title: A controlled trial of quetiapine XR coadministration treatment of SSRI-resistant panic disorder A comparison of low-dose risperidone to paroxetine in the treatment of panic attacks: a randomized, single-blind study Hypersensitivity to inhalation of carbon dioxide and panic attacks Sensitivity to 35% carbon dioxide in patients with generalized anxiety disorder. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Influence of panic-agoraphobic spectrum symptoms on treatment response in patients with recurrent major depression. Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. A randomized, double-blind, placebo-controlled study of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder. Antipanic Drug Modulation Of 35% CO2 Hyperreactivity and Short-Term Treatment Outcome Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety.
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 # : Background Because a large proportion of patients with panic attacks receiving approved pharmacotherapy do not respond or respond poorly to medication , it is important to identify additional therapeutic strategies for the management of panic symptoms . This article describes a r and omized , rater-blind study comparing low-dose risperidone to st and ard-of-care paroxetine for the treatment of panic attacks . Methods Fifty six subjects with a history of panic attacks were r and omized to receive either risperidone or paroxetine .  The subjects were then followed for eight weeks . Outcome measures included the Panic Disorder Severity Scale ( PDSS ) , the Hamilton Anxiety Scale ( Ham-A ) , the Hamilton Depression Rating Scale ( Ham-D ) , the Sheehan Panic Anxiety Scale-Patient ( SPAS-P ) , and the Clinical Global Impression scale ( CGI ) . Results All subjects demonstrated a reduction in both the frequency and severity of panic attacks regardless of treatment received . Statistically significant improvements in rating scale scores for both groups were identified for the PDSS , the Ham-A , the Ham-D , and the CGI . There was no difference between treatment groups in the improvement in scores on the measures PDSS , Ham-A , Ham-D , and CGI . Post hoc tests suggest that subjects receiving risperidone may have a quicker clinical response than subjects receiving paroxetine . Conclusion We can identify no difference in the efficacy of paroxetine and low-dose risperidone in the treatment of panic attacks . Low-dose risperidone appears to be tolerated equally well as paroxetine . Low-dose risperidone may be an effective treatment for anxiety disorders in which panic attacks are a significant component . Trial Registration Clinical Trials.gov Identifier : Thirteen healthy subjects with infrequent panic attacks and without agoraphobia who did not meet DSM-III-R criteria for panic disorder , 43 patients with panic disorder , and 43 healthy control subjects who never experienced panic attacks underwent one vital capacity inhalation of 35 % CO2 . Healthy subjects with infrequent panic attacks reacted similarly to patients with panic disorder and more strongly than healthy subjects who never experienced panic attacks . The results suggest that ( a ) subjects with sporadic unexpected panic attacks and patients with panic disorder belong to the same spectrum of vulnerability and ( b ) CO2 hypersensitivity might be a trait marker of panic attacks rather than of a clinical diagnosis of panic disorder BACKGROUND Panic disorder and generalized anxiety disorder ( GAD ) are both characterized by severe anxiety , but there is evidence that indicates a qualitative difference between these 2 anxiety disorders . To investigate the specificity of the association between carbon dioxide ( CO2 ) hypersensitivity and panic disorder and the possible relationships between panic disorder and GAD , the responses to inhalation of a gas mixture of 35 % CO2 and 65 % oxygen ( O2 ) were assessed . METHOD Fifteen patients with panic disorder , 13 patients with GAD , and 10 patients with comorbid GAD and panic disorder according to a consensus diagnosis using Diagnostic Interview Schedule Version III-R ( DIS-R ) and DSM-IV criteria , and 12 healthy controls inhaled 2 vital capacities : 1 of 35 % CO2 and 1 of compressed air . A double-blind , r and omized , crossover design was used . RESULTS GAD patients showed reactions to 35 % CO2  that were similar to those of healthy controls and significantly weaker than that of panic disorder patients . Patients with comorbid panic disorder and GAD had anxiogenic reactions similar to those of subjects with panic disorder . CONCLUSION The results of the present study support the idea that panic disorder and GAD are separate disorders that have at least some differences in