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OBJECTIVE Recently , pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available . The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines . METHOD A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project , a prospect i ve longitudinal study of anxiety disorders . These patients were interviewed over the course of 10 years to examine their use of psychotropic medications . RESULTS Despite efforts aim ed at increasing the use of selective serotonin reuptake inhibitors ( SSRIs ) in patients with panic disorder ( e.g. , APA 's practice guideline for panic disorder , Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder ) , only a modest increase in their use was found . Treatment patterns for psychotropic drugs  appear to have remained stable over the past decade , with benzodiazepines being the most commonly used medication for panic disorder . In comparison , SSRI use throughout the follow-up period has remained low . Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine , nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly . CONCLUSIONS These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed . Factors potentially associated with promoting and ignoring treatment recommendations are discussed BACKGROUND Tricyclic antidepressants and selective serotonin reuptake inhibitors ( SSRIs ) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder . The introduction of SSRIs has enabled a greater underst and ing of the role of serotonin in the etiology of panic disorder ; however , the role of norepinephrine has been more challenging to ascertain . The aim of this study was to determine the efficacy and tolerability of reboxetine , a novel selective norepinephrine reuptake inhibitor , in patients with panic disorder with and without agoraphobia . METHOD Eighty-two patients ( aged 18 - 65 years ) with DSM-III-R panic disorder , with or without agoraphobia , were r and omly assigned to receive 6 to 8 mg/day of reboxetine ( 42 patients ) or placebo ( 40 patients ) for 8 weeks in this placebo-controlled , parallel-group , double-blind clinical trial . RESULTS Of the 82 patients enrolled in the trial , 75 were considered in the analysis ( 37 patients in the reboxetine group and 38 patients in the placebo group ) . At last assessment , there was a significant reduction in the mean number of panic attacks ( range , 9.3 - 1.2 ) and phobic symptoms ( range , 8.1 - 3.2 ) in the reboxetine group compared with the placebo group ( ranges , 8.5 - 5.8 and 7.7 - 5.2 , respectively ; p < .05 ) . Improvement in Hamilton Rating Scale for Depression , Hopkins Symptom Checklist-90 , and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group . Adverse events reported more frequently with reboxetine than placebo included dry mouth ( 36 % vs. 16 % ) , constipation ( 27 % vs. 22 % ) , and insomnia ( 26 % vs. 22 % ) . CONCLUSION Reboxetine was effective and well tolerated in the treatment of panic disorder The possibility that panic disorder might be due to abnormal activity of endogenous lig and s of the benzodiazepine receptor was investigated with the use of the benzodiazepine antagonist flumazenil .  Physiological and subjective psychological responses to this selective antagonist were measured in 10 patients with panic disorder and in 10 control subjects , by using a placebo-controlled crossover study design . Subjective anxiety responses after flumazenil infusion were significantly higher in the patient group with panic disorder than in the controls , and eight patients with panic disorder but no controls had panic attacks . This anxiogenic effect of flumazenil in the patients argues against the presence of endogenous anxiogenic ( inverse agonist ) lig and s. Possible explanations include the differential production of an anxiolytic endogenous lig and or an altered benzodiazepine receptor " set-point . " Such an abnormality may contribute to the pathogenesis of panic disorder Despite the widespread application of combined selective serotonin reuptake inhibitors ( SSRI ) and benzodiazepine treatment for panic disorder , there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy . Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment , this study is the first to address the critical question of whether continued combined treatment confers superior efficacy . This study is a r and omized , double-blind , three-arm study in patients with panic disorder ( n = 60 ) , comparing the efficacy and safety of paroxetine and placebo ( PP ) , paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase ( PC-D ) , and ongoing combination treatment ( PC-M ) . All treatment groups demonstrated significant improvement by endpoint . There was a significant advantage for the combined treatment groups early in treatment but , subsequently , outcome in all three groups was similar . A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered . The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout . Combined treatment with paroxetine and clonazepam result ed in more rapid response than with the SSRI alone , but there was no differential benefit beyond the initial few weeks of therapy . Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy The paper consists of two parts . A review of the relationship of panic disorder to the phobic states and the treatment of these disorders by means of tricyclic antidepressants , MAOIs , beta blocking drugs and benzodiazepines . A double blind study of alprazolam and placebo in 118 patients with agoraphobia and panic is presented . In an eight week study alprazolam was found to be significantly superior to placebo in the treatment of panic attacks , phobic avoidance , anticipatory anxiety and general anxiety Serotonergic mechanisms have been implicated in panic disorder , and several preliminary studies suggest that fluvoxamine , a selective serotonin reuptake inhibitor ( SSRI ) , is helpful in its treatment . This 8-week double-blind parallel-group study compared fluvoxamine with a placebo in 188 patients with DSM-III-R defined panic disorder with or without agoraphobia . Efficacy assessment s included a Daily Panic Attack Inventory , the Sheehan Disability Scale , the Clinical Anxiety Scale and the Clinical Global Impression Scale . When compared with the placebo , fluvoxamine produced highly significant improvements in most measures of the frequency and severity of panic disorder and in the more global aspects of disability and distress . Significant improvement was evident as early as week 1 for some panic variables . Fluvoxamine is a potent anti-panic agent with a relatively rapid onset of action BACKGROUND AND OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are currently the first-line treatment for panic disorder , although up to 30 % of patients either do not respond to SSRIs or withdraw due to adverse events . Reboxetine , a selective norepinephrine reuptake inhibitor ( selective NRI ) , is effective in treating depression and may alleviate depression-related anxiety . This study aim ed to investigate the efficacy of reboxetine in the treatment of patients with panic disorder who did not respond to SSRIs . METHOD In this 6-week , open-label study , 29 adult out patients with panic disorder who had previously failed to respond to SSRI treatment received reboxetine 2 mg/day , titrated to a maximum of 8 mg/day over the first 10 days .  Efficacy was assessed using the Panic Self- Question naire ( PSQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the 17-item Hamilton Rating Scale for Depression ( HRSD ) and the Global Assessment of Functioning ( GAF ) Scale . RESULTS The 24 patients who completed the study responded well to reboxetine treatment . Significant improvement ( p < 0.001 ) was observed in the number of daily panic attacks , and on the scales measuring anxiety , depression and functioning . Reboxetine was generally well tolerated . Five patients withdrew due to  adverse events . CONCLUSIONS Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients and warrants further clinical investigation BACKGROUND 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 CONTEXT This study makes a comparison between two subtypes of panic disorder regarding the clinical efficacy of clonazepam , a benzodiazepine . OBJECTIVES To evaluate the clinical efficacy of clonazepam in a fixed dosage ( 2 mg/day ) , compared to placebo , in the treatment of panic disorder patients and to verify whether there are any differences in the responses to clonazepam between panic disorder patients with the respiratory and non-respiratory subtypes . TYPE OF STUDY R and omized study with clonazepam and placebo . SETTING Outpatient Anxiety and Depression Unit of the Institute of Psychiatry , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil . PARTICIPANTS 34 patients with a diagnosis of panic disorder with agoraphobia , between 18 and 55 years old . PROCEDURES Administration of clonazepam or placebo for 6 weeks , in panic disorder patients , after they were classified within two subtypes of panic disorder : respiratory and non-respiratory . MAIN MEASUREMENTS Changes in the number of panic attacks in comparison with the period before the beginning of the study ; Hamilton Anxiety Scale ; Global Clinical Impression Scale ; and Patient 's Global Impression scale . RESULTS In the group that received clonazepam , by the end of the 6th week there was a statistically significant clinical improvement , shown by the remission of panic attacks ( p < 0.001 ) and decrease in anxiety ( p = 0.024 ) . In the group that received clonazepam there was no significant difference between the respiratory and non-respiratory subtypes of panic disorder , regarding the therapeutic response to clonazepam . CONCLUSION Clonazepam was equally effective in the treatment of the respiratory and non-respiratory subtypes of panic disorder , suggesting there is no difference in the therapeutic response between the two subtypes BACKGROUND Alprazolam has proven efficacy as a treatment for panic disorder , but the place of other benzodiazepines is less well established . METHOD To compare the efficacy and tolerability of diazepam and alprazolam for the disorder , a placebo-controlled , double-blind trial was undertaken in two sites . Two hundred forty-one subjects with panic disorder or agoraphobia with panic attacks were r and omly assigned to flexible doses of diazepam , alprazolam , or placebo for 8 weeks . RESULTS At the end of the trial , over 60 % of subjects taking either diazepam or alprazolam were at least moderately improved compared with less than 30 % of those taking placebo . On all measures of efficacy , subjects taking diazepam and alprazolam showed an equally favorable response . Despite some sedation early in the trial , both drugs were tolerated well . More severely ill subjects responded less well to either benzodiazepine . CONCLUSION The results indicate that diazepam is an effective alternative to alprazolam for the treatment of panic disorder BACKGROUND Escitalopram , the therapeutically active isomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram , has shown significant anxiolytic effects in placebo-controlled clinical trials of social anxiety disorder , generalized anxiety disorder , and anxiety symptoms associated with major depression . This study evaluated the safety and efficacy of escitalopram in out patients diagnosed with panic disorder . METHOD Male and female out patients between 18 and 80 years of age meeting DSM-IV criteria for panic disorder , with or without agoraphobia , were r and omly assigned to 10 weeks of double-blind treatment with escitalopram , citalopram , or placebo in a study conducted from September 1999 to July 2001 . The primary measure of efficacy was panic attack frequency at week 10 relative to baseline , as assessed by the Modified Sheehan Panic and Anticipatory Anxiety Scale . RESULTS A total of 366 subjects ( 128 escitalopram patients , 119 citalopram patients , and 119 placebo patients ) received at least 1 dose of double-blind treatment . The frequency of panic attacks was statistically significantly improved ( p = .04 ) , and the increase in percentage of patients with zero panic attacks reached borderline significance ( p = .051 ) , in the escitalopram-treated group relative to the placebo-treated group . Both escitalopram and citalopram statistically significantly reduced panic disorder symptoms and severity versus placebo at endpoint ( p < /=.05 ) , as measured by the Panic and Agoraphobia Scale total score , the Clinical Global Impressions scale , the Patient Global Evaluation , and the Quality of Life Enjoyment and Satisfaction Question naire . Treatment with escitalopram was safe and well tolerated , with a similar incidence of the most common adverse events for the escitalopram and placebo groups . The rate of discontinuation for adverse events was 6.3 % for escitalopram , 8.4 % for citalopram , and 7.6 % for placebo . CONCLUSION Escitalopram is efficacious , safe , and well tolerated in the treatment of panic disorder BACKGROUND Drug therapy of panic disorder , despite the intermittent nature of the panic attack , requires daily administration of antidepressants , which are often not tolerated , or benzodiazepines , which can result in physical dependence and withdrawal . The use of rapidly acting , low-dose intranasal midazolam to prevent incipient panic suggested itself to us as a novel alternative treatment strategy . METHOD We conducted a 6-week double-blind , placebo-controlled , crossover- design pilot study of the safety and efficacy of p.r.n . low-dose intranasal midazolam in five patients diagnosed with DSM-III-R panic disorder . RESULTS One to two drops of midazolam ( approximately 0.25 to 0.5 mg ) was well tolerated and highly effective in preventing incipient panic attacks and in reducing the overall weekly frequency of attacks . CONCLUSION Intermittent intranasal midazolam shows promise as a novel alternative treatment for panic , but a controlled study of its efficacy and safety ( including abuse potential ) must be conducted BACKGROUND There is debate about combining benzodiazepines with selective serotonin reuptake inhibitors in the acute treatment of panic disorder . Although this medication combination is widely used in clinical practice , there is no well-tested , optimal method of coadministering these medications for the treatment of panic disorder . The purpose of this study was to test the efficacy of early coadministration of clonazepam with sertraline in the treatment of panic disorder . METHODS Fifty patients with panic disorder were r and omized into a double-blind clinical trial . Patients received open-label sertraline for 12 weeks ( target dose , 100 mg/d ) , and in addition were r and omized to groups receiving either 0.5 mg of active clonazepam 3 times daily or placebo clonazepam for the first 4 weeks of the trial . The clonazepam dose was then tapered during 3 weeks and discontinued . RESULTS Thirty-four ( 68 % ) of 50 patients completed the trial .  Drop-out rates were similar in the sertraline/placebo vs the sertraline/clonazepam group ( 38 % vs 25 % ) ( P = .5 ) . An intent-to-treat analysis ( on last observation carried forward data ) revealed a much greater proportion of responders in the sertraline/clonazepam compared with the sertraline/placebo group at the end of week 1 of the trial ( 41 % vs 4 % ) ( P = .003 ) . There was also a significant between-group difference at the end of week 3 with 14 ( 63 % ) of 22 of the sertraline/clonazepam group responding to treatment vs 8 ( 32 % ) of 25 of the sertraline/placebo group ( P = .05 ) . This difference was not observed at other times during the trial . CONCLUSION These data indicate that rapid stabilization of panic symptoms can be safely achieved with a sertraline/clonazepam combination , supporting the clinical utility of this type of regimen for facilitating early improvement of panic symptoms relative to sertraline alone Despite its acute efficacy for the treatment of panic disorder , benzodiazepines ( BZs ) are associated with a withdrawal syndrome that closely mimics anxiety sensations , leading to difficulty with treatment discontinuation and often disorder relapse . An exposure-based cognitive-behavioral treatment for BZ discontinuation , Panic Control Treatment for BZ Discontinuation ( CBT ) targets the fear of these sensations and has demonstrated efficacy in preventing disorder relapse and facilitating successful BZ discontinuation among patients with panic disorder . In this r and omized controlled trial , CBT was compared to taper alone and a taper plus a relaxation condition to control for the effect of therapist contact and support among 47 patients with panic disorder seeking taper from BZs . Based on the primary outcome of successful discontinuation of BZ use , results indicate that adjunctive CBT provided additive benefits above both taper alone and taper plus relaxation , with consistently medium and large effect sizes over time that reached significance at the six month follow-up evaluation . The efficacy of CBT relative to either of the other taper conditions reflected very large and significant effect sizes at that time . These findings suggest that CBT provides specific efficacy for the successful discontinuation from BZs , even when controlling for therapist contact and relaxation training BACKGROUND The serotonin selective reuptake inhibitors are increasingly being used for the treatment of panic disorder . We examined the efficacy and safety of the serotonin selective reuptake inhibitor sertraline hydrochloride in patients with panic disorder . METHODS One hundred seventy-six nondepressed out patients with panic disorder , with or without agoraphobia , from 10 sites followed identical protocol s that used a flexible-dose design . After 2 weeks of single-blind placebo , patients were r and omly assigned to 10 weeks of double-blind , flexible-dose treatment with either sertraline hydrochloride ( 50 - 200 mg/d ) or placebo . RESULTS Sertraline-treated patients exhibited significantly greater improvement ( P=.01 ) at end point than did patients treated with placebo for the primary outcome variable , panic attack frequency . Significant differences between groups were also evident for clinician and patient assessment s of improvement as measured by the Clinical Global Impression Improvement ( P=.01 ) and Severity ( P=.009 ) Scales , Panic Disorder Severity Scale ratings ( P=.03 ) , high end-state function assessment ( P=.03 ) , Patient Global Evaluation rating ( P=.01 ) , and quality of life scores ( P=.003 ) . Adverse events , generally characterized as either mild or moderate , were not significantly different in overall incidence between the sertraline and placebo groups . CONCLUSION Results support the safety and efficacy of sertraline for the short-term treatment of patients with panic disorder In this open label pilot study , we studied the efficacy of mirtazapine ( Remeron ) in panic disorder . Twenty-eight patients with a DSM-IV diagnosis of panic disorder , with or without agoraphobia ( 10 males/18 females ) , were included and 19 patients completed the study . The 15-week trial started with a 3-week single-blind placebo run-in period . After this run-in period , the 12-week active treatment phase started . As primary efficacy measures , we studied the decrease in the number of full symptom panic attacks and the number of patients completely free of panic during the last 3 weeks of the study . Seventy-four percent of the patients were considered responders , according to a decrease of at least 50 % in panic attack frequency . All primary and secondary efficacy measures showed a significant improvement from the second week of active treatment onwards to endpoint . The main side-effects were different from the usual side-effects in selective serotonin reuptake inhibitors ( SSRIs ) ( initial drowsiness , weight gain and pain in the legs ) . The results of this open label study in panic disorder suggest that mirtazapine seems to be a fast and effective treatment alternative for SSRIs in panic disorder The purpose of this study was to test the following interrelated hypotheses in a larger sample by attempting to replicate supportive results from a small therapeutic study : ( 1 ) the pathogenesis of panic disorder includes at least two identifiable components : a biological component represented by spontaneous ( unexpected ) panic attacks , and a cognitive component represented by situational attacks and especially by phobias ; ( 2 ) these components respond differently to treatment ; ( 3 ) many biological processes respond to an effective intervention in proportion to their deviance from " normal " prior to treatment ( " Law of Initial Value " ) ; and ( 4 ) the response of spontaneous panic attacks to an effective treatment conforms to that model . Previously , the authors reanalyzed an 8-week therapeutic study of panic disorder that included groups treated with  placebo  and with  imipramine ( 225 mg daily ) . The criteria of response were spontaneous panic attacks ( biological component ) , situational panic attacks ( both components ) , and agoraphobia ratings ( cognitive component ) . The analyses compared the regression lines for posttreatment status on pretreatment status in the imipramine and placebo groups . The effect of imipramine on spontaneous panic attacks fitted the hypothesized model : the pre-post slope in the placebo group was approximately 1 ( 45 degrees ) , whereas the slope in the imipramine group was approximately 0 . There was no significant difference in pre-post slopes between the imipramine and placebo groups for situational panic attacks or agoraphobia ratings . For this report , the authors applied the same approach to another larger data set from a study using a similar design , but a different antidepressant . In this multicenter , double-blind study , patients with panic disorder were r and omly assigned to receive 10 weeks of treatment with  placebo ( N = 78 ) or fluoxetine 10 mg ( N = 84 ) or 20 mg ( N = 81 ) daily . Spontaneous and situational panic attacks were registered in a daily diary , and agoraphobia was rated at each visit . Using baseline and endpoint data , fluoxetine had a statistically significant , dose-dependent , suppressive effect on spontaneous panic attacks , as measured by the pre-post slopes in the three treatment groups . The placebo group showed some response ( slope = 0.69 ) . There were no significant drug effects on situational panic attacks . On ratings of agoraphobia , the slopes in the placebo and the fluoxetine 20 mg groups did not differ , but the slope in the fluoxetine 10 mg group was significantly less than that in the placebo group , suggesting a therapeutic drug effect on agoraphobia only at the lower dose . These results are consistent with the stated hypotheses . They suggest that the therapeutic effects of antidepressants on panic disorder may be due primarily to the specific suppression of spontaneous panic attacks among patients with high baseline pathologic findings . Implication s of these results for concepts of pathogenesis , clinical practice , and therapeutic research regarding panic disorder are discussed Following promising preliminary evidence , the benzodiazepine-derivative alprazolam was studied in a large , placebo-controlled , eight-week , flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder . Of 526 patients , 481 completed three weeks of treatment ; however , significantly more placebo ( 102/234 ) than alprazolam ( 21/247 ) recipients subsequently dropped out of the trial , primarily citing ineffectiveness ( of placebo ) as the reason . Alprazolam was found to be effective and well tolerated . There were significant alprazolam-placebo differences in improvement for ( 1 ) spontaneous and situational panic attacks , ( 2 ) phobic fears , ( 3 ) avoidance behavior , ( 4 ) anxiety , and ( 5 ) secondary disability , all significant by the end of week 1 . At the primary comparison point ( week 4 ) , 82 % of the patients receiving alprazolam were rated moderately improved or better vs 43 % of the placebo group . At that point , 50 % of the alprazolam recipients vs 28 % of placebo recipients were free of panic attacks It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments ( interaction between treatment and baseline score ) . Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks , but not for the frequency of situational panic attacks or measures of agoraphobia . This report presents similar analyses of data from a study using moclobemide .  Patients ( N = 452 ) with panic disorder were r and omized to placebo  or a fixed dose of moclobemide ( 75 , 150 , 300 , 600 , or 900 mg/day ) . They were treated double-blindly and evaluated at baseline and 1 , 2 , 3 , 4 , 6 , and 8 weeks later . The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary , and fear and avoidance ratings based on the patient ’s main phobia using baseline ( pre ) and end-point ( post ) values for all r and omized patients . Adjoining dose groups were combined . Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes . Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms . This study replicates the authors ’ earlier findings , except for situational panic attacks , which probably were not reliably identified . Antidepressants selectively suppress panic attacks , especially unexpected attacks , but not agoraphobia . The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinical ly separable biologic and cognitive components that respond differentially to treatment . Antidepressants benefit primarily patients with many unexpected panic attacks . Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means ( analysis of covariance ) Forty-eight patients currently experiencing panic attacks were r and omly assigned to double-blind treatment with alprazolam , diazepam , or placebo .  