title: Reduced Serotonin Type 1A Receptor Binding in Panic Disorder Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? Therapeutic Effects and Effects on Actual Driving Performance of Chronically Administered Buspirone and Diazepam in Anxious Outpatients Study and course of the psychological profile in 77 patients expressing panic disorder with agoraphobia after cognitive behaviour therapy with or without buspirone. Serotonergic anxiolytics in the treatment of panic disorder: a controlled study with buspirone. Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Assessing the efficacy of antianxiety agents. Anxiety in primary care: is short-term drug treatment appropriate? Ipsapirone: evidence for efficacy in depression. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. 5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo Prevalence of psychiatric disorder in the general population: results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS) Smoking Modulates Neuroendocrine Responses to Ipsapirone in Patients with Panic Disorder The relative efficacy of buspirone, imipramine and placebo in panic disorder: A preliminary report Comparison of buspirone in two separate studies. Buspirone Therapy in Anxious Elderly Patients: A Controlled Clinical Trial Subsensitivity of the 5-hydroxytryptamine1A (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. A controlled study of cognitive behaviour therapy with buspirone or placebo in panic disorder with agoraphobia. 5-HT1A receptor-effector system responsivity in panic disorder A Double‐Blind Comparison of Buspirone, Clobazam, and Placebo in Patients with Anxiety Treated in a General Practice Setting Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. Drug interactions in controlled clinical trials. Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Long-term buspirone therapy for chronic anxiety: a multicenter international study to determine safety. Is Buspirone Effective for Panic Disorder?
abstract: Recent animal models suggest that disturbances in serotonin type-1A receptor ( 5-HT1AR ) function may contribute to chronic anxiety , although it is not clear at all whether such models constitute relevant models for panic disorder ( PD ) in humans . The selective 5-HT1AR radiolig and [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ( FCWAY ) permits in vivo assessment of central 5-HT1AR binding using positron emission tomography ( PET ) . We studied 16 unmedicated symptomatic out patients with PD and 15 matched healthy controls . Seven patients had an additional diagnosis of a current major depressive episode , however PD was the primary diagnosis . A 120 min PET study of  5-HT1AR  binding was acquired using a GE Advance scanner in three-dimensional mode . Using quantitative PET image analysis , regional values were obtained for [18F]-FCWAY volume of distribution ( DV ) , corrected for plasma protein binding , and K1 , the delivery rate of [18F]-FCWAY from plasma to tissue . MRI scanning was performed using a GE Signa Scanner ( 3.0 Tesla ) to provide an anatomical framework for image analysis and partial volume correction of PET data . PD patients showed lower DV in the anterior cingulate ( t = 4.3 ; p < 0.001 ) , posterior cingulate ( t = 4.1 ; p < 0.001 ) , and raphe ( t = 3.1 ; p = 0.004 ) . Comparing patients with PD , patients with PD and comorbid depression , and healthy controls revealed that DVs did not differ between PD patients and PD patients with comorbid depression , whereas both patient groups differed significantly from controls . These results provide for the first time in vivo evidence for the involvement of 5-HT1ARs in the pathophysiology of PD CONTEXT Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions . OBJECTIVE To explore whether the association between funding and conclusions in r and omized drug trials reflects treatment effects or adverse events . DESIGN Observational study of 370 r and omized drug trials included in meta-analyses from Cochrane review s selected from the Cochrane Library , May 2001 . From a r and om sample of 167 Cochrane review s , 25 contained eligible meta-analyses ( assessed a binary outcome ; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment ) . The primary binary outcome from each meta- analysis was considered the primary outcome for all trials included in each meta- analysis . The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect , adverse events , and additional confounding factors ( method ological quality , control intervention , sample size , publication year , and place of publication ) . MAIN OUTCOME MEASURE Conclusions in trials , classified into whether the experimental drug was recommended as the treatment of choice or not . RESULTS The experimental drug was recommended as treatment of choice in 16 % of trials funded by nonprofit organizations , 30 % of trials not reporting funding , 35 % of trials funded by both nonprofit and for-profit organizations , and 51 % of trials funded by for-profit organizations ( P<.001 ; chi2 test ) . Logistic regression analyses indicated that funding , treatment effect , and double blinding were the only significant predictors of conclusions . Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice ( odds ratio , 5.3 ; 95 % confidence interval , 2.0 - 14.4 ) compared with trials funded by nonprofit organizations . This association did not appear to reflect treatment effect or adverse events . CONCLUSIONS Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results . Readers should carefully evaluate whether conclusions in r and omized trials are supported by data Two groups of 12 out patients each ( six men and six women ) with generalized anxiety disorder , participated in this study . Each patient was treated single-blind with placebo during the first 7 days ( baseline ) , followed by a double-blind drug treatment period of 4 consecutive weeks ( active ) and ending again with 7 days single-blind placebo treatment ( washout ) . One group received buspirone 5 mg three times a day in the first week and continued with 10 mg in the morning , 5 mg in the afternoon , and 5 mg in the evening during the second , third , and fourth weeks . The other group received diazepam 5 mg three times a day in all 4 weeks . On the evening of the seventh day of each treatment week the  Hamilton Rating Scale for Anxiety and the Symptom Check List  ( 90 items ) were applied to assess the therapeutic effects , followed by an on-the-road driving test that started 1.5 hours after the last drug or placebo intake . The test consisted of operating an instrumented vehicle over a 100 kilometer highway circuit while attempting to maintain a constant speed and a steady lateral position within the right traffic lane . Two patients in the diazepam group were unable to complete their test after the first and second treatment week , respectively , because of serious sedative reactions . Both buspirone and diazepam were equally effective in reducing overall anxiety symptoms . The specific profiles showed that buspirone also reduced concomitant depressive symptoms and symptoms of interpersonal sensitivity and anger-hostility . In contrast , diazepam was found to be slightly more effective in reducing somatic symptoms and to positively affect sleep disturbances . Moreover , abrupt discontinuation of diazepam result ed in a relapse of psychic anxiety symptoms comparable with the placebo-baseline level and a partial relapse of somatic anxiety symptoms . Chronic treatment with buspirone had no significant effects on lateral position and speed control . In contrast , diazepam significantly impaired control of lateral position in the first 3 weeks of treatment . There was no significant impairment in the fourth treatment week and the placebo-washout week . Speed control was significantly impaired only in the first week . The relevance of the trend toward decreasing performance impairment during chronic treatment remains to be established BACKGROUND The change of psychopathological dimensions during treatment of panic disorder is attracting increasing interest . METHODS A population of subjects experiencing panic disorder with agoraphobia is evaluated with the French version of the factor structure of the Symptom Checklist 90 R ( SCL 90 R ) . Two groups of patients are compared : a group receiving cognitive behaviour therapy ( CBT ) combined with buspirone and a group receiving cognitive behaviour therapy combined with placebo .  RESULTS Comparative analysis of pre- and post-test changes between both groups completing treatment showed that the combination cognitive behaviour therapy plus buspirone provided better results than those in patients who had received cognitive behaviour therapy plus placebo . This difference between treatments did not persist at the 1-year follow-up , since , while results had been effectively maintained in the CBT plus buspirone group , the CBT plus placebo group continued to improve significantly for the target dimensions of treatment . CONCLUSIONS Psychopathological dimensions on the SCL 90 R show that combination of buspirone and cognitive behaviour therapy accelerates the behaviour modification process only in the short term 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 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 Proper evaluation of anxiolytic therapy , involving the possible use of rating scales as well as the physician 's skill in observation and communication , is essential in identifying the most appropriate treatment for a given patient and facilitating the management of therapy . These issues are discussed herein , using the clinical trials of buspirone , a new , nonsedating antianxiety agent , as a model for the process of