MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy Predicting treatment response to cognitive behavioral therapy in panic disorder with agoraphobia by integrating local neural information. Cognitive behavior therapy vs exposure in vivo in the treatment of panic disorder with agoraphobia (corrected from agrophobia). Overcoming resistance to exposure in panic disorder with agoraphobia Long‐term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2‐year naturalistic follow‐up Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. A prospective naturalistic study of 326 panic-agoraphobic patients treated with antidepressants. Minnesota Multiphasic Personality Inventory correlates of panic disorder with agoraphobia: changes with treatment. Treatment of Panic Disorder with Agoraphobia: Randomized Placebo‐Controlled Trial of Four Psychosocial Treatments Combined with Imipramine or Placebo Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Pharmacological treatment of agoraphobia: imipramine versus imipramine with programmed practice. Global measures of outcome in a controlled comparison of pharmacological and psychological treatment of panic disorder and agoraphobia in primary care. Long-term stability of cognitive behavioral therapy effects for panic disorder with agoraphobia: a two-year follow-up study. Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder? Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Treatment of phobias. II. Behavior therapy and supportive psychotherapy: are there any specific ingredients? Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in CBT.
Panic disorder with agoraphobia ( PD/AG ) is a prevalent mental disorder featuring a substantial complex genetic component . At present , only a few established risk genes exist . Among these , the gene encoding monoamine oxidase A ( MAOA ) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels . Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity . Here , we have thus investigated the impact of MAOA-uVNTR on therapy response , behavioral avoidance and brain activity in fear conditioning in a large controlled and r and omized multicenter study on cognitive behavioral therapy ( CBT ) in PD/AG . The study consisted of 369 PD/AG patients , and genetic information was available for 283 patients . Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale ( 46 % responders vs 67 % , P=0.017 ) . This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation , that is , the behavioral avoidance task . All but one panic attack that happened during this task occurred in risk allele carriers and , furthermore , risk allele carriers did not habituate to the situation during repetitive exposure . Finally , functional neuroimaging during a classical fear conditioning paradigm evidence d that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear . Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes , suggesting differential brain activation patterns upon CBT . Taken together , we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms . These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches IMPORTANCE Although neuroimaging research has made substantial progress in identifying the large-scale neural substrate of anxiety disorders , its value for clinical application lags behind expectations . Machine-learning approaches have predictive potential for individual-patient prognostic purpose s and might thus aid translational efforts in psychiatric research . OBJECTIVE To predict treatment response to cognitive behavioral therapy ( CBT ) on an individual-patient level based on functional magnetic resonance imaging data in patients with panic disorder with agoraphobia ( PD/AG ) . DESIGN , SETTING , AND PARTICIPANTS We included 49 patients free of medication for at least 4 weeks and with a primary diagnosis of PD/AG in a longitudinal study performed at 8 clinical research institutes and outpatient centers across Germany . The functional magnetic resonance imaging study was conducted between July 2007 and March 2010 . INTERVENTIONS Twelve CBT sessions conducted 2 times a week focusing on behavioral exposure . MAIN OUTCOMES AND MEASURES Treatment response was defined as exceeding a 50 % reduction in Hamilton Anxiety Rating Scale scores . Blood oxygenation level-dependent signal was measured during a differential fear-conditioning task . Regional and whole-brain gaussian process classifiers using a nested leave-one-out cross-validation were used to predict the treatment response from data acquired before CBT . RESULTS Although no single brain region was predictive of treatment response , integrating regional classifiers based on data from the acquisition and the extinction phases of the fear-conditioning task for the whole brain yielded good predictive performance ( accuracy , 82 % ; sensitivity , 92 % ; specificity , 72 % ; P < .001 ) . Data from the acquisition phase enabled 73 % correct individual-patient classifications ( sensitivity , 80 % ; specificity , 67 % ; P < .001 ) , whereas data from the extinction phase led to an accuracy of 74 % ( sensitivity , 64 % ; specificity , 83 % ; P < .001 ) . Conservative reanalyses under consideration of potential confounders yielded nominally lower but comparable accuracy rates ( acquisition phase , 70 % ; extinction phase , 71 % ; combined , 79 % ) . CONCLUSIONS AND RELEVANCE Predicting treatment response to CBT based on functional neuroimaging data in PD/AG is possible with high accuracy