than with placebo . As determined by a life table analysis of response , the probability of response during the 12 months was significantly greater with all treatment regimens than with placebo ( p < .05 ) , with citalopram 20 or 30 mg/day demonstrating the best response . Panic attacks tended to disappear in all patients remaining in the study until the end of follow-up . Analysis of the difference in the number of patients in different treatment groups remaining in the study ( perhaps the best measure of long-term efficacy ) also demonstrated that the patients treated with citalopram in dosage ranges of 20 or 30 mg/day and 40 or 60 mg/day had better response than placebo-treated patients ( p < .0002 and p < .004 , respectively ) . HAM-A and Global Improvement Scale scores also showed that patients treated with active drug showed greater improvement than placebo-treated patients . All treatment groups showed no new or exceptional adverse event clusters . CONCLUSION Citalopram in the dosage range of 20 to 60 mg/day is effective , well tolerated , and safe in the long-term treatment of patients who have panic disorder BACKGROUND In the treatment of panic disorder with agoraphobia  , the efficacy of pharmacological , psychological and combined treatments has been established . Unanswered questions concern the relative efficacy of such treatments . AIMS To demonstrate that moclobemide and cognitive-behavioural therapy ( CBT ) are effective singly and more effective in combination . METHOD Fifty-five patients were r and omly assigned to an eight-week treatment of : moclobemide plus CBT ; moclobemide plus clinical management ( ' psychological placebo ' ) ; placebo plus CBT ; or placebo plus clinical management . RESULTS Comparisons between treatments revealed strong effects for CBT . Moclobemide with clinical management was not superior to placebo . The combination of moclobemide with CBT did not yield significantly better short-term results than CBI with placebo . The CBT results remained stable during a six-month follow-up , although a substantial proportion of patients treated with placebo plus CBT needed additional treatment . CONCLUSIONS CBT was highly effective in the treatment of panic disorder with agoraphobia and reduced agoraphobia to levels that were comparable to those of non- clinical controls BACKGROUND Although panic disorder can be effectively alleviated by drug treatment , the relapse rate is high . By adding brief dynamic psychotherapy focused on the psychosocial vulnerability of patients with panic disorder to an established drug treatment regimen , we hypothesized that this would result in a lower relapse rate after pharmacotherapy . METHODS Patients with panic disorder ( defined by DSM-III-R ) were r and omized to treatment with either clomipramine for 9 months ( n = 20 ) , or clomipramine for 9 months combined with 15 weekly sessions of brief dynamic psychotherapy ( n = 20 ) . Measures of anxiety and depression were collected at intake and at regular intervals . The patients had blind follow-up interviews at 6 , 12 , and 18 months after beginning treatment . RESULTS All patients in both groups became free of panic attacks within 26 weeks of the start of treatment . On termination of pharmacotherapy , the relapse rate was significantly higher in the clomipramine-only group during the follow-up period . There were significantly lower scores for most anxiety measures in the clomipramine plus psychotherapy group at the 9-month follow-up . CONCLUSION The addition of brief dynamic psychotherapy to treatment with clomipramine significantly reduces the relapse rate of panic disorder compared with clomipramine treatment alone Panic disorder is a common and disabling psychiatric disorder . Despite treatment advances , refractory panic disorder requires novel interventions . One such pharmacologic intervention with theoretical and case study support includes olanzapine , a thienobenzodiazepine medication currently approved for schizophrenia in the United States . Ten people with refractory DSM-IV diagnosed panic disorder completed an 8-week , open-label , flexible-dose clinical trial . Baseline , in-treatment , and end-of-treatment data for panic attacks , anticipatory anxiety , phobic avoidance , and impairment were collected . Data were analyzed using SPSS software . Refractory panic disorder patients required a wide dose range averaging 12.3 mg/day of olanzapine to significantly improve or ablate panic attacks . On the average , number of attacks decreased from 6.1/week at baseline to 1.1/week at the end of treatment , and anticipatory anxiety from 32 % of the day to 8 % of the day . At treatment end , 5 of 10 participants ( 50 % ) were panic free , 4 ( 40 % ) had one attack in the previous week , 1 ( 10 % ) had seven attacks in the previous week , and 6 of 10 participants ( 60 % ) were anticipatory anxiety free . There were also statistically and clinical ly significant improvements in impairment over the course of the trial . There were no significant changes in vital signs , emergent side effects , or average weight , although 6 of 10 people did gain weight .  