drug selection 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 Sixty-five in patients of a psychosomatic hospital in the Federal Republic of Germany with the diagnosis of anxiety neurosis ( n = 31 ) or neurotic depression ( n = 34 ) as defined by the International Classification of Disease ( ICD-9 ) , were r and omized to a 4-week course of  ipsapirone at 7.5 mg t.i.d . or placebo in a prospect i ve , double-blind clinical trial to assess safety , tolerability , and efficacy . This article reports the efficacy results for those patients with the diagnosis of neurotic depression . The primary efficacy variable for patients with neurotic depression was the change from baseline in the Hamilton Rating Scale for Depression ( HAM-D ) at 4 weeks of treatment . Considering all of the r and omized patients with neurotic depression ( n = 34 , the intent-to-treat population ) , the mean change from baseline in the HAM-D at Week 4 ( observed cases ) was -13.13 + /- 6.06 ( n = 16 ) for the ipsapirone group , and -3.19 + /- 5.99 ( n = 16 ) for the placebo group ( p less than .001 ) . A parallel analysis of the change from baseline in the Core Depression score of the HAM-D ( defined as the sum of items 1 , 2 , 3 , 7 , and 8) also showed a significant treatment difference ( p less than .01 ) . Results were similar for the intent-to-treat population , last observation carried forward . Safety and tolerability were evaluated for all study patients independent of diagnosis . Treatment-emergent events ( n = 65 ) were reported by 76 percent of patients treated with ipsapirone ( n = 33 ) and by 38 percent of patients treated with placebo ( n = 32 ) . ( ABSTRACT TRUNCATED AT 250 WORDS In this double-blind study , 56 adult psychoneurotic out patients with a primary diagnosis of anxiety neurosis were r and omly assigned to receive buspirone ( N = 18 ) , diazepam ( N = 20 ) , or placebo ( N = 18 ) over a four-week period . A battery of tests administered weekly indicated that buspirone , a new agent not chemically related to any currently marketed drugs , was as effective an antianxiety agent as diazepam and produced no more and perhaps fewer side effects .  Buspirone showed excellent antidepressant effects as well . If further studies confirm the authors ' findings and determine that buspirone does not result in tolerance and addiction , it would be more advantageous than the benzodiazepines in the treatment of anxiety Blunted neuroendocrine and physiological responses to the selective 5-HT(1A ) receptor agonist , ipsapirone , have been observed in patients with panic disorder and /or agoraphobia ( PDA ) . In order to examine whether this hyporesponsiveness to ipsapirone is modified by pharmacological or non-pharmacological therapeutic interventions , challenges with an oral dose of ipsapirone ( 0.3 mg/kg ) and placebo were performed in patients with PDA before and after 10 weeks of treatment with clomipramine , aerobic exercise and placebo . Before treatment , administration of ipsapirone was followed by significant increases of cortisol , anxiety and other psychopathological symptoms in comparison to the placebo challenge . In addition , a significant decrease of body temperature was observed . After the 10-week treatment period , the psychological responses to ipsapirone were significantly reduced in the clomipramine and the exercise group . In contrast , there was a non-significant trend towards higher cortisol responses after clomipramine and exercise treatment . The hypothermic response to ipsapirone was significantly reduced by clomipramine treatment . In conclusion , our results demonstrate that effective treatment of panic disorder has divergent effects on the psychological , neuroendocrine and temperature responses to ipsapirone Abstract This article reports the initial results of a prospect i ve study on the prevalence of  psychiatric disorders in the Dutch population aged 18–64 . The objectives and the design of the study are described elsewhere in this issue . A total of 7076 people were interviewed in person in 1996 . The presence of the following disorders was determined by means of the CIDI : mood disorders , anxiety disorders , eating disorders , schizophrenia and other non-affective psychoses , and substance use disorders . Psychiatric disorders were found to be quite common . Some 41.2 % of the adult population under 65 had experienced at least one DSM-III-R disorder in their lifetime , among them 23.3 % within the preceding year . No gender differences were found in overall morbidity . Depression , anxiety , and alcohol abuse and dependence were most prevalent , and there was a high degree of comorbidity between them . The prevalence rate encountered for schizophrenia was lower ( 0.4 % lifetime ) than generally presumed . A comparison with findings from other countries is made . Relevant determinants of