Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: Outcome and predictors of remission. Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. SECOND-STAGE TREATMENTS FOR RELATIVE NONRESPONDERS TO COGNITIVE BEHAVIORAL THERAPY (CBT) FOR PANIC DISORDER WITH OR WITHOUT AGORAPHOBIA-CONTINUED CBT VERSUS SSRI: A RANDOMIZED CONTROLLED TRIAL. Maintenance drug therapy of panic disorder. Brief cognitive-behavioral versus nondirective therapy for panic disorder. A randomized effectiveness trial of cognitive-behavioral therapy and medication for primary care panic disorder. Long‐term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2‐year naturalistic follow‐up Next-step strategies for panic disorder refractory to initial pharmacotherapy: a 3-phase randomized clinical trial. 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. A prospective naturalistic study of 326 panic-agoraphobic patients treated with antidepressants. Medical illness and response to treatment in primary care panic disorder. Long-term maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Guidelines for the pharmacological treatment of anxiety disorders, obsessive–compulsive disorder and posttraumatic stress disorder in primary care Does the addition of cognitive behavioral therapy improve panic disorder treatment outcome relative to medication alone in the primary-care setting? Poverty and response to treatment among panic disorder patients in primary care.
BACKGROUND Current recommendations suggest that pharmacotherapy for patients with panic disorder should be continued for at least 1 year [ Am . J. Psychiatry 155 ( 1998 ) 1 ] , despite a paucity of data systematic ally examining outcome for periods greater than 3 - 6 months . It is critically important to obtain more information on the effectiveness of medications over time for patients who initially responded to pharmacotherapy for panic disorder . METHODS Long-term outcome was examined for 78 patients who attained a 2-month period of sustained remission on medication and received maintenance pharmacotherapy for up to 24 months during the Massachusetts General Hospital Longitudinal Study of Panic Disorder , a prospect i ve , naturalistic study . Participants were categorized by their maintenance treatment condition at remission : benzodiazepine alone ( N = 45 , 58 % ) , antidepressant alone ( N = 12 , 16 % ) , and combined treatment with a benzodiazepine and an antidepressant ( N = 21 , 27 % ) . RESULTS Approximately half ( N = 36 , 46 % ) of the patients who had achieved remission relapsed at some time over the 2-year naturalistic study period , despite continued and adequate pharmacotherapy . There was no difference in timing or frequency of relapse by type of maintenance pharmacotherapy . LIMITATIONS Interpretation of the data is limited by the naturalistic nature of the study , and by the relatively low sample size . CONCLUSIONS This data suggests that patients with panic disorder have a high rate of relapse even after acute response to pharmacotherapy , despite continued treatment . In addition , the use of combined pharmacotherapy with antidepressants and benzodiazepines does not appear to provide greater protection from relapse than monotherapy Non-response to pharmacotherapy for panic disorder ( PD ) is a well-documented problem . However , little information exists to guide next-step strategies for these non-responders . In addition to pharmacologic augmentation strategies , several studies support the efficacy of cognitive-behavior therapy ( CBT ) for these patients , although data on long-term outcomes has been lacking . In this study , we provide one-year outcomes on a sample of 63 patients who completed group CBT for PD after failing to respond adequately to previous pharmacotherapy . Sustained significant benefit was found for all dimensional outcome scores , and nearly two-thirds of the sample met remission criteria . This occurred with reductions in medication use over the follow-up period . Negative predictors of remission status included comorbid dysthymia , social phobia , and generalized anxiety disorder . These results provide additional evidence for the efficacy of CBT for medication non-responders with PD One hundred six patients diagnosed according to DSM-III as suffering from agoraphobia with panic disorder , panic disorder with limited phobic avoidance , or uncomplicated panic disorder entered an acute 8-week treatment phase . Patients who improved received an additional 6 months ' maintenance treatment . Significantly more patients treated with alprazolam than with imipramine hydrochloride or placebo remained in therapy and experienced panic attack and phobia relief during the acute treatment phase . During the maintenance phase , neither tolerance nor daily dose increase was observed . All patients who completed the maintenance phase ( 27 in the alprazolam group , 11 in the imipramine group , and 10 in the placebo group ) were panic free at the end of 8 months of study treatment . Alprazolam therapy was effective and well tolerated at a mean daily dose of 5.7 mg . Imipramine hydrochloride ( 175 mg/d ) also produced significant panic relief but was associated with poor patient acceptance 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 BACKGROUND Cognitive behavioral therapy ( CBT ) and pharmacotherapy are efficacious for the short-term treatment of panic disorder . Less is known about the efficacy of these therapies for individuals who do not respond fully to short-term CBT .  