Efficacy was assessed using the Hamilton Rating Scale for Anxiety and a panic attack frequency rating scale . Results indicate that the two active treatments appeared equally effective in reducing both the frequency of panic attacks and the severity of generalized anxiety when compared with placebo . Overall , these data support the use of benzodiazepines in the treatment of panic disorder OBJECTIVE This study evaluated time to response in the treatment of panic disorder with a selective serotonin reuptake inhibitor ( SSRI ) or serotonin norepinephrine reuptake inhibitor ( SNRI ) combined with alprazolam orally disintegrating tablets ( ODT ) , or SSRI/SNRI alone . DESIGN Subjects were r and omized to eight weeks open-label treatment with alprazolam ODT ( 4 weeks treatment followed by 3 - 4 week taper ) combined with an SSRI or SNRI , or treatment with SSRI/SNRI alone . SETTING The study was conducted under naturalistic conditions at 62 primary care and 34 psychiatric practice s. PARTICIPANTS Male or female subjects ≥18 years of age diagnosed with panic disorder , with or without agoraphobia . MEASUREMENTS The primary efficacy measure was time to response , defined as ≥50-percent decrease from baseline Hamilton Rating Scale for Anxiety ( HAM-A ) total score . Secondary measures included change from baseline in HAM-A scores and the Clinical Global Impression of Improvement ( CGI-I ) and Patient Global Impression ( PGI ) scales . RESULTS The intent-to-treat ( ITT ) population comprised 245 subjects . There was no statistical difference between treatment groups in time to response in the ITT population ; however , a prospect ively defined per protocol analysis revealed a statistically significant earlier onset of effect in subjects receiving SSRI/SNRI plus alprazolam ODT ( P<0.05 ) . Mean change from baseline in HAM-A total score and clinician and patient measures of global improvement also showed statistically significant early advantages for combination therapy compared with SSRI/SNRI monotherapy . CONCLUSION Combined treatment of panic disorder with alprazolam ODT and an SSRI/SNRI may be associated with more rapid improvement in anxiety symptoms compared with an SSRI/SNRI alone OBJECTIVE The authors ' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia . METHOD Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week , fixed-dose , double-blind , placebo-controlled , dose-response study of 2 mg/day or 6 mg/day of alprazolam . Assessment s were made of panic attacks , avoidance behavior , generalized anxiety , and global response . Blood sample s were collected throughout the study and analyzed for alprazolam and other benzodiazepines . RESULTS Patient compliance with the protocol was judged to be good on the basis of plasma concentrations . According to logistic regression analysis , the relationships between plasma alprazolam concentration and response , as reflected by number of panic attacks reported , phobia ratings , physicians ' and patients ' ratings of global improvement , and the emergence of side effects , were significant . However , there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms . CONCLUSIONS The authors conclude that plasma concentration of alprazolam  is related to treatment response , particularly in panic attacks . The  alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals , highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects 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 Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder . The advent of selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) ( e.g. citalopram ) and , more recently , selective noradrenergic ( NA ) reuptake inhibitors ( NRIs ) ( e.g. reboxetine ) has provided potentially important avenues of treatment for the disorder . To date , the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved . Nineteen patients with panic disorder were r and omized in a single-blind , cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug . At week 18 , seven of 13 patients ( 54 % ) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram ( 82 % ) . Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy . However , citalopram demonstrated superior efficacy in treating depressive symptoms . One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram . Although SSRIs are viewed as a first-line treatment for panic disorder , these results suggest that a NA agent such as reboxetine may also have a role . These data also suggest an advantage for citalopram in treating comorbid depressive symptoms , although some patients may respond preferentially to an SSRI and other patients to an NRI In a double-blind controlled study lasting 8 weeks , 50 anxious psychoneurotic out patients with a primary diagnosis of generalized anxiety or panic disorder were r and omly assigned to alprazolam ( n=30 ) , a new benzodiazepine , or placebo ( n=20 ) , after a washout period of 1 week . Alprazolam at dosages between 0.25 and 3 mg/day was found to be significantly better than placebo in the treatment of either disorder . The finding that alprazolam was effective in the treatment of panic disorder is of interest as this diagnostic category is usually treated with tricyclic antidepressants or MAO inhibitors OBJECTIVE The primary disadvantage of high-potency benzodiazepine treatment for panic disorder is the difficulty of discontinuing the treatment . During treatment discontinuation , new symptoms may emerge and anxiety may return , preventing many patients from successfully discontinuing their treatment . In this controlled , r and omized trial the authors investigated the efficacy of a cognitive-behavioral program for patients with panic disorder who were attempting to discontinue treatment with high-potency benzodiazepines .  METHOD Out patients treated for panic disorder with alprazolam or clonazepam for a minimum of 6 months and expressing a desire to stop taking the medication ( N = 33 ) were r and omly assigned to one of two taper conditions : a slow taper condition alone or a slow taper condition in conjunction with 10 weeks of group cognitive-behavioral therapy . RESULTS The rate of successful discontinuation of benzodiazepine treatment was significantly higher for the patients receiving the cognitive-behavioral program ( 13 of 17 ; 76 % ) than for the patients receiving the slow taper program alone ( four of 16 ; 25 % ) . There was no difference in the likelihood of discontinuation success between the patients treated with alprazolam and those who received clonazepam . At the 3-month follow-up evaluation , 77 % of the patients in the cognitive-behavioral program who successfully discontinued benzodiazepine treatment remained benzodiazepine free . CONCLUSIONS These findings support the efficacy of cognitive-behavioral interventions in aiding benzodiazepine discontinuation for patients with panic disorder 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 OBJECTIVE This study was design ed to determine the minimum paroxetine dose effective for treating panic disorder . METHOD Of 425 patients with DSM-III-R panic disorder with or without agoraphobia who underwent a 2-week drug-free screening period , 278 patients were r and omly assigned to double-blind treatment with a 10-week course of placebo or paroxetine at a dose of 10 , 20 , or 40 mg/day . RESULTS At 40 mg/day , paroxetine was superior to placebo across the majority of outcome measures . Despite a mean of 9.5 to 11.6 full panic attacks during the screening period , 86.0 % of the patients taking 40 mg of paroxetine , 65.2 % of those taking 20 mg , 67.4 % of those taking 10 mg , and 50.0 % of the placebo-treated patients were free of full panic attacks during the 2 weeks ending at week 10 . The 40-mg paroxetine group experienced significantly greater global improvement than the placebo group and significantly greater improvement in frequency of full and limited-symptom panic attacks , intensity of full panic attacks , phobic fear , anxiety , and depressive symptoms , usually evident by week 4 . All doses of paroxetine were well tolerated , and adverse effects were consistent with those associated with selective serotonin reuptake inhibitors . CONCLUSIONS Paroxetine is an effective and well-tolerated short-term treatment of panic disorder . The minimum dose demonstrated to be significantly superior to placebo was 40 mg/day , although some patients did respond at lower doses Panic disorder with or without agoraphobia is a common , often chronic and refractory anxiety disorder . Although a number of pharmacotherapies are now indicated for panic disorder , many patients do not respond to available interventions . We hypothesized that duloxetine , a serotonin‐norepinephrine reuptake inhibitor ( SNRI ) that has greater initial noradrenergic effects than venlafaxine , would have broad efficacy for individuals with panic disorder . Fifteen individuals with panic disorder with or without agoraphobia received 8 weeks of open label duloxetine flexibly dosed from 60 to 120 mg per day . Duloxetine treatment result ed in significant anxiolysis as measured by the primary outcome measure , the Panic Disorder Severity Scale ( PDSS ) ( paired t(df ) = 4.02(14 ) , P= 0.0013 ) , as well as measures of generalized anxiety , depression and quality of life ( all P < 0.05 ) . Although definitive conclusions are limited due to its small open‐label nature , this first prospect i ve study provides preliminary support for the efficacy of duloxetine for panic disorder and suggests larger r and omized controlled study is warranted Panic disorder , which is found in about 1.5 percent of the population at some time in their lives , includes recurrent episodes of sudden , unpredictable , intense fear accompanied by symptoms such as palpitations , chest pain , and faintness . Panic attacks , which do not meet these diagnostic criteria fully , are two to three times more prevalent . Since panic symptoms can mimic those of other medical disorders , patients with these symptoms use medical services frequently . To determine the risk of suicidal ideation and suicide attempts in panic disorder and attacks , we studied a r and om sample of 18,011 adults drawn from five U.S. communities . Subjects who had panic disorder , as compared with other psychiatric disorders , had more suicidal ideation and suicide attempts , with an adjusted odds ratio for suicide attempts of 2.62 ( 95 percent confidence interval , 1.83 to 3.74 ) . The odds ratio was 17.99 ( 95 percent confidence interval , 12.18 to 26.58 ) when the group with panic disorder was compared with subjects who had no psychiatric disorder . Twenty percent of the subjects with panic disorder and 12 percent of those with panic attacks had made suicide attempts . These results could not be explained by the coexistence of major depression or of alcohol or drug abuse . We conclude that panic disorder and attacks are associated with an increased risk of suicidal ideation and suicide attempts . Physicians working in general medical setting s and emergency departments should be alert to this problem OBJECTIVE The purpose of this study was to examine the use of benzodiazepines ( BZs ) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors ( SSRIs/SNRIs ) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia , social phobia , or generalized anxiety disorder . SETTING AND PARTICIPANTS Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project ( HARP ) . HARP is a naturalistic , longitudinal , multisite study of adults with anxiety disorders who are recruited from psychiatric setting s. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis . DESIGN The authors examined patterns of medication use ( BZs and SSRIs/SNRIs ) in participants with anxiety disorders as they aged , by assessing the proportion of participants taking these medications using generalized estimating equation modeling . MEASUREMENTS The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Third Edition-R Non-Affective Disorder , Patient Version , Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime , and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis . RESULTS Findings showed that rates of BZ use were high among both the older ( 53 % at baseline ) and the younger ( 57.4 % ) age groups and did not significantly decrease over time , after controlling for time in episode of their anxiety disorders . There was a statistically significant increase in  SSRI/SNRI use over time in both groups . At the beginning of the study , 18 % of the older group and 21 % of the younger group were using SSRIs/SNRIs ; however , at the end of the study , the rates increased to 35 % and 43 % , respectively . CONCLUSIONS Although there was an increase in  SSRI/SNRI use in older participants with anxiety disorders over the course of study , at nine years of follow-up , only 35 % of participants were utilizing SSRI/SNRI medication , while more than one-half of the same participants were continuing to use BZs . To the authors ' knowledge , there are no r and omized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population . However , there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older population To date , no large-scale , controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported . This double-blind study compares the efficacy of venlafaxine extended-release ( ER ) and paroxetine with placebo . A total of 664 nondepressed adult out patients who met DSM-IV criteria for panic disorder ( with or without agoraphobia ) were r and omly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER ( 75 mg/day or 150 mg/day ) , or paroxetine 40 mg/day . The primary measure was the percentage of patients free from full-symptom panic attacks , assessed with the Panic and Anticipatory Anxiety Scale ( PAAS ) . Secondary measures included the Panic Disorder Severity Scale , Clinical Global Impressions -- Severity ( CGI-S ) and --Improvement ( CGI-I ) scales ; response ( CGI-I rating of very much improved or much improved ) , remission ( CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks ) ; and measures of depression , anxiety , phobic fear and avoidance , anticipatory anxiety , functioning , and quality of life . Intent-to-treat , last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo . No significant differences were observed between active treatment groups . Panic-free rates at end point with active treatment ranged from 54 % to 61 % , compared with 35 % for placebo . Approximately 75 % of patients given active treatment were responders , and nearly 45 % achieved remission . The placebo response rate was slightly above 55 % , with remission near 25 % . Adverse events were mild or moderate and similar between active treatment groups . Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder OBJECTIVE This study was design ed to examine the possibility that patients with panic disorder are especially vulnerable to alprazolam withdrawal , as well as to evaluate the efficacy of carbamazepine as adjunctive treatment during alprazolam discontinuation . METHOD After a 2-month open trial of alprazolam , 36 patients with panic disorder and 35 with generalized anxiety disorder entered a controlled discontinuation phase .  Carbamazepine or placebo was added in a r and omized , double-blind fashion , followed after 1 week by single-blind dose reduction of alprazolam , approximately 25 % every third day . RESULTS Fifty-two percent of the patients were able to discontinue alprazolam , but only 37 % completed the study , maintaining alprazolam-free status for 4 weeks . Survival analysis revealed that among the patients receiving placebo as adjunctive therapy , panic disorder patients had a significantly greater dropout rate than patients with generalized anxiety disorder . While carbamazepine exerted no beneficial effect for patients with generalized anxiety disorder , it appeared to improve outcome in the panic disorder group . CONCLUSIONS Results of this study indicate that panic disorder patients are more vulnerable to alprazolam withdrawal than patients with generalized anxiety disorder , and this may reflect a general diathesis of panic disorder patients to encounter more difficulty during drug withdrawal . Carbamazepine may selectively assist with alprazolam withdrawal in panic disorder patients . However , these data do not support its widespread use during benzodiazepine discontinuation , especially given its potential toxicity . In light of a proposed greater vulnerability of panic disorder patients to withdrawal , future studies need to account for differential effects related to specific diagnosis BACKGROUND Panic disorder ( PD ) is generally regarded as a chronic condition with considerable variation in severity of symptoms . AIMS To describe the long-term outcome of naturalistically treated PD . METHODS Fifty-five out patients with PD , who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study . RESULTS Complete recovery ( no panic attacks and no longer on medication during the last 10 years ) was seen in 18 % of patients , and an additional 13 % recovered but were still on medication . Fifty-one percent experienced recurrent anxiety attacks whereas 18 % still met diagnostic criteria for PD . The incidence of agoraphobia decreased from 69 % to 20 % . Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission , although both groups reported improved daily functioning at follow-up . Maintenance medication was common . No benzodiazepine abuse was reported . CONCLUSION PD has a favourable outcome in a substantial proportion of patients . However , the illness is chronic and needs treatment . The short-term treatment given in the drug trial had no influence on the long-term outcome Thirty-six patients with generalised anxiety disorder , panic disorder or agoraphobia with panic attacks , diagnosed by DSM-III criteria , were treated with a new non-benzodiazepine anti-anxiety drug , buspirone , and with diazepam and placebo , in a cross-over design . Each patient took buspirone , diazepam and placebo for one week each in flexible dosage and balanced order . Ratings of symptomatology using the Comprehensive Psychopathological Rating Scale were made after each week 's treatment and a sub-scale used for measuring anxiety change alone was used separately . There was no overall difference in efficacy between the drugs , but when the scores for individual symptoms were analysed , diazepam was significantly superior to the other treatments for the symptom of muscle tension only . The results suggest that the common practice of giving short-term therapy with tranquilising drugs for anxiety in primary care is pharmacologically suspect The response to diazepam and propranolol hydrochloride was compared in 21 patients who ( with one exception ) met DSM-III criteria for panic disorder and agoraphobia . Each drug was administered for two weeks in double-blind fashion according to a crossover design . The response to diazepam was significantly superior on all measures . By observer rating , 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol .  Panic attacks and phobic symptoms responded to diazepam , but not to propranolol . The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders Ten long-term users of benzodiazepines ( average daily dose , 20 mg of diazepam or equivalent ) who had experienced problems in withdrawing from the drugs were given an i.v . challenge with either the benzodiazepine antagonist flumazenil ( 1 mg injected over 30 s ) or placebo ( vehicle solution ) in a r and omized double-blind design . There were no ' pseudo withdrawal ' responses to either single-blind or double-blind placebo injections , whereas flumazenil produced dramatic panic reactions in all four subjects tested , followed by characteristic benzodiazepine withdrawal symptoms . There were also small but significant rises in pulse rate and blood pressure , but no change in serum cortisol .  Flumazenil-induced panic could not be entirely accounted for by a past or present diagnosis of panic disorder , and did not seem to be related to previous withdrawal problems , present benzodiazepine dosage , or to the severity of withdrawal symptoms precipitated by flumazenil in the same challenge test . Attempts to reduce  benzodiazepine intake over the next 3 weeks tended to be more successful in the flumazenil group . The results are discussed with reference to possible changes in the GABA-benzodiazepine system in long-term benzodiazepine users 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 OBJECTIVE The purpose of this study was to compare the effects of discontinuing treatment with intermediate- and long-acting benzodiazepines . METHOD Fifty patients with panic disorder who had taken part in a double-blind treatment study and had responded to alprazolam , diazepam , or placebo for 8 months were asked to stop taking these medications gradually . RESULTS After a relatively rapid dose reduction , the majority of patients relapsed . Rebound anxiety and withdrawal symptoms were identified in a substantial minority of patients . Those who were taking alprazolam showed earlier and more intense rebound anxiety and withdrawal symptoms than did the patients who received diazepam . Both the level of pretreatment anxiety and the drug the patient was taking predicted the level of anxiety when drug treatment was discontinued . CONCLUSIONS The findings indicate that withdrawal phenomena commonly occur after patients stop taking benzodiazepines and that they are more frequent after discontinuation of treatment with shorter-acting drugs High-potency benzodiazepines , such as clonazepam , are frequently used in the treatment of panic disorder ( PD ) because of their rapid onset of action and good tolerability . However , there is concern about their potential to cause withdrawal symptoms . We aim ed to develop a protocol for safely tapering off clonazepam in patients with PD who had been receiving treatment for at least 3 years . A specific scale for judging withdrawal was also developed , the Composite Benzodiazepine Discontinuation Symptom Scale . We selected 73 patients with PD who had been asymptomatic for at least 1 year and who wished to discontinue the medication . The trial consisted of a 4-month period of tapering and an 8-month follow-up period . The dosage of clonazepam was decreased by 0.5 mg per 2-week period until 1 mg per day was reached , followed by a decrease of 0.25 mg per week . The mean dosage at the start of tapering was 2.7 ± 1.2 mg/d . In total , 51 ( 68.9 % ) of the patients were free of the medication after the 4 months of tapering according to the protocol , and 19 ( 26.0 % ) of the patients needed another 3 months to be free of  medication . Clonazepam discontinuation symptoms were mostly mild and included mainly : anxiety , shaking/trembling/tremor , nausea/vomiting , insomnia/nightmares , excessive sweating , tachycardia/palpitations , headache , weakness , and muscle aches . The improvement in PD and general well-being was maintained during both the taper and follow-up phases . Clonazepam can be successfully discontinued without any major withdrawal symptoms if the dose is reduced gradually . We recommend reducing the dosage of clonazepam after intermediate-term use by 0.25 mg/wk BACKGROUND The widespread use of benzodiazepines has led to increasing recognition of their unwanted effects . The efficacy of alprazolam and placebo in panic disorder with agoraphobia , and the side-effect and adverse effect profiles of both drug groups were measured . METHOD In London and Toronto 154 patients who met DSM-III criteria for panic disorder with agoraphobia were r and omised to alprazolam or placebo .  Subjects in each drug group also received either exposure or relaxation . Treatment was from weeks 0 to 8 and was then tapered from weeks 8 to 16 . RESULTS Mean alprazolam dose was 5 mg daily . Compared with placebo subjects , alprazolam patients developed more adverse reactions ( 21 % v. 0 % ) of depression , enuresis , disinhibition and aggression ; and more side-effects , particularly sedation , irritability , impaired memory , weight loss and ataxia . Side-effects tended to diminish during treatment but remained significant at week 8 . Despite this , the drop-out rate was low . CONCLUSIONS Alprazolam caused side-effects and adverse effects during treatment but many patients were willing to accept these Pagoclone is a cyclopyrrolone that is believed to act as a partial agonist at the γ-aminobutyric acid ( GABA ) A/benzodiazepine ( BDZ ) receptor . In theory , such partial agonists should be anxiolytic but lack the adverse side-effects of sedation , tolerance and withdrawal associated with full GABA-A/BDZ agonists . The objective of the r and omized double-blind crossover study was to assess whether pagoclone was an effective anti-panic agent and also to assess its side-effect profile . Patients recruited had a diagnosis of Panic Disorder ( DSM-IV ) with at least one panic attack per week . Following a 2-week screening period , patients entered a 6-week trial consisting of two 2-week treatment periods , each followed by a 1-week washout . Patients were r and omly assigned to receive either pagoclone 0.1 mg t.d.s . or placebo on their first treatment period and the converse on their second . The primary measure was daily panic attack dairy . Fourteen patients completed the study , the mean number of panic attacks during screening was 5.8 ± 0.8 ( SEM ) , this fell to 3.6 ± 0.5 during treatment with pagoclone ( p = 0.05 ) and 4.3 ± 0.8 with placebo ( p = 0.14 ) . There was no significant difference on direct comparison of pagoclone with placebo or in any of the secondary measures ( including Rickels withdrawal scale ) or the adverse event profiles . The study provides preliminary evidence that pagoclone has anxiolytic properties in the absence of typical BDZ side-effects . This is consistent with its theoretical mode of action as a partial agonist at the GABAA/BDZ receptor BACKGROUND Although serotonin reuptake inhibitors are effective in panic disorder , questions concerning whether doses associated with antidepressant efficacy are also effective for panic disorder remain . AIMS To assess the efficacy of the usual antidepressant dose of fluoxetine in treating full panic attacks . METHOD Patients with panic disorder were r and omised to placebo or to fluoxetine initiated at 10 mg daily for 1 week and then increased to 20 mg daily . The trial lasted 12 weeks , but after 6 weeks patients who had failed to achieve a satisfactory response were eligible for dose escalation to a maximum of 60 mg of fluoxetine daily . RESULTS Fluoxetine was associated with a statistically significantly greater proportion of panic-free patients compared with placebo after 6 weeks and at end-point . CONCLUSIONS Fluoxetine at a dose of 20 mg daily is safe and efficacious in reducing symptoms of panic disorder . Patients who fail to obtain a satisfactory response at 20 mg daily may benefit from further dose increases Panic disorder ( PD ) is an acute psychobiologic reaction manifested by intense anxiety and panic attacks , that occur unpredictably with subjective sense of intense apprehension or terror , accompanied by temporary loss of the ability to plan , think , or reason and the intense desire to escape or flee the situation . Panic attacks may last from a few seconds to an hour or longer . Symptoms typically include , among others , palpitations , tachycardia , hypertension , chest pain , dyspnoea , and fear of loosing control or going crazy and vague feeling of imminent doom or death . Since pharmacotherapy of PD includes the administration of selective serotonin reuptake inhibitors and tricyclic antidepressants , the objective of this study was to perform a pilot double blind clinical trial design ed to compare the effects of two studied drugs in the treatment of PD . A total number of 40 patients with a history of panic disorder were r and omly assigned into two groups of 20 patients each . Hamilton anxiety rating scale and St and ard Psychiatric Interview were methods for PD assessment . One group was treated with clomipramine hydrochloride ( ANAFRANIL ) 75 mg/day and the other with fluoxetine ( OXETIN ) 60 mg/day . Both drugs were administrated by mouth ( PO ) two times-a-day in equally divided doses for 6 weeks . Both studied agents produced similar antipanic effectiveness . Favourable response was achieved in 95 % of patients treated with fluoxetine and 90 % of patients treated with clomipramine . The onset of antipanic effects was quicker in all clomipramine treated patients , while fluoxetine produced more-favourable response in male patients . The duration of treatment with both antidepressants studied should be at least 10 weeks , instead of 6 weeks Objective The present study examined the prevalence of  panic disorder  with or without agoraphobia according to DSM-IV criteria in the Swedish general population . Method Data were obtained by means of a postal survey administrated to 1000 r and omly selected adults . The panic disorder module of the World Health Organization 's Composite International Diagnostic Interview ( CIDI ) was included in the survey . Results 12-month prevalence was estimated at 2.2 % ( CI 95 % 1.02 % – 3.38 % ) . There was a significant sex difference , with a greater prevalence for women ( 5.6 % ) compared to men ( 1 % ) . Conclusion The Swedish panic disorder prevalence is relatively consistent with findings in most other parts of the western world BACKGROUND Interpersonal psychotherapy ( IPT ) seems to be as effective as cognitive behavioral therapy ( CBT ) in the treatment of major depression . Because the onset of panic attacks is often related to increased interpersonal life stress , IPT has the potential to also treat panic disorder . To date , a preliminary open trial yielded promising results but there have been no r and omized controlled trials directly comparing CBT and IPT for panic disorder . METHOD This study aim ed to directly compare the effects of CBT versus IPT for the treatment of panic disorder with agoraphobia . Ninety-one adult patients with a primary diagnosis of DSM-III or DSM-IV panic disorder with agoraphobia were r and omized . Primary outcomes were panic attack frequency and an idiosyncratic behavioral test . Secondary outcomes were panic and agoraphobia severity , panic-related cognitions , interpersonal functioning and general psychopathology . Measures were taken at 0 , 3 and 4 months ( baseline , end of treatment and follow-up ) . RESULTS Intention-to-treat ( ITT ) analyses on the primary outcomes indicated superior effects for CBT in treating panic disorder with agoraphobia . Per- protocol analyses emphasized the differences between treatments and yielded larger effect sizes . Reductions in the secondary outcomes were equal for both treatments , except for agoraphobic complaints and behavior and the credibility ratings of negative interpretations of bodily sensations , all of which decreased more in CBT . CONCLUSIONS CBT is the preferred treatment for panic disorder with agoraphobia compared to IPT . Mechanisms of change should be investigated further , along with long-term outcomes Selective serotonin re-uptake inhibitors ( SSRIs ) and cognitive behavioral therapies ( CBTs ) are both considered as first-line treatments for panic disorder , but the advantages of a combined therapy have yet to be definitively demonstrated . We evaluated in this pilot study the effects of combining SSRIs ( vs. a placebo ) with a very brief form of cognitive-behavioral therapy provided to all participants . Thirty-three subjects with DSM-IV panic disorder , with or without agoraphobia , were r and omized to receive either paroxetine or a placebo with flexible dosing ( 10 - 50 mg/day ) . Medication visits were brief ( 15 min ) , infrequent ( 6 in total ) and non-directive . An expert cognitive-behavior therapist administered one initial 45-min session and one subsequent 30-min session of very brief CBT ( vbCBT ) at weeks 5 and 7 , respectively . Sessions were supplemented with educational and directive reading material s. Patients in both groups ( i.e. vbCBT+paroxetine ; vbCBT+placebo ) improved similarly and substantially on most measures during the 10 weeks of acute treatment . At week 10 , the proportion of panic-free patients was significantly higher in the paroxetine-treated group than in the placebo group ( 80 vs. 25 % ; P<0.007 ) , as was the proportion of subjects who rated themselves as ' very much improved ' at week 10 ( 60 vs. 13 % ; P<0.017 ) . These findings point to the need for additional studies to confirm the effectiveness of very brief forms of CBT , and to document the circumstances in which combined treatment with an SSRI would be warranted BACKGROUND A new 13-item scale has been developed for measuring severity of illness in patients with panic disorder and agoraphobia , the Panic and Agoraphobia Scale ( P & A ) . The scale has five subscales covering the main factors that reduce quality of life in panic disorder patients ( panic attacks , avoidance , anticipatory anxiety , disability and worries about health ) . The application of this scale in a double-blind placebo-controlled panic disorder trial is described . At the same time , the aim of the study was to compare the therapeutic effects of aerobic exercise with a treatment of well-documented efficacy . METHODS Patients with Panic disorder ( DSM-IV ) were r and omly assigned to three treatment modalities : running ( n=45 ) , clomipramine ( n=15 ) or placebo ( n=15 ) . Treatment efficacy was measured with the Panic and Agoraphobia Scale ( P & A ) and other rating scales . RESULTS According to the P & A and other scales , both exercise and clomipramine led to a significant decrease of symptoms in comparison to placebo treatment . Clomipramine was significantly more effective and improved anxiety symptoms significantly earlier than exercise . The evaluation of the P & A subscales revealed that exercise exerted its effect mainly reducing anticipatory anxiew and panic-related disability . CONCLUSIONS The new Panic and Agoraphobia Scale was shown to be sensitive to differences between different panic treatments . Analysis of the scales five subscores may help to underst and mechanisms of action of panic disorder treatments OBJECTIVE The concept of fearful spells ( FS ) denotes distressing spells of anxiety that might or might not qualify for criteria of panic attacks ( PA ) . Few studies examined prospect ive-longitudinal associations of FS not meeting criteria for PA with the subsequent onset of mental disorders to clarify the role of FS as risk markers of psychopathology . METHOD A representative community sample of adolescents and young adults ( N = 3021 , age 14 - 24 at baseline ) was prospect ively followed up in up to 3 assessment waves over up to 10 years .  FS , PA , anxiety , depressive , and substance use disorders were assessed using the DSM-IV/M-CIDI . Odds Ratios ( OR ) from logistic regressions were used to examine the predictive value of  FS-only ( no PA ) and PA at baseline for incident disorders at follow-up . RESULTS In logistic regressions adjusted for sex and age , FS-only predicted the onset of any subsequent disorder , any anxiety disorder , panic disorder , agoraphobia , GAD , social phobia , any depressive disorder , major depression , and dysthymia ( ORs 1.54 - 4.36 ) ; PA predicted the onset of any anxiety disorder , panic disorder , GAD , social phobia , any depressive disorder , major depression , dysthymia , any substance use disorder , alcohol abuse/dependence , and nicotine dependence ( ORs 2.08 - 8.75 ; reference group : No FS-only and no PA ) . Associations with psychopathology were slightly smaller for FS-only than for PA , however , differences in associations ( PA compared to FS-only ) only reached significance for any anxiety disorder ( OR = 3.26 ) and alcohol abuse/dependence ( OR = 2.26 ) . CONCLUSIONS Findings suggest that compared to PA , FS-only have similar predictive properties regarding subsequent psychopathology and might be useful for an early identification of high-risk individuals This article focuses on social morbidity and health care utilization in persons with panic attacks not meeting full diagnostic criteria for panic disorder . The findings are based on data from a r and om sample of over 18,000 adults drawn from five US communities . Panic attacks not meeting full criteria for panic disorder have a relatively high lifetime prevalence ( 3.6 % of the adult population ) . Persons with panic attacks had impairment in perceived physical and emotional health , and in occupational and financial functioning , increased use of health care facilities , emergency departments , and psychoactive drugs . Persons with panic attacks were intermediate in severity between those with panic disorder and those with other psychiatric disorders . The findings could not be explained by comorbidity with other psychiatric disorders . We conclude that panic attacks have clinical significance and are associated with substantial morbidity OBJECTIVE Evidence from pre clinical and clinical studies suggests a role for alterations in the benzodiazepine/GABAA receptor complex in stress and anxiety .  Flumazenil is a relatively pure benzodiazepine/GABAA antagonist with limited intrinsic activity . In panic disorder patients , but not healthy controls , flumazenil has been demonstrated to provoke panic attacks . METHOD Vietnam combat veterans with PTSD ( n = 14 ) received 90-second intravenous infusions of flumazenil 2 mg or placebo in a double-blind , crossover study design . PTSD symptomology was assessed using the PTSD Symptom Scale , and anxiety symptoms were measured with visual analogue rating scales . RESULTS There was no significant difference in PTSD and anxiety symptoms between administration of flumazenil and placebo . CONCLUSION Flumazenil administration does not produce an increase in anxiety and PTSD symptoms in patients with PTSD . This suggests that PTSD and panic disorder are dissimilar in terms of benzodiazepine/GABAA system function 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 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 Mirtazapine is an antidepressant whose side effect profile differs from that of first-line agents ( selective serotonin reuptake inhibitors ) used in the treatment of panic disorder . The present study compared the effect of mirtazapine and fluoxetine in the treatment of panic disorder in a double-blind , r and omized , flexible-dose trial conducted with out patients . After a 1-week single-blind placebo run-in , 27 patients entered an 8-week double-blind phase in which they were r and omly assigned to treatment with either mirtazapine or fluoxetine . Both groups improved significantly in all but one efficacy measure ( P < or = 0.01 ) . ANOVA showed no significant differences between the two treatment groups in number of panic attacks , Hamilton Anxiety Scale or Sheehan Phobic Scale , whereas measures of patient global evaluation of phobic anxiety were significantly different between groups ( F1,20 = 6.91 , P = 0.016 ) favoring mirtazapine . For the 22 patients who completed the study , the mean daily dose of mirtazapine was 18.3 + /- 1.3 vs 14.0 + /- 1.0 mg for fluoxetine at the endpoint . Weight gain occurred more frequently in the mirtazapine group ( 50 vs 7.7 % , P = 0.04 ) and nausea and paresthesia occurred more often in the fluoxetine group ( P = 0.01 ) . Results suggest that mirtazapine has properties that make it attractive for the treatment of panic disorder Simultaneous coexistence of anxiety with depressive disorders is probably one of the major current problems in Medicine . The pharmacological approach for Panic Disorder and Major Depression includes " high-powered " benzodiazepines for the rapid , but transitory relief of same symptoms and especially antidepressant compounds . Recently physical-instrumental approaches have been tested for the treatment of these complex diseases , like Cranial Electrotherapy Stimulation ( CES ) , Trans-cranial Magnetic Stimulation ( TMS ) , and Radio Electric Asymmetric Treatment ( REAC ) . The REAC apparatus was design ed to deliver an alternate current of several hundred picoamperes for a time span of 0.5 seconds by means of a small metallic probe directly connected to the properly fabricated electronic circuit in an AC/RF generator with frequency of 2.4 , 5.8 or 10.5 GHz and power of 20 mW. Compared the efficacy of  REAC  and Es-Citalopram in the treatment of simultaneous coexistence of Panic Disorder with Major Depression in 9-weeks open label naturalistic study . After the 1st week , patients treated with  REAC therapy  showed a significant relief of depressive symptoms compared with Es-Citalopram .  