on an individual-patient level . This novel machine-learning approach brings personalized medicine within reach , directly supporting clinical decisions for the selection of treatment options , thus helping to improve response rates Seventy-three psychiatric out patients with DSM-IV diagnosis of panic disorder with agoraphobia were assessed with a battery of independent assessor , self-observation , self-report and behavioral measures before and after therapy , and at a 1-yr follow-up . They were r and omly assigned to Exposure in vivo ( E ; n = 25 ) , Cognitive Behavior Therapy ( CBT ; n = 26 ) , or a Wait-list control ( WLC ; n = 22 ) and received 12 - 16 individual therapy sessions , once weekly . The treatments yielded significant improvements , both on panic/agoraphobia measures and on measures of general anxiety , depression , social adjustment and quality of life , which were maintained at follow-up . However , there were no significant differences between E and CBT . The three criteria of clinical ly significant improvement were achieved by 67 % of the E- patients and 79 % of the CBT- patients at post-treatment , and 74 % and 76 % , respectively , at follow-up . The conclusion that can be drawn is that adding cognitive therapy to exposure did not yield significantly better results than for exposure alone The issue of panic disorder resistant to treatment ( whether pharmacological or psychological ) has attracted little research attention , despite its clinical frequency and importance . The aim of this study was to compare three treatment modalities , namely exposure alone ( E ) , exposure associated with imipramine ( EI ) and cognitive therapy supplementing exposure ( EC ) , in a sample of 21 patients with DSM‐IV panic disorder and agoraphobia , who failed to respond to a first st and ard course of individual behavioural treatment based on exposure in vivo . Treatments were administered according to a cross‐over , controlled design ( E‐EI‐EC , EI‐EC‐E , EC‐E‐EI ) . Twelve of the 21 patients  achieved remission ( panic‐free status ) during the trial . In 8 cases this occurred after exposure alone ( E ) and in two cases each after the other treatments ( EI and EC ) . The results revealed a significant effect of the factor time on a number of variables , and the superiority of exposure alone compared to other treatment modalities with regard to some variables . These findings suggest that long‐term behavioural treatment based on exposure may be necessary in some patients , and may induce clinical remission . However , patients who do not respond to exposure show poor tolerance of and compliance with pharmacological treatment , and are unlikely to achieve remission  with imipramine or cognitive therapy , even though this may occur in individual cases 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 Existing literature on panic disorder ( PD ) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy ( CBT ) , Selective Serotonin Reuptake Inhibitor ( SSRI ) or both combined ( CBT+SSRI ) . METHOD Patients were r and omized to CBT , SSRI or CBT+SSRI which each lasted one year including three months of medication taper . Participating patients kept record of the frequency of panic attacks throughout the full year of treatment . Rate of improvement on panic frequency and the relationship between rate of improvement and baseline agoraphobia ( AG ) were examined . RESULTS A significant decline in frequency of panic attacks was observed for each treatment modality . SSRI and CBT+SSRI were associated with a significant faster rate of improvement as compared to CBT . Gains were maintained after tapering medication . For patients with moderate or severe AG , CBT+SSRI was associated with a more rapid improvement on panic frequency as compared to patients receiving either mono-treatment . LIMITATIONS Frequency of panic attacks was not assessed beyond the full year of treatment . Second , only one process variable was used . CONCLUSIONS Patients with PD respond well to each treatment as indicated by a significant decline in panic attacks .  CBT is associated with a slower rate of improvement as compared to SSRI and CBT+SSRI . Discontinuation of SSRI treatment does not result in a revival of frequency of panic attacks . Our data suggest that for patients without or with only mild AG , SSRI-only will suffice . For patients with moderate or severe AG , the combined CBT+SSRI treatment is recommended 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 Forty-seven patients meeting DSM-III-R criteria for panic disorder with agoraphobia ( PAG ) were assessed by the Minnesota Multiphasic Personality Inventory ( MMPI ) at baseline and after 8 weeks of treatment with imipramine , clomipramine and placebo . At pre-treatment patients had higher MMPI scores than the local normative data , the highest scores being for depression , hypochondria and hysteria . At week 8 the scores of most MMPI scales were significantly reduced . In addition , patients who showed clinical improvement had pre- and post-treatment scores lower than the unimproved patients . The results suggest that the abnormal MMPI profile found in PAG patients reflects the clinical state and that personality pathology relates to treatment outcome . The reduction in MMPI scores was associated with response to active treatment . We conclude that therapeutic interventions that successfully reduce PAG symptoms also modify personality scores Few r and omized