METHOD The current trial is a second-step stratified r and omized design comparing two treatment conditions-selective serotonin reuptake inhibitor ( SSRI ; paroxetine or citalopram ; n = 34 ) and continued CBT  ( n = 24)-in a sample of individuals classified as treatment nonresponders to an initial course of CBT for panic disorder . Participants were r and omized to 3 months of treatment and then followed for an additional 9 months . Only treatment responders after 3 months were maintained on the treatment until 12-month follow-up . Data analysis focused on panic disorder symptoms and achievement of response status across the first 3 months of treatment . Final follow-up data are presented descriptively . RESULTS Participants in the SSRI condition showed significantly lower panic disorder symptoms as compared to continued CBT at 3 months . Results were similar when excluding individuals with comorbid major depression or analyzing the entire intent-to-treat sample . Group differences disappeared during 9-month naturalistic follow-up , although there was significant attrition and use of non study therapies in both arms . CONCLUSIONS These data suggest greater improvement in panic disorder symptoms when switching to SSRI after failure to fully respond to an initial course of CBT . Future studies should further investigate relapse following treatment discontinuation for nonresponders who became responders . Clinical trials.gov Identifier : NCT00000368 ; https:// clinical trials.gov/show/NCT00000368 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 Thirty panic disorder patients were assigned r and omly to four weekly sessions of either cognitive-behavioral therapy or nondirective , supportive therapy . Dependent variables included clinician ratings , st and ardized self-report question naires , and self-monitoring .  Cognitive-behavioral therapy led to significant reductions in worry about the recurrence of panic , and in overall ratings of phobic distress .  Nondirective supportive therapy did not produce significant effects . In addition , proportionately more patients who were actively panicking at pre assessment and underwent cognitive-behavioral treatment were free of panic after treatment . More than one third ( 38 % ) of patients who received cognitive-behavioral treatment were sufficiently improved that they withdrew from the pharmacological trial and /or did not meet criteria for panic disorder by the end of the four weeks BACKGROUND Panic disorder is a prevalent , often disabling condition among patients in the primary care setting . Although numerous studies have assessed the effectiveness of treatments for depression in primary care , few such studies have been conducted for panic disorder . OBJECTIVE To implement and test the effectiveness of a combined pharmacotherapy and cognitive-behavioral intervention for panic disorder tailored to the primary care setting . DESIGN R and omized , controlled study comparing intervention to treatment as usual . SETTING Six primary care clinics associated with 3 university medical schools , serving an ethnically and socioeconomically diverse patient population . PARTICIPANTS Two hundred thirty-two primary care patients meeting DSM-IV criteria for panic disorder . Comorbid mental and physical disorders were permitted , provided these did not contraindicate the treatment to be provided and were not acutely life threatening . INTERVENTION Patients were r and omized to receive either treatment as usual or an intervention consisting of a combination of up to 6 sessions ( across 12 weeks ) of cognitive-behavioral therapy ( CBT ) modified for the primary care setting , with up to 6 follow-up telephone contacts during the next 9 months , and algorithm-based pharmacotherapy provided by the primary care physician with guidance from a psychiatrist . Behavioral health specialists , the majority inexperienced in CBT for panic disorder , were trained to deliver the CBT and coordinated overall care , including pharmacotherapy . MAIN OUTCOMES MEASURES Proportion of subjects remitted ( no panic attacks in the past month , minimal anticipatory anxiety , and agoraphobia subscale score < 10 on Fear Question naire ) and responding ( Anxiety Sensitivity Index score < 20 ) and change over time in World Health Organization Disability Scale and short form 12 scores . RESULTS The combined cognitive-behavioral and pharmacotherapeutic intervention result ed in sustained and gradually increasing improvement relative to treatment as usual , with significantly higher rates at all points of both the proportion of subjects remitted ( 3 months , 20 % vs 12 % ; 12 months , 29 % vs 16 % ) and responding ( 3 months , 46 % vs 27 % ; 12 months , 63 % vs 38 % ) and significantly greater improvements in World Health Organization Disability Scale ( all points ) and short form 12 mental health functioning ( 3 and 6 months ) scores . These effects were obtained in spite of similar rates of delivery of guideline -concordant pharmacotherapy to the 2 groups . CONCLUSION Delivery of evidence -based CBT and medication using the collaborative care model and a CBT-naive , midlevel behavioral health specialist is feasible and significantly more effective than usual care for primary care panic disorder Two years after completion of a controlled outcome study of treatments for panic disorder with agoraphobia , patients were revisited and interviewed about their complaints . In the initial study , four treatments had been compared : ( i ) fluvoxamine combined with exposure ; ( ii ) placebo medication plus exposure ; ( iii ) psychological panic management plus exposure : and ( iv ) exposure alone . Comparison of the results at post‐test had revealed superior efficacy of fluvoxamine combined with exposure over the other three treatments in reducing agoraphobic avoidance . The current naturalistic follow‐up study investigated the long‐term efficacy of the treatments with regard to abatement of complaints and reduced dem and for further treatment . In addition , we examined whether patients were able to taper off the study medication without a recurrence of complaints . In total , 71 of the 76 patients of the original trial ( 93 % ) were interviewed . Comparison of the mean level of psychopathology at follow‐up revealed no difference between the original treatment groups . The effect in the fluvoxamine plus exposure group was maintained , but was no longer superior , due to further improvements in the other treatment groups . Most patients received additional treatment during the follow‐up period , usually because the 12 treatment sessions in the controlled study had yielded insufficient improvement . There was a trend for patients who received the fluvoxamine plus exposure treatment to require less aftercare than those who received the other treatments . Finally , almost 50 % of the patients who had received medication in the original trial were able to taper off the use of fluvoxamine without a recurrence of complaints 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 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 How far the results of r and omized controlled studies apply to everyday care can not be judged without regular measurements of outcomes in daily practice . We report on systematic data from a 3-year naturalistic prospect i ve study on panic disorder-agoraphobic ( PDA ) patients treated with antidepressants in a setting of routine clinical practice . Our aim is to describe the evolution of PDA in relation to the treatments employed , and to explore demographic and clinical characteristics that might be predictive of outcome . METHODS 326 DSM-III-R PDA patients treated with antidepressants in a setting of routine clinical practice were included in a 3-year naturalistic prospect i ve study . We utilized structured and semi-structures instruments , including the Structured Clinical Interview for Diagnosis and the Longitudinal Interview Follow-up Examination . The main antidepressants used were imipramine ( 39 % ) , clomipramine ( 28.5 % ) and paroxetine ( 23.3 % ) ; only 9 % of patients received other antidepressants . RESULTS 147 patients ( 45.1 % ) stayed on medication throughout the entire period of the follow-up . Of those who interrupted the treatment , 38 % stayed in remission . The probability of achieving at least one remission during the 3-year follow-up period was 96.5 % for PD and 95.9 % for Agoraphobia . Relapses after a period of at least 2 months of complete remission were also common , and the probability of presenting at least one relapse during the 3-years follow-up period was 67.1 % for PD and 39 % for Agoraphobia . The longest period of remission of PD is associated with low severity , medium-lasting course in patients with an onset of the illness in young adulthood . Less severe agoraphobia associated with moderately severe panic attacks appears to confer a better control of phobic behavior . All three major drugs were reasonably well tolerated ( only 9 % dropped out because of side effects ) , with sexual dysfunction and increased appetite being the most common side effects at the last evaluation ; in the first phase of the treatment anticholinergic effects and jitteriness were more common with TCAs . CONCLUSION Both classical antidepressants and paroxetine emerge as a useful treatment in the long-term management of PDA ; paroxetine appears particularly useful in PDA patients because it was significantly less likely to induce jitteriness , thereby reducing barriers to compliance OBJECTIVE Although studies have suggested that comorbid medical illness can affect the outcome of patients with depression , little is known about whether medical illness comorbidity affects treatment outcome in patients with anxiety . METHOD Primary care patients with panic disorder ( n=232 ) , participating in a r and omized collaborative care intervention of CBT and pharmacology  , were divided into those above ( n=125 ) and below ( n=107 ) the median for burden of chronic medical illness and assessed at 3 , 6 , 9 and 12 months . RESULTS Subjects with a greater burden of medical illness were more psychiatrically ill at baseline , with greater anxiety symptom severity , greater disability and more psychiatric comorbidity . The intervention produced significant and similar increases in amount of evidence -based care , and reductions in clinical symptoms and disability that were comparable in the more and less medically ill groups . CONCLUSIONS The comparable response of individuals with more severe medical illness suggests that CBT and pharmacotherapy for panic disorder work equally well regardless of medical illness comorbidity . However , the more severe psychiatric illness both at baseline and follow-up in these same individuals suggest that treatment programs may need to be extended in time to optimize treatment outcome 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 Abstract Objective . Anxiety disorders are frequently under-diagnosed conditions in primary care , although they can be managed effectively by general practitioners . Methods . This paper is a short and practical summary of the World Federation of Biological Psychiatry ( WFSBP ) guidelines for the pharmacological treatment of anxiety disorders , obsessive – compulsive disorder ( OCD ) and posttraumatic stress disorder ( PTSD ) for the treatment in primary care . The recommendations were developed by a task force of 30 international experts in the field and are based on r and omized controlled studies . Results . First-line pharmacological treatments for these disorders are  selective serotonin reuptake inhibitors  ( for all disorders ) ,  serotonin-norepinephrine reuptake inhibitors  ( for some ) and  pregabalin  ( for generalized anxiety disorder only ) . A combination of  medication and cognitive behavior/exposure therapy  was shown to be a clinical ly desired treatment strategy . Conclusions . This short version of an evidence -based guideline may improve treatment of anxiety disorders , OCD , and PTSD in primary care BACKGROUND R and omized clinical trials indicate a benefit from combining medications with cognitive behavioral therapy ( CBT ) relative to medication alone for panic disorder . Using an as-treated analysis , we evaluated whether the addition of CBT enhanced outcomes for panic disorder relative to medications alone in the primary -care setting . METHOD Primary -care patients with panic disorder reported on their receipt of CBT and medications over the 3 months following baseline assessment . The degree to which outcomes for those who used anti-panic medications were enhanced by the receipt of at least one component of CBT was analyzed using a propensity score model that took into account observable baseline patient characteristics influencing both treatment selection and outcomes . RESULTS The addition of CBT result ed in statistically and clinical ly significant improvements at 3 months on anxiety sensitivity , social avoidance , and disability . Also , patients receiving CBT in the first 3 months of the study were more improved at 12 months than patients who took medications only during the first 3 months of the study . CONCLUSIONS The clinical utility of the findings are discussed in terms of the importance of primary -care physicians encouraging their panic disorder patients to receive CBT as well as medications OBJECTIVE Despite well-established links between poverty and poor mental illness outcome as well as recent reports exploring racial and ethnic health disparities , little is known about the outcomes of evidence -based psychiatric treatment for poor individuals . METHOD Primary care patients with panic disorder ( N=232 ) who were participating in a r and omized controlled trial comparing a cognitive behavior therapy ( CBT ) and pharmacotherapy intervention to usual care were divided into those patients above ( N=152 ) and below ( N=80 ) the poverty line .  Telephone assessment s  at 3 , 6 , 9 , and 12 months were used to compare the amount of evidence -based care received as well as clinical and functional outcomes . RESULTS Poor subjects were more severely ill  at baseline , with more medical and psychiatric comorbidity . The increases in the amount of evidence -based care and reductions in clinical symptoms and disability were comparable in the two groups such that poorer individuals , although responding equivalently , continued to be more ill and disabled at 12 months . CONCLUSIONS The comparable response of poor individuals in this study suggests that st and ard CBT and pharmacotherapy treatments for panic disorder do not need to be " tailored " to be effective in poor population s. However , the more severe illness both at baseline and follow-up in these poor individuals suggests that treatment programs may need to be extended in order to treat residual symptoms and disability in these patients so that they might achieve comparable levels of remission
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
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 .