Olanzapine is potentially effective and safe in panic disorder . Due to study limitations , further clinical trials are needed to demonstrate effectiveness The mortality of anxiety syndromes  between 1972 and 1992 was investigated in a prospect i ve study of a normal population , the 1947 Lundby cohort . 121 persons with anxiety according to the Lundby definition ( Anx ) , and 74 persons with panic disorder with/without agoraphobia ( PD-Ag ) according to the DSM-III-R , all of them developing their first episode between 1947 and 1972 , were analyzed with regard to general mortality and special cause of death . Sex- and age-specific mortality rates for these groups were calculated and compared with the corresponding rates of the cohort 's 1,877 remaining subjects without first episodes of Anx/PD-Ag . In contrast to the females , the annual rates of general mortality in males with Anx/PD-Ag were 1.9/2.2 times higher in the age group 65 - 84 years , compared with the rates of the non-Anx/PD-Ag groups . They also had an increase in death due to circulatory disorders , most pronounced in males with PD-Ag before the age of 65 . There were no suicides in any of the Anx/PD-Ag groups during the observation period Dose escalation is often used in depressed patients who fail to respond to st and ard doses of selective serotonin reuptake inhibitors , but clinical efficacy is equivocal . We aim ed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter ( SERT ) more than placebo dose escalation in a r and omized controlled trial . We recruited 107 nonpsychotic , unipolar depressed out patients ( 18 - 70 years ; Hamilton Depression Rating Scale ( HDRS(17 ) ) > 18 ) from primary care and psychiatric outpatient departments . After 6 weeks , open-label paroxetine 20 mg per day ( T0 ) , nonresponding patients ( HDRS(17 ) decrease < 50 % ; n=60 ) were r and omized to double-blind paroxetine ( 30 - 50 mg per day as tolerable ) or placebo dose escalation ( paroxetine 20 mg per day+placebo ) . Patients were followed until 6 weeks after r and omization ( T1 ) . Forty-nine patients , drug free at study entry , underwent single-photon emission-computed tomography ( SPECT ) scanning before treatment and were scanned repeatedly at T0 and T1 .  Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 ( n=32 ) . We terminated the dose-escalation trial after an interim analysis . Thirty nonresponding patients were r and omized to paroxetine ( 46.7+/-5.5 mg per day ) , 27 to placebo dose escalation . Response rates were 10/30 ( 33.3 % ) and 10/27 ( 37.0 % ) , respectively . Repeated measurement analyses showed no significant effect for treatment ( p=0.88 , exceeding a priori stopping rules for futility ( p>0.5 ) ) . Overall dropout was higher for placebo ( 26.7 % ) than paroxetine ( 3.3 % ; p=0.03 ) . Paroxetine dose escalation increased  paroxetine serum concentrations ( p<0.001 ) . SPECT measurements ( 12 patients r and omized to paroxetine ( 46.9+/-4.8 mg ) and 14 to placebo dose escalation ) showed no significant increase of midbrain SERT occupancy ( 2.5+/-26.4 % , paroxetine ; 3.1+/-25.8 % placebo ; p=0.687 ) nor in diencephalon ( p=0.529 ) . Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation . This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation , despite increased paroxetine serum concentrations ( IS RCT N44111488 )
target: A Medline search of research on pharmacotherapy was undertaken , and a previous systematic review on the evidence -based pharmacotherapy of panic disorder was up date d. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder , with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option .
  Temporary co-administration of benzodiazepines can be considered .
  For patients not responding to first-line agents several pharmacotherapy options are available , but there is a notable paucity of data on the optimal choice
background: The evidence -based pharmacotherapy of panic disorder continues to evolve .
  This paper review s data on first-line pharmacotherapy , evidence for maintenance treatment , and management options for treatment-refractory patients .