For Panic Disorder ,  REAC treatment had more effective results than the drug especially after the 3rd week of observation . The REAC treatment obtained better results during the entire study , and its high safety and tolerability profile has been confirmed 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 Cognitive behavioral treatment ( CBT ) has been shown to reduce risk for adverse reactions ( e.g. , rebound panic ) following benzodiazepine taper for patients with panic disorder ( PD ) . This study evaluated the effects of antidepressant discontinuation for patients with PD in the context of CBT .  Patients with PD ( n=21 ) on a stable dose of antidepressants completed a 12-week group CBT treatment and were r and omly assigned to discontinue antidepressants during week 8 of the treatment . There were no statistically significant differences between groups at posttreatment or 6-month follow-up . Data indicate no apparent immediate or long-term adverse effects for antidepressant discontinuation for patients with PD receiving CBT 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 Fifty-five patients completed a 5-week double-blind study comparing alprazolam , propranolol , and placebo in the treatment of panic disorder and agoraphobia with panic attacks . There was no concomitant behavioral treatment . Patient and therapist rating scales included Sheehan 's Panic and Anxiety Attack Scales , the Marks-Sheehan Phobia Scale , the Hamilton Anxiety Scale , the Hamilton Depression Scale , and the Side Effects Checklist . The results generally support the efficacy of alprazolam , but not propranolol , in the treatment of panic disorder and agoraphobia with panic attacks . The significance of the results are discussed , as well as a number of the unique aspects of our procedures and patient population Objective : Several studies have documented that a variety of pharmacological compounds are quite effective in controlling acute symptomatology of panic disorder in the general population . However , there is a paucity of such studies in the management of  panic disorder in older adults ( ages 55 and above ) . The purpose of this study was to gather pilot data in older patients with panic disorder to begin to assess the efficacy of two commonly-used antipanic medications , imipramine and alprazolam . Method : Twenty-five ( n = 25 ( 23 females ; 2 males ) ; 18 completers , 7 dropouts ) older panic disorder ( DSM-III-R ) patients ( age range = 55–73 ; mean = 61.24 ) were studied in an eight-week r and omized , parallel-groups , double-blind , placebo-controlled , flexible dose design . Outcome was assessed weekly by global change ratings ( Hamilton Anxiety and Depression Scales ; Physicians ' Global Impression ratings ) and panic diaries . Because of small sample size , we present data descriptively . Results : Subjects in active medication groups evidence d reductions in panic attacks and in levels of overall anxiety and depression . Therapeutic dosages were approximately half those commonly used in younger panic disorder patients . Conclusion : Our data suggest the comparable efficacy of alprazolam and imipramine in the short-term treatment of older adults with panic disorder . There is clearly the need for a larger scale placebo-controlled study , preferably comparing imipramine and /or alprazolam with one of the SSRIs , to substantiate our findings 23 patients with a diagnosis of panic disorder with agoraphobia were r and omly assigned to 8 weeks ' treatment with alprazolam or placebo . They filled in self-ratings before and after treatment and competed on a competitive reaction time task , design ed to measure behavioural aggression , after 8 weeks ' treatment . Patients taking both alprazolam and placebo rated decreased anxiety after 8 weeks ' treatment but those on alprazolam also tended to report less hostility . On the behavioural task , patients on alprazolam behaved more aggressively in response to provocation . This is the first study to confirm clinical reports of benzodiazepine-induced dyscontrol on an objective laboratory measure . It is important that it is followed up in a larger group of patients The effects of a single inhalation of a 35 % CO2/65 % O2 gas mixture were examined in 71 patients with panic disorder with or without agoraphobia and 44 normal control subjects . Compared with the placebo condition , inhalation of air , the CO2/O2 mixture elicited a clear anxiety reaction only in panic disorder patients , who experienced a sudden rise of subjective anxiety as well as of several panic symptoms . Respiratory symptoms and the fear of dying best distinguished the patients from the control subjects . Baseline anxiety was not the key factor in explaining this differential reaction . The clinical features of panic disorder ( namely , frequency of panic attacks , agoraphobia , anticipatory anxiety , and duration of illness ) were not significantly related to the response to the challenge test , suggesting that CO2 reactivity might be a trait marker of panic disorder Urinary free cortisol ( UFC ) levels were measured at baseline and at four and eight weeks after initiation of treatment in 66 patients who met DSM-III-R criteria for primary panic disorder ( PD ) . Thirty-seven normal control subjects also had UFC levels  measured three times at monthly intervals . Patients were r and omly assigned to treatment with alprazolam , diazepam , or placebo . At baseline , complicated PD patients ( those with agoraphobia and secondary depression ) had significantly higher UFC levels than did normal controls . At four and eight weeks , complicated PD patients receiving alprazolam and diazepam had significant reductions in UFC excretion compared to baseline . Patients with uncomplicated PD maintained UFC levels comparable to controls at each sampling period . Treatment with benzodiazepines did not lower UFC levels in this group . These findings suggest that patients with complicated PD demonstrate hyperactivity of the hypothalamo-pituitary-adrenal axis that is decreased by treatment with benzodiazepines 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 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 OBJECTIVE The purpose of this comparative outcome study was to investigate whether the effects of exposure in vivo treatment for panic disorder with agoraphobia could be enhanced by adding interventions specifically for panic attacks before the start of exposure treatment . The additional effect of two types of treatment for panic attacks -- pharmacological ( fluvoxamine ) and psychological ( repeated hyperventilation provocations and respiratory training)--was examined . Thus , the combined treatment of panic interventions with exposure in vivo could be compared to exposure in vivo alone . METHOD Ninety-six patients were r and omly assigned to four treatment conditions : double-blind , placebo-controlled fluvoxamine followed by exposure in vivo , psychological panic management followed by exposure , and exposure in vivo alone . Outcome was assessed by self-report measures , a st and ardized multitask behavioral avoidance test , and continuous monitoring of panic attacks .  Seventy-six patients completed the study . RESULTS All four treatments were effective and result ed in a significant decrease of agoraphobic avoidance . Moreover , the combination of fluvoxamine and exposure in vivo demonstrated efficacy superior to that of the other treatments and had twice as large an effect size ( difference between pre- and posttreatment scores ) on self-reported agoraphobic avoidance . The other treatments did not differ among each other in effectiveness . CONCLUSIONS Results of the study indicate that the short-term outcome of exposure in vivo treatment can be enhanced by adding fluvoxamine treatment . Psychological panic management combined with exposure was not superior to exposure alone of equal duration OBJECTIVE To assess the efficacy and tolerability of controlled-release paroxetine ( paroxetine CR ) in the treatment of adults with panic disorder . METHOD  Paroxetine CR ( 25 - 75 mg/day ; N = 444 ) was compared with  placebo ( N = 445 ) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical , double-blind , placebo-controlled , 10-week clinical trials that were pooled for analysis . RESULTS Paroxetine CR was statistically superior to placebo in the primary outcome measure , percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint . Of the total population that completed or prematurely terminated treatment , 63 % and 53 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free during the final 2 weeks ( p < .005 ; odds ratio [ OR ] = 1.63 ; 95 % CI = 1.21 to 2.19 ) . For week 10 completers ( 72 % of total ) , 73 % and 60 % of paroxetine CR- and placebo-treated patients , respectively , were panic-free at week 10 ( p < .005 ; OR = 2.11 ; 95 % CI = 1.45 to 3.07 ) . Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale . Adverse events leading to study withdrawal were minimal and occurred in 11 % of the paroxetine CR group and 6 % of the placebo group . Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study . There were no unexpected adverse events , and serious adverse events were uncommon ( 10 [ 2.3 % ] of the 444 patients treated with paroxetine CR vs. 8 [ 1.8 % ] of the 445 patients treated with placebo ) . CONCLUSION Paroxetine CR is an effective and well-tolerated treatment for panic disorder . Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events BACKGROUND Venlafaxine extended-release ( ER ) has proven efficacy in the treatment of anxiety symptoms in major depression , generalised anxiety disorder and social anxiety disorder . AIMS To evaluate the efficacy , safety and tolerability of venlafaxine ER in treating panic disorder . METHOD Adult out- patients ( n=361 ) with panic disorder were r and omly assigned to receive venlafaxine ER ( 75 - 225 mg/day ) or placebo for up to 10 weeks in a double-blind study . RESULTS Venlafaxine ER was not associated with a greater proportion of patients free from full-symptom panic attacks at the final on-therapy evaluation , but was associated with lower mean panic attack frequency and a higher proportion free from limited-symptom panic attacks , higher response and remission rates , and improvements in anticipatory anxiety , fear and avoidance . Adverse events were comparable with those of the drug in depression and anxiety disorders . CONCLUSIONS Venlafaxine ER seems to be effective and well tolerated in the short-term treatment of panic disorder OBJECTIVE Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessment s are unreliable , studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement . The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement . METHOD Patients with a diagnosis of panic disorder ( N = 243 ) were r and omly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo . Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores . Other assessment s included a panic attack inventory , clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale , a phobia rating scale , the Hamilton Anxiety Rating Scale , the 21-item Hamilton Depression Rating Scale , and the Sheehan Disability Scale . Correlations were determined between outcomes in individual symptom domains and overall clinical outcome . RESULTS Fluoxetine , particularly the 20-mg/day dose , was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures , including global improvement , total panic attack frequency , phobic symptoms , and functional impairment . Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks .  Fluoxetine treatment for panic disorder was well tolerated , with a safety profile consistent with that observed for fluoxetine in other disorders . CONCLUSIONS These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks , phobic symptoms , anxiety , and depressive symptoms in patients with panic disorder . Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance , anxiety , depressive symptoms , and functional impairment , suggesting that outcome measures in this disorder should be more broadly based OBJECTIVE To assess the effectiveness of clonazepam , in a fixed dose ( 2 mg/day ) , compared with placebo in the treatment of panic disorder patients . METHOD 24 panic disorder patients with agoraphobia were r and omly selected . The diagnosis was obtained using the structured clinical interview for DSM-IV . All twenty-four subjects were r and omly assigned to either treatment with clonazepam ( 2 mg/day ) or placebo , during 6 weeks . Efficacy assessment s included : change from baseline in the number of panic attacks ; CGI scores for panic disorder ; Hamilton rating scale for anxiety ; and panic associated symptoms scale . RESULTS At the therapeutic endpoint , only one of 9 placebo patients ( 11.1 % ) were free of panic attacks , compared with 8 of 13 ( 61.5 % ) clonazepam patients ( Fisher exact test ; p=0,031 ) . CONCLUSION the results provide evidence for the efficacy of clonazepam in panic disorder patients BACKGROUND Citalopram is a serotonin reuptake inhibitor which has been demonstrated to be highly selective and with a superior tolerability profile to the classical tricyclic antidepressants . This study was design ed to test whether there was any difference in efficacy in the management of panic disorder ( PD ) between citalopram and placebo . METHOD This was a double-blind , placebo and clomipramine controlled , parallel group eight-week study . A total of 475 patients with PD , with or without agoraphobia , were r and omised to treatment with either placebo , clomipramine 60 or 90 mg/day , or citalopram 10 or 15 mg/day , or 20 or 30 mg/day , or 40 or 60 mg/day . Doses were increased over the first three weeks , stabilised during the fourth week and fixed between weeks five and eight . RESULTS Treatment with citalopram at 20 or 30 mg , 40 or 60 mg and clomipramine were significantly superior to placebo , judged by the number of patients free of panic attacks in the week prior to the final assessment . All rating scales examined suggested that citalopram 20 or 30 mg was more effective than citalopram 40 or 60 mg . CONCLUSION The most advantageous benefit/risk ratio for the treatment of PD was associated with citalopram 20 or 30 mg/day Pretreatment with imipramine , buspirone , or placebo was compared in 40 patients meeting the Diagnostic and Statistical Manual of Mental Disorders , Revised Third Edition criteria for panic disorder and in patients who were discontinuing long-term benzodiazepine use . The average duration of benzodiazepine use was 75 ± 64 months , and the average benzodiazepine intake expressed as diazepam equivalents was 25.7 ± 19 mg/d . We hypothesized that pretreatment with either imipramine or buspirone , in contrast to pretreatment with placebo , would lead to a significant decrease of symptoms of anxiety and depression before tapering benzodiazepines , thus making the taper process easier to complete . All 3 treatments ( imipramine , buspirone , and placebo ) caused a reduction in anxiety and depression symptoms as measured by changes in the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale . Neither discontinuation severity nor taper-free status 12 weeks posttaper differed between the 3 treatment groups The present study examined the efficacy of an 8-wk , cognitive-behavioral group treatment for panic disorder . Patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia were r and omly assigned to treatment ( N = 34 ) or delayed treatment control ( N = 33 ) . The treatment consisted of : ( a ) education and corrective information ; ( b ) cognitive therapy ; ( c ) training in diaphragmatic breathing ; and ( d ) interoceptive exposure . At posttreatment , 85 % of treated Ss were panic free , compared to 30 % of controls . Treated Ss also showed clinical ly significant improvement on indices of anxiety , agoraphobia , depression and fear of fear . Recovery , as estimated conservatively by the attainment of normal levels of functioning on each of the major clinical dimensions of the disorder ( i.e. panic , anxiety and avoidance ) , was achieved in 64 % of the treated Ss and 9 % of the controls . At the 6 month follow-up , 63 % of the treated patients met criteria for recovery . These findings mirror those from recently-completed trials of individually-administered cognitive-behavioral treatment , and suggest that CBT is a viable alternative to pharmacotherapy in the treatment of panic disorder Several reports suggest that selective serotonin reuptake blockers are helpful in the treatment of panic disorder . The aim of the study was to compare fluvoxamine with placebo in 50 panic disorder patients by using an 8-week , double-blind , parallel-groups design . Weekly assessment included a panic attack diary ( frequency and severity ) , the Montgomery-Asberg Depression Scale , the Clinical Anxiety Scale , and the Sheehan Disability Scale . Although both groups improved on all measures , the fluvoxamine group experienced significantly less frequent major panic attacks from the third week on and significantly lower ratings on anxiety , depression , and disability from the sixth week on . Mean ratings of the severity of major and the severity and frequency of minor attacks were not affected differently by fluvoxamine and placebo . At the end of the study , significantly more patients on fluvoxamine were free of major and minor panic attacks . The results indicate that : ( 1 ) the administration of fluvoxamine , as compared with placebo , led to a significant reduction in the number of panic attacks . ( 2 ) The severity of panic attacks was not affected by fluvoxamine . ( 3 ) The effect of fluvoxamine on anxiety , depressive mood , and disability differed from placebo only after 6 weeks of treatment , after which the placebo group showed either no further improvement or a reversal of symptoms . ( 4 ) Participation in a drug study , even without additional psychotherapy , led to significant improvement in all patients RATIONALE Few r and omized , placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder . OBJECTIVES The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release ( ER ) with placebo in treating panic disorder . Secondary objectives included comparing paroxetine with venlafaxine ER and placebo . METHODS Out patients aged > or = 18 years ( placebo , n = 157 ; venlafaxine ER 75 mg , n = 156 ; venlafaxine ER 225 mg , n = 160 ; paroxetine , n = 151 ) , with a primary diagnosis of panic disorder ( + /-agoraphobia ) based on the Diagnostic and Statistical Manual of Mental Disorders ( Fourth Edition ) criteria for > or =3 months were r and omly assigned to receive venlafaxine ER ( titrated to 75 mg/day or 225 mg/day ) , paroxetine ( titrated to 40 mg/day ) , or placebo for 12 weeks . The primary efficacy measure was the percentage of patients free of full-symptom panic attacks ( > or = four symptoms ) at endpoint . Key secondary outcomes included the Panic Disorder Severity Scale ( PDSS ) mean score change and response . RESULTS At endpoint , all active treatment groups showed a significantly ( P < 0.01 ) greater proportion of patients free of full-symptom panic attacks , compared with placebo , and were superior ( P < 0.05 ) on most secondary measures . The venlafaxine ER 225 mg group had significantly ( P < 0.05 ) greater mean PDSS score improvement than the paroxetine group ( -12.58 vs -11.87 ) and a significantly higher proportion of patients free of full symptom panic attacks ( 70.0 vs 58.3 % ) . Both drugs were generally well tolerated . CONCLUSION Venlafaxine ER 75 mg/days and 225 mg/days and paroxetine 40 mg/day were both well tolerated and effective for short-term treatment of panic disorder In order to evaluate serotonin ( 5-HT ) function in panic disorder , a double blind placebo controlled study was conducted with ritanserin , a specific 5-HT2 receptor antagonist , and fluvoxamine , a selective 5-HT reuptake inhibitor , in 60 patients with panic disorder . Patients were treated for 8 weeks with 150 mg fluvoxamine , 20 mg ritanserin or placebo ; these dose levels were reached after 1 week . In addition , as an index of 5-HT function in panic disorder , plasma concentration of β-endorphin , cortisol and 5-hydroxyindolacetic-acid ( 5-HIAA ) were measured . Furthermore , 5-HT uptake in blood platelets was assessed . Noradrenergic function was assessed by measuring plasma MHPG concentration . In addition , plasma melatonin concentration was measured . Treatment with fluvoxamine result ed in a profound reduction in the number of panic attacks , followed by a decrease in avoidance behavior . Treatment with ritanserin appeared to be ineffective . During treatment no significant changes were observed in plasma concentrations of β-endorphin , cortisol , 5-HIAA and MHPG . With respect to 5-HT kinetics in blood platelets , a substantial increase in Km was observed after treatment with fluvoxamine , whereas Vmax decreased . After treatment with fluvoxamine , plasma concentration of melatonin was significantly increased , which suggests that melatonin synthesis is in part under serotonergic control . The findings of the present study do not support the hypothesis that 5-HT2 receptors are supersensitive in patients suffering from panic disorder , but allow no conclusions about the involvement of other 5-HT receptor subtypes 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 The pharmacokinetics and pharmacodynamics of the benzodiazepine alprazolam ( 1 mg , administered orally ) were compared between eight patients with panic disorder and eight age- and sex-matched healthy volunteers . Subjects received orally administered placebo and alprazolam in a r and omized , double-blind , single-dose crossover study . The elimination half-life , time of maximum plasma concentration , maximum concentration , volume of distribution , and clearance of alprazolam were similar for both groups . For each cohort , alprazolam treatment ( vs. placebo ) produced significant changes in typical benzodiazepine agonist effects , such as increased sedation and impaired cognitive performance on the digit-symbol substitution test . For the panic disorder group only , there was a significant increase in the subjective rating of"contented " and a reduction in the rating of " easily irritated . " For the healthy volunteer group , alprazolam produced increases in ratings of " fatigued " and " slowed thinking , " but also increases in ratings of " relaxed . " In each group , alprazolam significantly increased the electroencephalographic ( EEG ) measure of relative beta amplitude ( range , 13 - 30 Hz ) compared with placebo .  