psychiatric morbidity were analysed Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD ) and /or agoraphobia ( PDA ) . Although many of these patients are regular smokers , it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist , ipsapirone , are affected by the smoking status of the patients .In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone ( 0.3 mg/kg ) and placebo were performed in 39 patients with PDA , and results were compared between patients who smoked ( > 10 cigarettes per day , n = 17 ) and patients who had been non-smokers for at least two years ( n = 22 ) . Patients who were smokers ( but did not smoke during the challenge procedure ) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature . In comparison to placebo , administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations . The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers . In conclusion , smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders . The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers , since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone There is a need for safe effective alternatives to benzodiazepines in the treatment of panic disorder . Buspirone , a new nonbenzodiazepine anxiolytic , is compared to imipramine and placebo in the treatment of panic disorder in an 8 week double-blind controlled study of 52 r and omly assigned patients . Weekly assessment s were made using the Hamilton Anxiety Scale , the Sheehan Clinician Rated Anxiety Scale , the Sheehan Patient Rated Anxiety Scale , the Phobia Scale , the Disability Scale , the Hamilton Depression Scale , the Montgomery Asberg Depression Scale , the Investigator Rated Global Improvement Scale and the Patient Rated Global Improvement Scale . Preliminary results of repeated measures Anovas are reported . Imipramine was superior to placebo on many of the outcome measures . Imipramine was superior to buspirone on the Patient Rated Global Improvement Scale and on the Investigator Rated Global Improvement Scale , but not on other measures . Although buspirone appeared to be more effective than placebo , differences were not statistically significant . Some buspirone patients did very well compared to others , suggesting a possible bimodal distribution of response . Patients on buspirone had fewer and less disruptive side effects than those on imipramine Two double-blind studies are described in which buspirone was compared with placebo and diazepam ( Study A ) or clorazepate ( Study B ) in out patients with moderate to severe anxiety . Results , assessed on the Hamilton Rating Scales for Depression and Anxiety , the SCL-56 , the Profile of Mood States , and the Covi and Raskin scales , indicated that buspirone consistently relieved both anxiety and associated depression . In Study B , trends in favor of buspirone were seen on several SCL-56 items and the Hamilton somatic factor ; significant differences in this direction were found for several POMS items . Sedation was seen less often with buspirone than either diazepam or clorazepate & NA ; Forty patients over 65 years of age with anxiety symptoms due to an anxiety state ( N = 20 ) or secondary to neurotic depression ( N = 20 ) took part in a double‐blind , placebo‐controlled trial conducted in a primary care practice . All patients were receiving concomitant drug therapy for chronic medical conditions ; 70 % were receiving two or more nonpsychotropic drugs in addition to the study medication . Patients were r and omly assigned to treatment with buspirone 5‐30 mg/day or placebo for 4 weeks , with clinical evaluations made weekly . One buspironetreated and two placebo‐treated patients discontinued treatment after 2 weeks because of lack of efficacy  . Buspirone treatment result ed in significantly greater ( p ≤ 0.05 ) improvement on the Hamilton Rating Scale for Anxiety , Hamilton Rating Scale for Depression , and Clinical Global Impression assessment than did placebo  . Mild adverse experiences were reported by five buspirone‐treated and nine placebotreated patients . Buspirone ( mean dose , 18 mg/day ) proved equally effective for elderly patients suffering anxiety states or neurotic depression at doses similar to those used in younger patients , and was well tolerated by elderly patients receiving treatment for other chronic medical conditions The selective 5-HT1A receptor lig and ipsapirone ( IPS ) induces  hypothermia in humans . To explore 5-HT1A receptor-mediated thermoregulation in depression , 24 subjects ( 12 patients with unipolar depression and 12 individually matched controls ) received 0.3 mg/kg IPS or placebo in r and om order . Compared with controls , the depressed patients exhibited significantly attenuated hypothermic responses to IPS . The impaired hypothermic response following 5-HT1A receptor activation in unipolar depression could have result ed from subsensitivity of the ( presynaptic ) 5-HT1A receptor and /or related effector mechanisms , thus supporting the hypothesis that altered serotonergic activity may be present in affective disorders . Future studies of the hypothermic response to direct-acting 5-HT1A lig and s , such as IPS should facilitate the assessment of 5-HT receptor function in various affective disorders and its involvement in psychotropic drug effects BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions BACKGROUND This multicentre study compared a 16-week buspirone treatment with placebo in patients presenting with panic disorder with agoraphobia and also receiving cognitive behaviour therapy ( CBT ) .  METHOD Double-blind testing was maintained until week 68 , but not tested ; 91 patients were included ; 14 placebo-responders excluded ; 77 patients r and omised ; 48 reached week 16 and 41 reached week 68 . RESULTS At week 16 , within-group analysis showed significant improvements in agoraphobia , panic attacks , and depression in both groups . Generalised anxiety improved only in CBT+buspirone . Between-group comparisons showed buspirone to have an effect on generalised anxiety and agoraphobia . Changes in degree of agoraphobia and depression were correlated in subjects on CBT+buspirone only . A significantly higher proportion of women , and of subjects showing high avoidance dropped out . Positive expectations regarding medication predicted success in both groups . At week 68 , improvement was retained without significant buspirone effect . CONCLUSION Buspirone enhanced the effects of cognitive behaviour therapy on generalised anxiety and agoraphobia in the short term To explore 5-HT1A receptor responsivity in panic disorder ( PD ) , hypothermic , neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone ( IPS ) were investigated in patients with primary PD and healthy controls . Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind , r and om-assignment conditions . IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior . Compared with controls , the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS . Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS , no consistent changes in ratings of anxiety or panic symptoms were recorded . The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system , thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD . Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes ( e.g. 5-HT2 , 5-HT3 ) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects & NA ; Sixty patients being treated for anxiety in a primary care facility received ( double‐blind ) buspirone , the benzodiazepine drug clobazam , or placebo for 3 weeks . The mean daily dose at the end of treatment was 23 mg for buspirone and 21 mg for clobazam . Patients were assessed weekly using the Hamilton Rating Scale for Anxiety and Clinical Global Impression scale . Both active treatments produced significant improvement in anxiety symptoms compared with placebo as early as the first week of treatment , and there was progressive improvement over the subsequent 2 weeks . Response to buspirone was equally favorable in anxious patients who experienced depressive symptomatology Sixty-two chronically agoraphobic patients completed a controlled study to assess the effects of 1 ) imipramine up to 200 mg/day ( mean = 130 mg/day ) , 2 ) 12 weekly therapist-assisted in vivo exposure sessions ( flooding ) , and 3 ) imipramine plus flooding . The control group received systematic therapeutic instructions for self-directed in vivo exposure ( programmed practice ) .  Clinical measures of global severity , phobia , panic , anxiety , depression , and behavioral performance tests were administered before treatment and at Weeks 4 , 8 , and 12 of treatment . Results revealed significant improvement in all groups on all measures over the course of treatment ; almost a third of the control patients showed marked improvement . Imipramine had significant effects on improvement of phobias and markedly increased clinical response rates in patients receiving 150 - 200 mg/day . Less chronicity and severity of condition also predicted better clinical outcome . Flooding had limited effects above and beyond programmed practice , and no imipramine-flooding interactions effects were found As much information as possible should be obtained in clinical trials to assess possible interactions between test drugs and concomitant medications prescribed for other medical indications . Side effect profiles were compared in patients taking buspirone  , mean = 20 mg/day ; diazepam  , 20 mg/day ; clorazepate  , 23 mg/day ; and placebo , with or without concomitant medications . Approximately 1,000 anxious patients were included in the analysis ; 700 received buspirone .  The use of a variety of common medications did not affect the side effect profile in the buspirone , clorazepate , and placebo groups , but did increase the incidence of side effects in the diazepam group . The increased incidence of sedation noted with diazepam and clorazepate , however , was not due to concomitant medication OBJECTIVE Patients with generalized anxiety disorder ( N=107 ) who had been long-term benzodiazepine users ( average duration of use=8.5 years ) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine ( 180 mg/day ) and buspirone ( 38 mg/day ) compared to placebo in facilitating benzodiazepine discontinuation . METHOD After a benzodiazepine stabilization period taking either diazepam , lorazepam , or alprazolam , patients were treated for 4 weeks with imipramine , buspirone , or placebo under double-blind conditions while benzodiazepine intake was kept stable ( treatment phase ) . Patients then entered a 4 - 6 week benzodiazepine taper and a 5-week posttaper phase with imipramine , buspirone , and placebo treatment being continued until 3 weeks into the posttaper phase , at which time all patients were switched to placebo for 2 weeks .  Benzodiazepine plasma levels were assayed weekly . Benzodiazepine-free status was assessed 3 and 12 months posttaper . RESULTS Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts . The success rate of the taper in this study was significantly higher for patients who received imipramine ( 82.6 % ) , and nonsignificantly higher for patients who received buspirone ( 67.9 % ) , than for patients who received placebo ( 37.5 % ) . The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success : benzodiazepine dose , level of anxious symptoms at baseline , and duration of benzodiazepine therapy . CONCLUSIONS Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper . Daily benzodiazepine dose , severity of baseline symptoms of anxiety and depression , and duration of benzodiazepine use were additional significant predictors of successful taper outcome This report presents results from an international multicenter trial of the safety of buspirone in the treatment of  anxiety disorders  for periods up to one year , if needed ; 424 patients were treated for six months , and 264 patients completed a full year of treatment . Chronic use of buspirone for up to 52 weeks was associated with emergence of no new or unexpected side effects that were not previously reported during shorter periods of treatment . Most patients were successfully managed on daily doses ranging from 15 to 30 mg/day . When buspirone therapy was abruptly discontinued after more than six months of therapy , assessment s of patients yielded no evidence of a withdrawal syndrome or unusual events . Although long-term anxiolytic drug therapy is not generally recommended , this open study provides evidence of the potential usefulness of buspirone when used for up to one year . As a general guideline , when an anxiolytic agent is used for several months or longer to treat chronic anxiety , the need for drug therapy should be reevaluated periodically Buspirone was compared with imipramine and placebo in the treatment of panic disorder in an 8-week , double-blind controlled study of 52 r and omly assigned patients . The side effect profile of buspirone was less disruptive than that of imipramine . Buspirone was not significantly superior to placebo in its antipanic or anxiolytic effects in panic disorder patients
target: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low- quality evidence for secondary efficacy outcomes .
  A small amount of moderate- quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo .
  If further research is to be conducted , studies with larger sample sizes , with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder
background: BACKGROUND Panic disorder is common in the general population .
  It is often associated with other psychiatric disorders , such as drug dependence , major depression , bipolar disorder , social phobia , specific phobia and generalised anxiety disorder .
  Azapirones are a class of drugs used as anxiolytics .
  They are associated with less drowsiness , psychomotor impairment , alcohol potentiation and potential for addiction or abuse than benzodiazepines .
  However , azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear .
  It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder .
  OBJECTIVES To assess the effects of azapirones on panic disorder in adults , specifically:1 .
  to determine the efficacy of azapirones in alleviating symptoms of panic disorder , with or without agoraphobia , in comparison with placebo;2 .
  to review the acceptability of azapirones in panic disorder , with or without agoraphobia , in comparison with placebo ; and 3 .
  to investigate adverse effects of azapirones in panic disorder with or without agoraphobia , including general prevalence of adverse effects , compared with placebo .