title: A controlled trial of quetiapine XR coadministration treatment of SSRI-resistant panic disorder A Randomized, Naturalistic, Parallel-Group Study for the Long-Term Treatment of Panic Disorder With Clonazepam or Paroxetine Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators. One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: Outcome and predictors of remission. Is there a hypersensitive visual alarm system in panic disorder? Serotonergic modulation of the balance system in panic disorder: An open study Comparison of the treatment with paroxetine and reboxetine in panic disorder: a randomized, single-blind study. Modulation of Hyperreactivity to 35% CO2 After One Week of Treatment With Paroxetine and Reboxetine: A Double-Blind, Randomized Study Paroxetine Decreases Respiratory Irregularity of Linear and Nonlinear Measures of Respiration in Patients with Panic Disorder Olanzapine Augmentation in Treatment-Resistant Panic Disorder: A 12-Week, Fixed-Dose, Open-Label Trial A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. Comparison of aerobic exercise, clomipramine, and placebo in the treatment of panic disorder. Next-step strategies for panic disorder refractory to initial pharmacotherapy: a 3-phase randomized clinical trial. Pindolol augmentation in patients with treatment-resistant panic disorder: A double-blind, placebo-controlled trial. Antipanic Drug Modulation Of 35% CO2 Hyperreactivity and Short-Term Treatment Outcome 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. Treating Treatment-Resistant Patients with Panic Disorder and Agoraphobia Using Psychotherapy: A Randomized Controlled Switching Trial Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder. Feedback of end-tidal pCO2 as a therapeutic approach for panic disorder. Aripiprazole as augmentation treatment of refractory generalized anxiety disorder and panic disorder. Quality of Life and Treatment Outcome in Panic Disorder: Cognitive Behavior Group Therapy Effects in Patients Refractory to Medication Treatment A comparison of citalopram and paroxetine in the treatment of panic disorder: a randomized, single-blind study. Potential effectiveness and safety of olanzapine in refractory panic disorder.
abstract: Background Open-label quetiapine coadministration with SSRI therapy , in a diagnostically mixed sample of comorbid anxiety patients , offered additional anxiolytic benefit . Therefore , we design ed the following controlled trial to confirm these findings in a comorbid , SSRI-resistant , panic disorder ( PD ) patient sample . Methods This was a single-site , double-blind , placebo-controlled  ( PLAC ) , r and omized , parallel group ( 2 groups ) , 8-week , quetiapine extended release ( XR ) coadministration trial . SSRI resistance was determined either historically or prospect ively . Patients were r and omized if they remained moderately ill ( CGI-S score ≥ 4 )  . Change in the PDSS scale total score was the primary efficacy outcome measure . Responders were identified as those with a ≥50 % decrease from their baseline PDSS score . In the early weeks of therapy , XR was flexibly and gradually titrated from 50 to 400 mg/day . Results 43 patients were screened in total , and 26 of these were r and omized and evaluable . 21 patients ( 78 % of the r and omized group ) completed the trial ( 10 XR ; 11 PLAC ) . The endpoint quetiapine XR mean daily dose ± SD was 150 ± 106 mg . While , in the sample as a whole , there was improvement in PDSS scores across the 8-week trial ( ANOVA main effect of time , F = 10.9 , df8,192 , p < 0.0001 ) , the treatment × time interaction effect was not statistically significant ( F = 0.8 , df8,192 , p = 0.61 ) . There was no between-group difference in responder frequency at endpoint . Conclusions This proof-of-concept RCT did not support the efficacy of this treatment strategy for SSRI-resistant PD . Quetiapine XR was generally well-tolerated . Important limitations were the small sample size , and the relatively low average dose of quetiapine XR used . Clinical Trials.gov ID # : Abstract This long-term extension of an 8-week r and omized , naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam  ( n = 47 ) and paroxetine  ( n = 37 ) over a 3-year total treatment duration . Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine ( both taken at bedtime ) . This study reports data from the long-term period ( 34 months ) , following the initial 8-week treatment phase . Thus , total treatment duration was 36 months . Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine , but patients with partial primary treatment success were switched to the combination therapy . At initiation of the long-term study , the mean doses of clonazepam and paroxetine were 1.9 ( SD , 0.30 ) and 38.4 ( SD , 3.74 ) mg/d , respectively . These doses were maintained until month 36 ( clonazepam 1.9 [ SD , 0.29 ] mg/d and paroxetine 38.2 [ SD , 3.87 ] mg/d ) . Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)–Improvement rating than treatment with paroxetine ( mean difference : CGI-Severity scale −3.48 vs −3.24 , respectively , P = 0.02 ; CGI-Improvement scale 1.06 vs 1.11 , respectively , P = 0.04 ) . Both treatments similarly reduced the number of panic attacks and severity of anxiety . Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine ( 28.9 % vs 70.6 % , P < 0.001 ) . The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course . There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events 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 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 Agoraphobia in panic disorder ( PD ) has been related to abnormal balance system function . Vision influences balance and behavioural adaptations ; peripheral vision influences orienting and fast defensive reactions whereas central vision analyzes details of objects . We have hypothesized that the abnormal balance function in PD could be mainly related to peripheral vision as part of a defensive alarm system in the brain . In 25 patients with PD and agoraphobia and 31 healthy controls we assessed , by posturography ,  balance system reactivity to video-films projected in peripheral and central visual fields ( r and omized sequence ) . Length , velocity and surface of body sway were calculated . Patients increased their body sway during peripheral stimulation , whereas controls did not ; the two groups showed a similar increase of body sway during central stimulation . Anxiety levels during peripheral stimulation significantly influenced the postural response in the group of patients . These preliminary results suggest that the higher visual sensitivity to peripheral stimulation in patients with PD and agoraphobia may be linked to a more active " visual alarm system " involving visual , vestibular and limbic areas that might influence the development of agoraphobia in situations where environmental stimuli are uncertain Experimental evidence suggests that panic disorder is characterized by abnormalities in the balance system function and that these abnormalities might be related to the severity of agoraphobic avoidance . Since the balance system can be modulated by the serotonergic system , we investigated the effect of a 6‐week treatment with citalopram on the balance system function in patients with panic disorder . Fifteen patients with panic disorder with/without agoraphobia underwent static posturography on days 0 and 42 . Static posturography and clinical assessment s were carried out by different investigators who were blind to each other . Static posturography showed high percentages of abnormal scores . Patients with no or low agoraphobic avoidance showed less abnormal posturographic measures than those with moderate to severe agoraphobia . After 6 weeks of treatment with citalopram there was a significant decrease of four out of six posturography measures in eyes‐closed and neck extension conditions , whereas no significant effect was found in the eyes‐open condition . This is the first report that suggests that the modulation of the serotonergic system can improve the balance system function in patients with panic disorder , particularly when visual information is lacking . In addition , our findings confirm the observation that many patients with panic disorder have abnormalities in their balance system function , supporting the idea that these abnormalities are mainly related to agoraphobic avoidance . Depression and Anxiety 17:101–106 , 2003 . © 2003 Wiley‐Liss , 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 Abstract : The effects of short treatments ( 7 days ) with paroxetine and with reboxetine on the reactivity to inhalations of 35 % carbon dioxide (CO2)/65 % oxygen ( O2 ) were compared in 28 patients with Panic Disorder who had positive responses to 35 % CO2 inhalations . A double-blind , r and omized design was applied . Each patient was given the 35 % CO2 challenge on days 0 ( before starting the treatment ) and 7 . Anxiety reactivity to CO2 decreased significantly with both drugs but the decrease was significantly stronger in the group treated with paroxetine . The rate of patients whose reactivity has reduced of at least 50 % after 7 days was significantly higher in the group treated with paroxetine ( 10/14 , 71.5 % ) than in the one treated with reboxetine ( 3/14 , 21.5 % ) . These results indicate that the modulation of the serotonergic system is more relevant for CO2 hyperreactivity than the modulation of the noradrenergic one Previous studies indicate that serotonin reuptake inhibitors do not appear to have serious cardiac side effects . However , the effects of these agents on respiratory measures have not been studied in detail . Several studies indicate that patients with anxiety exhibit irregular breathing patterns as measured by tidal volume and respiratory rate . In this study , we evaluated the effects of a serotonin reuptake inhibitor , paroxetine , on respiratory variability in patients with panic disorder ( n = 13 ) , using linear and nonlinear measures of regularity , approximate entropy ( APEN ) and a measure of chaos , the largest Lyapunov exponent ( LLE ) , with pre- and posttreatment lung volume time series ( 256 s long sample d at 4 Hz ) . Our results show that paroxetine significantly decreases some of the linear measures of variability and supine APEN and st and ing LLE of lung volume series after successful treatment . The implication s of these findings on respiratory and cardiovascular function have been discussed 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 BACKGROUND Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors ( SSRIs ) have proved to be effective in the treatment of panic disorder . The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone . METHOD 161 patients with panic disorder with or without agoraphobia ( DSM-IV criteria ) underwent a manual-guided cognitive-behavioral therapy of 15 sessions . Forty-three unsuccessfully treated patients from this group were included in a double-blind , placebo-controlled , next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo . RESULTS Overall , patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior ( p < .05 ) and anxiety discomfort ( p < .01 ) , whereas patients in the cognitive-behavioral therapy plus placebo condition did not . Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition , from 0.4 to 1.0 . CONCLUSION Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality . The importance of timely evaluation of treatment results is emphasized 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 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 objective of this study was to determine the efficacy of pindolol as an augmentor of fluoxetine in treatment-resistant panic disorder ( PD ) . Twenty-five out patients having PD with or without agoraphobia were included . These patients had not responded to two different trials with antidepressants and an 8-week trial of fluoxetine 20 mg/day . Treatment-resistant PD was defined as a less than 20 % reduction in score on the Panic Self- Question naire ( number of attacks per week ) ( PSQ ) and the Clinical Anxiety Scale With Panic Attacks ( CAS+PA ) . These patients continued to receive fluoxetine 20 mg/day and were r and omly assigned to additionally receive either pindolol ( 2.5 mg three times daily ) or placebo for the following 4 weeks . Evaluations were performed weekly using the Hamilton Rating Scale for Anxiety , the Hamilton Rating Scale for Depression ( HAM-D ) , the CAS+PA , the NIMH Anxiety Scale , the PSQ , and the Clinical Global Impression Scale . The data were analyzed using a repeated- measures analysis of variance ( ANOVA ) and a t-test for independent sample s. Patients treated with the combination of pindolol and fluoxetine ( N = 13 ) demonstrated a significant improvement over the patients treated with fluoxetine and placebo on all rating scales , with the exception of HAM-D. The statistical differences were shown using the repeated- measures ANOVA ( baseline , week 2 , week 4 ) and also with t-tests from the second week of the trial . These preliminary results demonstrate that pindolol has an augmenting effect on fluoxetine in patients with treatment-resistant PD Carbon dioxide ( CO2 ) inhalation induces acute anxiety and panic attacks in patients with Panic Disorder ( PD ) . Anti-panic drugs decrease CO2 reactivity after the first days of treatment ; however , the clinical meaning of this finding has not yet been established . This study investigated the effects of treatment with tricyclic antidepressants and selective serotonin re-uptake inhibitors ( SSRIs ) on CO2 reactivity and compared the relationships between 35 % CO2 hyperreactivity modulation and short-term clinical outcome .  