controlled trials have included panic disorder patients with moderate to severe agoraphobia . Therefore , this population was studied using pharmacotherapy as well as psychotherapy . At the time of the study , imipramine was widely used as a pharmacological treatment . Also , current practice guidelines for patients with panic disorder find selective serotonin reuptake inhibitors and tricyclic antidepressants roughly comparable in terms of efficacy . Therefore , the main objective of this study is to compare four psychosocial treatments — cognitive and grade d in vivo exposure treatments , grade d in vivo exposure , cognitive treatment , and supportive therapy — to evaluate the benefits of combining cognitive therapy with exposure in vivo . These treatments were combined with imipramine or placebo for a total of eight experimental conditions . Participants presented moderate to severe agoraphobia . The method involved a r and omized , double‐blind , placebo‐controlled trial with 137 participants who completed a 14‐session protocol involving the treatments just mentioned . Measures were taken at baseline and posttreatment and at 3‐ , 6‐ , and 12‐month follow‐up . All treatment conditions were statistically and clinical ly effective in reducing self‐reported panic – agoraphobia symptoms over the 1‐year follow‐up . No statistical differences were observed between imipramine and placebo conditions . This study found that all treatment modalities helped reduce panic and agoraphobic symptomatology over a 1‐year follow‐up period . These surprising results support the need to document the relations among the various components of an intervention . This would make it possible to assess the relative efficacy of the treatment components rather than of the intervention as a whole 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 Eighteen agoraphobic patients with r and omly assigned to 12 week treatment with imipramine ( I ) or imipramine and programmed in-vivo exposure practice ( I+BT ) to investigate the contribution of behavioural instructions to the clinical effects of pharmacotherapy . Significantly greater improvement on phobic measures was found in the I+BT group compared to the I group . Differences were less marked on measures of panic and anxiety . The results suggest that imipramine possesses an antiphobic effect which can be substantially enhanced with programmed practice . Controlled large-scale investigations of the pharmacological and instructional effects of the phamacotherapy of agoraphobia are needed for a definitive evaluation of the specific antiphobic effect of antidepressant drugs BACKGROUND Panic disorder , with and without agoraphobia , is a prevalent condition which presents primarily in general practice . Previous clinical outcome studies have been conducted mainly in specialist university departments or hospital setting s , and have tended to employ complex rating scales that are not well suited for use as outcome measures in primary care . AIM To evaluate the outcome , in a primary care setting , of fluvoxamine versus cognitive behaviour therapy , each used alone and in combination in a double-blind placebo-controlled framework , balanced for therapist contact . METHOD A total of 149 patients satisfying DSMIII-R criteria for panic disorder were r and omly allocated to receive one of the following : fluvoxamine , placebo , fluvoxamine plus cognitive behaviour therapy , placebo plus cognitive behaviour therapy , and cognitive behaviour therapy alone . These five treatment groups represent the minimum number acceptable for such a comparison to be made . All patients received an identical schedule of contact over 13 weeks . Measures of symptom severity , general health and social disruption were taken at entry point and end point ; measures of change in symptoms were taken at end point only . Outcome was reported in terms of brief global ratings of severity of illness and change in symptoms , and of ratings of general health and social disruption that are suitable for use in general practice . RESULTS All active treatment groups showed statistically significant advantages over placebo over a range of outcome ratings . The groups employing cognitive behaviour therapy showed the most robust and consistent response . CONCLUSION The brief global measures reported here proved adequate to the task of assessing treatment outcome . Results indicate that treatments including cognitive behaviour therapy can be effective in the treatment of panic disorder and agoraphobia in primary care OBJECTIVE Cognitive-behavioral therapy ( CBT ) aims to help patients establish new behaviors that will be maintained and adapted to the dem and s of new situations . The long-term outcomes are therefore crucial in testing the durability of CBT . METHOD A two-year follow-up assessment was undertaken on a sub sample of n = 146 PD/AG patients from a multicenter r and omized controlled trial . Treatment consisted of two variations of CBT : exposure in situ in the presence of the therapist ( T+ ) or on their own following therapist preparation ( T- ) . RESULTS Both variations of CBT had high response rates and , overall , maintained the level of symptomatology observed at post-treatment with high levels of clinical significance . Effect sizes 24 months following treatment were somewhat lower than at the 6-month follow up . Once patients reached responder status , they generally tended to remain responders at subsequent assessment s. Differences were observed for patients that obtained additional treatment during the follow-up period . Expert opinion and subjective appraisal of treatment outcome differed . No robust baseline predictors of 2-year outcome were observed . CONCLUSION Most patients maintain clinical ly meaningful changes two years following treatment across multiple outcome measures . Approximately 1/3 of patients continued to experience meaningful residual problems Summary The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study ( n=1134 patients ) ; in this double blind r and omized trial alprazolam , imipramine and placebo were compared during an 8-week treatment period . Patients with extensive avoidance behaviour ( agoraphobia ) had the most profit from the active drugs . Counter expectancy these specific drug effects were most pronounced in avoidance behaviour . Active drugs ( in particular imipramine ) were especially more effective than placebo if the patients presented with associated avoidance behaviour . The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder 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 Systematic hierarchical desensitization ( behavior therapy [ BT ] ) was compared with supportive psychotherapy ( ST ) during a 26-week treatment trial of patients with agoraphobia , mixed phobia , or simple phobia . We found essentially no difference in effectiveness , not because patients treated with BT had done badly , but because patients receiving ST had done well . A detailed method ologic review concludes that this finding is entirely compatible with the major critical review s of the psychotherapy literature . Is the active ingredient in psychotherapy simply the generation of hopeful expectancies ? This is necessary but not sufficient . For phobics , the psychotherapy session serves primarily as an instigator . The specific corrective activity occurs outside of the formal session in the form of maintained exposure in vivo . Supposed differences between therapies may be entirely due to the rapidly with which the instigational function becomes effective OBJECTIVE Cognitive-behavioral therapy ( CBT ) is a first-line treatment for panic disorder with agoraphobia ( PD/AG ) . Nevertheless , an underst and ing of its mechanisms and particularly the role of therapist-guided exposure is lacking . This study was aim ed to evaluate whether therapist-guided exposure in situ is associated with more pervasive and long-lasting effects than therapist-prescribed exposure in situ . METHOD A multicenter r and omized controlled trial , in which 369 PD/AG patients were treated and followed up for 6 months . Patients were r and omized to 2 manual-based variants of CBT ( T+/T- ) or a wait-list control group ( WL ; n = 68 ) and were treated twice weekly for 12 sessions . CBT variants were identical in content , structure , and length , except for implementation of exposure in situ : In the T+ variant ( n = 163 ) , therapists planned and supervised exposure in situ exercises outside the therapy room ; in the T- group ( n = 138 ) , therapists planned and discussed patients ' in situ exposure exercises but did not accompany them . Primary outcome measures were ( a ) Hamilton Anxiety Scale , ( b ) Clinical Global Impression , ( c ) number of panic attacks , and ( d ) agoraphobic avoidance ( Mobility Inventory ) . RESULTS For T+ and T- compared with WL , all outcome measures improved significantly with large effect sizes from baseline to post ( range = -0.5 to -2.5 ) and from post to follow-up ( range = -0.02 to -1.0 ) . T+ improved more than T- on the Clinical Global Impression and Mobility Inventory at post and follow-up and had greater reduction in panic attacks during the follow-up period . Reduction in agoraphobic avoidance accelerated after exposure was introduced . A dose-response relation was found for Time × Frequency of Exposure and reduction in agoraphobic avoidance . CONCLUSIONS Therapist-guided exposure is more effective for agoraphobic avoidance , overall functioning , and panic attacks in the follow-up period than is CBT without therapist-guided exposure . Therapist-guided exposure promotes additional therapeutic improvement -- possibly mediated by increased physical engagement in feared situations -- beyond the effects of a CBT treatment in which exposure is simply instructed
Paroxetine , sertraline , citalopram , escitalopram , and clomipramine showed the most consistent results , while fluvoxamine , fluoxetine , and imipramine showed limited efficacy .
Preliminary results suggested the potential efficacy of inositol ; D-cycloserine showed mixed results for its ability to improve the outcome of exposure-based cognitive behavioral therapy .
No studies have been specifically oriented toward evaluating the effect of drugs on AG ; in the available studies , the improvement of AG might have been the consequence of the reduction of panic attacks .
BACKGROUND Although there are controversial issues ( the " American view " and the " European view " ) regarding the construct and definition of agoraphobia ( AG ) , this syndrome is well recognized and it is a burden in the lives of millions of people worldwide .
To better clarify the role of drug therapy in AG , the authors summarized and discussed recent evidence on pharmacological treatments , based on clinical trials available from 2000 , with the aim of highlighting pharmacotherapies that may improve this complex syndrome .