pathogenetic mechanisms and suggest that the 35 % CO2 test might be a valid tool for discriminating between these 2 disorders Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE The authors tested the hypothesis that a lifetime history of panic-agoraphobic spectrum symptoms predicts a poorer response to  depression treatment . METHOD A threshold for clinical ly meaningful panic-agoraphobic spectrum symptoms was defined by means of receiver operating characteristic curve analysis of total scores on the Structured Clinical Interview for Panic-Agoraphobic Spectrum in a group of 88 out patients with and without panic disorder . This threshold was then applied to a group of 61 women with recurrent major depression , who completed a self-report version of the same instrument , in order to compare treatment outcomes for patients above and below this clinical threshold . RESULTS Women with high scores ( > or = 35 ) on the Panic-Agoraphobic Spectrum Self-Report were less likely than women with low scores ( < 35 ) to respond to interpersonal psychotherapy alone ( 43.5 % versus 68.4 % , respectively ) . Women with high scores also took longer ( 18.1 versus 10.3 weeks ) to respond to a sequential treatment paradigm ( adding a  selective serotonin reuptake inhibitor  when depression did not remit with interpersonal psychotherapy alone ) . This effect was only partially accounted for by the higher likelihood that patients with high scores required the addition of antidepressants . Although four domains from the Panic-Agoraphobic Spectrum Self-Report were individually associated with a longer time to remission , only stress sensitivity emerged as significant in multivariate regression analyses . CONCLUSIONS A lifetime burden of panic-agoraphobic spectrum symptoms predicted a poorer response to  interpersonal psychotherapy  and an 8-week delay in sequential treatment response among women with recurrent depression . These results lend clinical validity to the spectrum construct and highlight the need for alternate psychotherapeutic and pharmacologic strategies to treat depressed patients with panic spectrum features BACKGROUND Anxiety disorders complicate the treatment of bipolar disorder but are seldom the focus of bipolar treatment studies . METHODS The anxiolytic effect of quetiapine XR 50 - 300 mg/day compared to divalproex ER ( 500 - 3000 mg/day ) was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 149 patients with bipolar disorder and a co-occurring panic disorder or GAD . The primary efficacy measure was the Clinician Global Improvement-21 Anxiety Scale ( CGI-21 ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and Sheehan Panic Disorder Scale ( SPS ) . RESULTS Repeated measures last-observation-carried-forward ( LOCF ) analyses of variance demonstrated significant treatment-by-time interaction effects on 3 of the 4 anxiety measures .  Quetiapine XR at a mean endpoint dose of 186 mg/day produced rapid sustained improvements relative to baseline , divalproex ER and placebo on anxiety . Mean baseline-to-endpoint improvement was significantly greater for quetiapine XR compared to divalproex ER and placebo on the HAM-A and SPS . Both active medications were well tolerated , but weight gain was higher on quetiapine XR . LIMITATIONS The study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or GAD . The results may not be applicable to quetiapine XR as an add-on treatment to mood stabilizers or to bipolar disorder comorbid with other anxiety disorders . CONCLUSIONS Quetiapine XR in a dose range of 50 - 300 mg/day appears to reduce anxiety in bipolar patients with comorbid panic disorder or GAD treated for 8 weeks . The efficacy of other second-generation antipsychotics and mood stabilizers in patients with bipolar disorder and a co-occurring anxiety disorder should be investigated in double-blind , placebo-controlled studies OBJECTIVE Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the role of anxiety in bipolar disorder , the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder . METHOD The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder . Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms . RESULTS History of panic attacks proved to be a significant correlate of nonremission . Anxiety , as assessed with the composite variable , was associated with longer time to remission , as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms . Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects . They also required a greater number of medications , either sequentially or in combination , in order to achieve remission . CONCLUSIONS The findings suggest that anxiety is a clinical ly meaningful correlate of poor outcome in the acute treatment of bipolar I disorder OBJECTIVE Bipolar disorder often co-occurs with anxiety disorders . Evidence suggests that second-generation antipsychotics ( SGAs ) may be useful in treating both conditions . This study examined the efficacy of ziprasidone in the treatment of these disorders . METHOD This 3-site , r and omized , double-blind , placebo-controlled , parallel group , 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder ( with or without agoraphobia ) or generalized anxiety disorder ( GAD ) experiencing moderately severe anxiety symptoms at entrance into the study . Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria . Patients were screened and r and omized from June 25 , 2010 , through August 23 , 2011 . Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale ( CGI-21 Anxiety ) and the Sheehan Disability Scale ( SDS ) , with secondary measures monitoring anxiety and mood symptoms . RESULTS Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety ( F1 = 0.34 ; P = .564 ) or SDS ( F1 = 0.26 ; P = .611 ) . Secondary analysis using hierarchical linear modeling found similar results ( CGI-21 Anxiety : F1 = 1.82 ; P = .178 ; and SDS : F1 = 0.70 ; P = .408 ) . Regardless of group , time in the study was associated with significant decrease in anxiety ( F1 = 11.08 ; P = .001 ) and total disability ( F1 = 26.16 ; P < .001 ) . Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement , and 81.8 % ( n = 9 ) of the subjects who withdrew from the study due to adverse events , serious adverse events , or side effects were in the ziprasidone group . CONCLUSIONS Results suggest that ziprasidone monotherapy was not associated with a clinical ly significant improvement in anxiety symptoms or improved function for patients with bipolar disorder , lifetime panic disorder or GAD , and concurrent moderately severe anxiety symptoms , and it was associated with a more negative side-effect profile relative to placebo . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01172652 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 OBJECTIVE The authors performed an analysis of their published chromosome 18 linkage data on 28 families in which there was bipolar disorder to test the potential of comorbid panic disorder to define a genetic subtype of bipolar disorder . METHOD Families ascertained through prob and s with bipolar I disorder were stratified into three groups based on a history of panic disorder , panic attacks , or no panic attacks in the prob and s. Multipoint  nonparametric linkage analysis was performed on data from bipolar I and II family members in each group . RESULTS Linkage scores for five consecutive 18q marker loci were highest in the families of the prob and s with panic disorder and lowest for the families of the prob and s without panic attacks . CONCLUSIONS This study supports the authors ' previously reported clinical hypothesis of a genetic subtype of bipolar disorder identified by comorbid panic disorder . The hypothesis merits prospect i ve testing BACKGROUND The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder . Although second generation antipsychotics are being used with increasing frequency in bipolar patients , their anxiolytic effects have not been well studied in this population . METHODS The anxiolytic effect of risperidone 0.5 - 4 mg/day was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder ( GAD ) . The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale ( CGI-21 Anxiety ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and the Sheehan Panic Disorder Scale . RESULTS On the last-observation-carried forward analysis of repeated measures analysis of variance ( ANOVA ) , risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures .  Risperidone was well tolerated , with only two patients withdrawing because of adverse events . LIMITATIONS The  risperidone treated group had more patients with mixed states and lifetime panic disorder at r and omization than the placebo group . The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD . The results may not be applicable to risperidone as an add-on treatment to mood stabilizers , or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD . CONCLUSIONS Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5 - 4 mg/day over 8 weeks of treatment . The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind , placebo-controlled studies
target: Overall , a general lack of efficacy of SGAs on panic symptoms was observed .
  Except for ziprasidone , SGAs were well tolerated in these short-term trials
background: A role for second-generation antipsychotics ( SGAs ) in the treatment of  panic disorders ( PD ) has been proposed , but the actual usefulness of SGAs in this disorder is unclear .