One hundred twenty-three patients with PD with or without agoraphobia who were hyperreactive to CO2 were r and omly assigned to treatment groups with imipramine , clomipramine , paroxetine , sertraline , or fluvoxamine . A double-blind , r and omized design was applied . Each patient received the 35 % CO2 challenge on days 0 , 7 , and 30 . The severity of clinical symptomatology was measured on days 0 and 30 . Decreased hyperreactivity to 35 % CO2 in all five treatment groups was already evident after the first week . The decrease in CO2 reactivity at the end of treatment was proportional to the degree of clinical improvement . Multiple regression analyses showed that the decrease in CO2 reactivity after the first week was a significant predictor for good clinical outcome after one month . The results of this study confirm evidence that psychoactive drugs effective in the treatment of PD decrease CO2 hyperreactivity . They also suggest that precocious modulation of CO2 reactivity might fairly reliably predict short-term clinical outcome in patients with “ respiratory ” PD 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 Background : Nonresponsiveness to therapy is generally acknowledged , but only a few studies have tested switching to psychotherapy . This study is one of the first to examine the malleability of treatment-resistant patients using acceptance and commitment therapy ( ACT ) .  Methods : This was a r and omized controlled trial that included 43 patients diagnosed with primary panic disorder and /or agoraphobia ( PD/A ) with prior unsuccessful state-of-the-art treatment ( mean number of previous sessions = 42.2 ) . Patients were treated with an ACT manual administered by novice therapists and followed up for 6 months . They were r and omized to immediate treatment ( n = 33 ) or a 4-week waiting list ( n = 10 ) with delayed treatment ( n = 8) . Treatment consisted of eight sessions , implemented twice weekly over 4 weeks . Primary outcomes were measured with the Panic and Agoraphobia Scale ( PAS ) , the Clinical Global Impression ( CGI ) , and the Mobility Inventory ( MI ) . Results : At post-treatment , patients who received ACT reported significantly more improvements on the PAS and CGI ( d = 0.72 and 0.89 , respectively ) than those who were on the waiting list , while improvement on the MI ( d = 0.50 ) was nearly significant . Secondary outcomes were consistent with ACT theory . Follow-up assessment s indicated a stable and continued improvement after treatment . The dropout rate was low ( 9 % ) . Conclusions : Despite a clinical ly challenging sample and brief treatment administered by novice therapists , patients who received ACT reported significantly greater changes in functioning and symptomatology than those on the waiting list , with medium-to-large effect sizes that were maintained for at least 6 months . These proof-of-principle data suggest that ACT is a viable treatment option for treatment-resistant PD/A patients . Further work on switching to psychotherapy for nonresponders is clearly needed BACKGROUND Panic attacks can be induced in persons with panic disorder by inhalation of carbon dioxide . Hypercapnia also elicits a reflex hyperventilation , which is controlled in part by cholinergic mechanisms . This study investigated whether the exaggerated response to carbon dioxide in panic disorder ( PD ) can be modulated by antagonists of muscarinic cholinergic receptors . METHODS Twelve patients with PD received biperiden hydrochloride ( a muscarinic antagonist that crosses the blood-brain barrier ) , pirenzepine hydrochloride ( a muscarinic antagonist that does not cross the blood-brain barrier ) , or placebo 2 hours before a 35 % carbon dioxide-65 % oxygen respiratory challenge ( vs air as a placebo ) on 3 separate days , in a double-blind , r and om crossover design . RESULTS According to patients ' self-ratings of subjective anxiety , inhalation of the carbon dioxide/oxygen mixture provoked a significant and intense response after treatment with pirenzepine and placebo . After biperiden treatment , however , hypercapnia elicited a response profile similar to that elicited by air , whereby subjective anxiety remained similar to preinhalation levels . CONCLUSIONS Consistent with the hypothesis of the study , a central ly active muscarinic antagonist can block the response to carbon dioxide commonly observed in subjects with PD BACKGROUND Given growing evidence that respiratory dysregulation is a central feature of panic disorder ( PD ) interventions for panic that specifically target respiratory functions could prove clinical ly useful and scientifically informative . We tested the effectiveness of a new , brief , capnometry-assisted breathing therapy ( BRT ) on clinical and respiratory measures in PD . METHODS Thirty-seven participants with PD with or without agoraphobia were r and omly assigned to BRT or to a delayed-treatment control group .  Clinical status , respiration rate , and end-tidal pCO(2 ) were assessed at baseline , post-treatment , 2-month and 12-month follow-up . Respiratory measures were also assessed during homework exercises using a portable capnometer as a feedback device . RESULTS Significant improvements ( in PD severity , agoraphobic avoidance , anxiety sensitivity , disability , and respiratory measures ) were seen in treated , but not untreated patients , with moderate to large effect sizes . Improvements were maintained at follow-up . Treatment compliance was high for session attendance and homework exercises ; dropouts were few . CONCLUSIONS The data provide preliminary evidence that raising end-tidal pCO(2 ) by means of capnometry feedback is therapeutically beneficial for panic patients . Replication and extension will be needed to verify this new treatment 's efficacy and determine its mechanisms 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 Background : Improvements in quality of life ( QoL ) as well as symptomatic relief are important outcomes for the treatment of panic disorder ( PD ) . The aim of this study is to assess the impact of brief cognitive behavior group therapy ( CBGT ) for panic disorder on QoL and to identify the clinical features associated with these changes . Methods : Thirty-six patients with PD refractory to pharmacological treatment took part in a treatment protocol consisting of 12 sessions of CBGT . To evaluate the changes in QoL , the WHOQOL-bref was administered before and after treatment . Results : Thirty-two patients completed the treatment . Significant improvement in all domains of QoL was observed ( p < 0.001 ) , which was associated with reductions in general and anticipatory anxiety ( p = 0.018 ) and agoraphobic avoidance ( p = 0.046 ) . Consistent with previous findings , associations between QoL and panic-free status did not reach significance in this small study ( p = 0.094 ) . Conclusions : CBGT was efficacious in the treatment of PD ; the symptoms of anticipatory anxiety and avoidance appear to be more important than episodic panic episodes in affecting BACKGROUND Serotonin Selective Re-uptake Inhibitors ( SSRIs ) are the drugs of choice for treating panic disorder ( PD ) . In vitro studies have shown different pharmacodynamic profiles for SSRIs , but their clinical relevance is still unknown . Paroxetine , the SSRI with the strongest serotonergic effect , also shows significant cholinergic and noradrenergic activities . In this class of drugs , citalopram is the most selective for serotonin . We compared these two drugs and their effectiveness and tolerability in a sample of patients with PD in a two-month treatment course . METHOD Fifty-eight patients with PD were r and omly assigned to either the paroxetine or the citalopram treatment group in a single-blind , r and omized design . Each patient was assessed at days 0 , 7 and 60 by the Panic Associated Symptoms Scale ( PASS ) , the Sheehan Disability Scale ( SDS ) and the Fear Question naire ( FQ ) . Primary outcome measures were the percentage of patients free of panic attacks , anticipatory anxiety and phobic avoidance in the last week of the trial and the percentage of good responders , as defined by a reduction of at least 50 % from baseline of both PASS and SDS global scores at day 60 . RESULTS At day 60 , 86 % of patients receiving citalopram and 84 % of those receiving paroxetine responded well to treatment . No significant differences between the two drugs were found . Both were well tolerated , although sexual side effects and weight gain were frequent . Anticipatory anxiety decreased significantly after the first week of treatment , and no initial worsening in the panic attacks was observed . CONCLUSION Paroxetine and citalopram show similar anti-panic properties and a good tolerability profile . Our results support evidence that the serotonergic system plays a significant role in the anti-panic properties of these two SSRIs 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
target: Quetiapine extended-release augmentation has not been found to be beneficial , in comparison to placebo , in non-responders to previously recommended pharmacotherapy .
  In non-responders to cognitive behavioral therapy ( CBT ) , switching to paroxetine/citalopram has been found to be more effective than continuing CBT .
  Acceptance and commitment therapy ( ACT ) has shown some improvement in patients ’ resistance to previous psychological/pharmacological interventions compared with a waiting-list condition .
  Prolonged pharmacotherapy may produce significant improvement in patients with unsatisfactory response to short-term pharmacotherapy  , while switching to pharmacotherapy may help non-responders to CBT .
background: Purpose of Review Purpose of Review Management of treatment-resistant ( TR ) panic disorder ( PD ) is an unresolved issue .
  In this paper , we provide a brief summary of previous findings , an up date d ( 2015–2017 ) systematic review of pharmacological/non-pharmacological studies , and our personal perspective on this topic .