Concentration-EEG response curves fit a sigmoid E(max ) model , and there was greater sensitivity to EEG effects , as measured by a 28 % reduction in the EC50 value , in the panic disorder group compared with healthy control subjects . After alprazolam treatment , there was increased sensitivity to EEG and mood effects and fewer aversive effects in the panic disorder group compared with healthy subjects . There were no differences in the pharmacodynamic measures of sedation and cognition or differences in pharmacokinetics between the two groups OBJECTIVE To examine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of patients with panic disorder . METHOD In an open-label , fixed-flexible dose study , 18 patients with panic disorder with or without agoraphobia ( DSM-IV diagnostic criteria ) were treated with levetiracetam for 12 weeks . Outcome was assessed with st and ard rating instruments ( Clinical Global Impressions-Severity of Illness scale [ CGI-S ] , Clinical Global Impressions-Improvement scale [ CGI-I ] , and the 14-item Hamilton Rating Scale for Anxiety [ HAM-A ] ) and by the number of panic attacks during the previous week . The study was conducted in 2 outpatient clinics in New York City from January 2004 through July 2005 . RESULTS Of the 13 patients completing the study , 11 were rated " very much " or " much " improved on the CGI-I. Panic attack frequency , anxiety ( HAM-A ) , and global severity ( CGI-S ) ratings also demonstrated significant improvement ( all p < .00 ) . For most patients , clinical benefits were apparent after only 1 to 2 weeks of treatment . Levetiracetam was well tolerated with minimal side effects . CONCLUSION Given its favorable pharmacokinetics , side effect profile , and , if confirmed , early onset of action and efficacy , levetiracetam might represent significant progress in the pharmacologic management of panic disorder An international , multicentre , double blind parallel group study compared the tolerability and efficacy of moclobemide with the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine for panic disorder . SSRIs have been shown effective for panic . The target dose of moclobemide was 450 mg and of fluoxetine was 20 mg . There were two consecutive studies . An eight week study of acute adverse events , tolerability and efficacy was followed by a long-term extension study to 1 year . The efficacy data showed no significant difference between moclobemide and fluoxetine . Both had acute efficacy , with 63 % moclobemide and 70 % fluoxetine patients ( ns ) panic free at 8 weeks . Both agents were well tolerated to 8 weeks , but moclobemide had fewer severe adverse events ( 5 ) than fluoxetine ( 9 ) . There were no severe adverse events in the extension phase with either drug , and almost all patients completing 1 year extension treatment ( moclobemide 61 patients , fluoxetine 65 ) were much or very much improved . These data suggest moclobemide and fluoxetine are tolerated and effective for both acute panic treatment and maintenance therapy The 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 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 BACKGROUND Generalized social anxiety disorder ( GSAD ) is a pervasive form of social anxiety that affects approximately 5 % of persons in the community . Among evidence -based pharmacologic treatments for the disorder , selective serotonin reuptake inhibitors ( SSRIs ) have become widely used and are known to be efficacious . Monotherapy with the benzodiazepine clonazepam is also efficacious for GSAD , but the adjunctive use of clonazepam with an SSRI to potentially improve outcomes has not been studied to date . METHOD Twenty-eight patients ( 22 men and 6 women ) with DSM-IV-defined GSAD were r and omly assigned to receive double-blind clonazepam ( or placebo ) , 1.0 to 2.0 mg/day ( divided b.i.d . ) along with open-label paroxetine , 20 to 40 mg/day , for 10 weeks . A 2-week taper of double-blind medication was followed by an additional 8 weeks of open-label paroxetine treatment ( during which the dose of paroxetine could be increased to a maximum of 50 mg/day ) . Twenty-three patients ( 82 % ) met DSM-IV criteria for avoidant personality disorder . The patients ' mean + /- SD age was 31.2 + /- 7.7 years , and their mean duration of illness was 12.1 + /- 5.8 years . Data were gathered from August 2001 to April 2002 . RESULTS Nineteen ( 68 % ) of 28 patients completed treatment . At the end of the 10-week double-blind treatment , there was a trend ( p < .06 ) favoring the paroxetine/clonazepam group , who had a 79 % response rate ( Clinical Global Impressions-Global Improvement scale [ CGI-I ] score of 1 or 2 ) compared with a 43 % response rate for the paroxetine/placebo group . However , no significant differences on other outcome measures were noted between the 2 groups in an intent-to-treat analysis , in terms of either very early ( 2 - 4 weeks ) or not as early ( 5 - 10 weeks ) responses during treatment . Dropout rates due to adverse events were rare ( 1 patient in each group ) , indicating that the paroxetine/clonazepam combination was well tolerated . CONCLUSION Coadministration of clonazepam with an SSRI , in contrast to findings in panic disorder , did not lead to more rapid resolution of symptoms in GSAD . On the other h and , there is some evidence that the clonazepam-added group had superior global outcomes ( e.g. , as measured on the CGI-I ) , although power to detect such differences in this study was small . These observations suggest that a role for adjunctive benzodiazepines in patients with GSAD ( e.g. , for augmenting SSRI partial response or nonresponse ) is deserving of further controlled investigation OBJECTIVE To evaluate the efficacy , safety , and tolerability of venlafaxine extended release ( ER ) in short-term treatment of panic disorder . METHOD In this multicenter , double-blind study , conducted from April 2001 to December 2002 , 343 adult out patients who met criteria for panic disorder ( with and without agoraphobia ) according to the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , were r and omly assigned to flexible-dose venlafaxine ER ( 75 - 225 mg/d ) or placebo for 10 weeks ( N = 155 per group , intent-to-treat population ) . The primary outcome measure was the percentage of panic-free patients as assessed using the Sheehan Panic and Anticipatory Anxiety Scale . Key secondary measures included the Panic Disorder Severity Scale ( PDSS ) score and Clinical Global Impressions-Improvement ( CGI-I ) scale response ( score = 1 or 2 ) . Last-observation-carried-forward data were analyzed , and statistical significance was set at p < or= .05 . RESULTS At week 10 , the percentage of patients who were free from full-symptom panic attacks was 52 % in the venlafaxine ER group and 43 % in the placebo group ( p = .11 ) . Mean change from baseline in PDSS total score was significantly ( p = .006 ) greater for the venlafaxine ER group ( -9.3 ) than for the placebo group ( -7.5 ) , and significantly ( p = .03 ) more venlafaxine ER-treated patients achieved CGI-I response ( 71 % ) than did those receiving placebo ( 59 % ) at week 10 . Treatment with venlafaxine ER was generally safe and well tolerated . Adverse events were the primary or secondary cause for discontinuation for 7 placebo patients ( 4 % ) and 12 venlafaxine ER patients ( 7 % ) . CONCLUSIONS Venlafaxine ER appears to be effective , safe , and well tolerated in short-term treatment of panic disorder , although the results fell just short of significance on the primary outcome measure . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00038896 Summary The relevance of the chronology between panic disorder and avoidance behavior and of an early , medium or late onset of panic disorder was tested . Groups from the sample of the cross-national collaborative panic study ( CNCPS ) were compared for differences in basic characteristics and for the ability to predict treatment response . Patients who developed avoidance behavior before the full syndrome of panic disorder had less often a full agoraphobia but were not different in their response to treatment . Patients with an early onset of panic disorder suffered more often from agoraphobia . The treatment response was similar in the groups with early , medium or late onset of panic disorder . Neither the chronology between panic disorder and avoidance behavior nor the age of onset of panic disorder predicted outcome in short-term treatment with alprazolam or impiramine Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication . In this study , 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks . The medication was tapered over a period of four weeks , and patients were observed for another two weeks after all medication was discontinued . Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study . After improvement in the active treatment period , the alprazolam-treated group had significant relapse between the first and last week of taper . However , during the second postdiscontinuation week , outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper . Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13 % reported a rebound of anxiety on the Hamilton Anxiety Scale . No serious or life-threatening withdrawal symptoms were reported , but distinct , transient , mild to moderate withdrawal syndrome occurred in 35 % of the alprazolam-treated group and in none of the placebo-treated group . The coexistence of symptom rebound and a withdrawal syndrome occurred in 10 % of the alprazolam-treated group , but both subsided by the end of the second week without alprazolam . We recommend that patients with panic disorder be treated for a longer period , at least six months , and that medication be tapered over a more prolonged period , at least eight weeks , especially where high doses are employed The efficacy of buspirone for panic disorder was tested in 60 patients who met Diagnostic and Statistical Manual of Mental Disorders ( 3rd ed . ) criteria for panic disorder or agoraphobia with panic attacks . Patients were r and omly assigned to treatment with buspirone ( mean dose 29.5 mg/day ) , imipramine ( mean dose 140 mg/day ) , or placebo , and treated for 8 weeks after a 4- to 7-day placebo lead-in period . Patients with 4 or fewer attacks per month and those without attacks at the baseline visit were excluded from panic frequency comparisons . Both buspirone and imipramine tended to be better than placebo on total number of panic attacks , global psychopathology , and the Hamilton Anxiety rating scale , but end point differences among treatments were not statistically significant . At the end of the study , 25 % of the buspirone patients were panic-free , as were 7 % of the imipramine patients and 14 % of the placebo patients ; again , these differences were not statistically significant . The results of this study were inconclusive , partly because of the relatively small number of patients ( 10 - 11 ) completing the study in each treatment group , and partly because of a robust placebo response in this population . Possible reasons for this high placebo response are discussed , as well as suggestions for changes in study design for future studies OBJECTIVE The authors sought to determine whether the administration of flumazenil would induce marked panic symptoms in women suffering from premenstrual dysphoric disorder . METHOD Ten women with premenstrual dysphoric disorder and 11 comparison subjects were injected with flumazenil or placebo in a double-blind , r and omized , balanced crossover design in a single session in the luteal phase of their menstrual cycles . RESULTS Flumazenil induced a much greater panic response in the women with premenstrual dysphoric disorder than in the comparison subjects . CONCLUSIONS These preliminary results are consistent with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex during the premenstruum of women suffering from premenstrual dysphoric disorder BACKGROUND There is a paucity of data to support " next-step " treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy . METHOD Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder ( PD ) , social anxiety disorder ( SAD ) , or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate ( or maximally tolerated ) antidepressant and /or benzodiazepine trial of at least 8 weeks ' duration prior to study initiation received open-label augmentation with  flexibly dosed risperidone for 8 weeks . Participants were diagnosed using the Structured Clinical Interview for DSM-IV . RESULTS Risperidone augmentation at a mean + /- SD dose of 1.12 + /- 0.68 mg/day ( range , 0.25 - 3.00 mg/day ) result ed in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety ( HAM-A ) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale , the Liebowitz Social Anxiety Scale , and HAM-A-in the intent-to-treat sample . Seventy percent ( 21/30 ) of participants completed the 8-week trial , with premature discontinuation due primarily to sedation and weight gain . CONCLUSIONS Although conclusions are limited by the open-label , relatively brief nature of this trial , our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD , SAD , or GAD refractory to adequate initial intervention with antidepressants and /or benzodiazepines . Longer-term , controlled safety and efficacy data are needed to underst and the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders 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
Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo .
Low- quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders .
Due to these limitations , our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice .
BACKGROUND Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes .
Panic disorder is a common disorder , with an estimated lifetime prevalence of 1 % to 5 % in the general population and a 7 % to 10 % prevalence in primary care setting s. Its aetiology is not fully understood and is probably heterogeneous .
Panic disorder is treated with psychological and pharmacological interventions , often used in combination .
Although benzodiazepines are frequently used in the treatment of panic disorder , guidelines recommend antidepressants , mainly selective serotonin reuptake inhibitors ( SSRIs ) , as first-line treatment for panic disorder , particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines .
Despite these recommendations , benzodiazepines are widely used in the treatment of panic disorder , probably because of their rapid onset of action .
OBJECTIVES To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults .