Combined Paroxetine and Clonazepam Treatment Strategies Compared to Paroxetine Monotherapy for Panic Disorder Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? Cognitive-behavioral therapy helps prevent relapse and recurrence of panic disorder following alprazolam discontinuation: a long-term follow-up of the Peoria and Dartmouth studies. Early coadministration of clonazepam with sertraline for panic disorder. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: Further evaluation. Alprazolam withdrawal in patients with panic disorder and generalized anxiety disorder: vulnerability and effect of carbamazepine. Safety and side-effects of alprazolam. Controlled study in agoraphobia with panic disorder. Diazepam versus alprazolam for the treatment of panic disorder. Treatment of panic disorder with agoraphobia: comparison of fluvoxamine, placebo, and psychological panic management combined with exposure and of exposure in vivo alone. Emotion-focused psychotherapy for patients with panic disorder. The benefit of an insight-oriented and experiential approach on panic and agoraphobia symptoms. Results of a controlled comparison of client-centered therapy alone and in combination with behavioral exposure. Treatment of Panic Disorder with Agoraphobia: Randomized Placebo‐Controlled Trial of Four Psychosocial Treatments Combined with Imipramine or Placebo Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder? Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Reduced Anxiety Level by Therapeutic Interventions and Cell-Mediated Immunity in Panic Disorder Patients Therapeutic response to benzodiazepine in panic disorder subtypes. Psychiatric history and subthreshold symptoms as predictors of the occurrence of depressive or anxiety disorder within 2 years. Treatment outcomes for primary care patients with major depression and lifetime anxiety disorders. The use of low-dose intranasal midazolam to treat panic disorder: a pilot study. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. Time to response in panic disorder in a naturalistic setting: combination therapy with alprazolam orally disintegrating tablets and serotonin reuptake inhibitors compared to serotonin reuptake inhibitors alone. Anxiety in primary care: is short-term drug treatment appropriate? Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Effect of medication and psychotherapy on heart rate variability in panic disorder. The efficacy of drugs and psychotherapy in the treatment of acute depressive episodes. Long‐term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2‐year naturalistic follow‐up A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder. A crossover study of focused cognitive therapy for panic disorder. Objective and subjective sleep quality: Melatonin versus placebo add-on treatment in patients with schizophrenia or bipolar disorder withdrawing from long-term benzodiazepine use Efficacy and safety of alprazolam, imipramine and placebo in treating panic disorder. A Scandinavian multicenter study Randomised placebo-controlled trial of moclobemide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia. Influence of panic-agoraphobic spectrum symptoms on treatment response in patients with recurrent major depression. Maintenance drug therapy of panic disorder. Absence of Neuropsychologic Deficits in Patients Receiving Long-Term Treatment With Alprazolam-XR for Panic Disorder A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Effects of the benzodiazepine antagonist flumazenil in PTSD
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 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 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 BACKGROUND Although panic disorder can be effectively alleviated by drug treatment , the relapse rate is high . By adding brief dynamic psychotherapy focused on the psychosocial vulnerability of patients with panic disorder to an established drug treatment regimen , we hypothesized that this would result in a lower relapse rate after pharmacotherapy . METHODS Patients with panic disorder ( defined by DSM-III-R ) were r and omized to treatment with either clomipramine for 9 months ( n = 20 ) , or clomipramine for 9 months combined with 15 weekly sessions of brief dynamic psychotherapy ( n = 20 ) . Measures of anxiety and depression were collected at intake and at regular intervals . The patients had blind follow-up interviews at 6 , 12 , and 18 months after beginning treatment . RESULTS All patients in both groups became free of panic attacks within 26 weeks of the start of treatment . On termination of pharmacotherapy , the relapse rate was significantly higher in the clomipramine-only group during the follow-up period . There were significantly lower scores for most anxiety measures in the clomipramine plus psychotherapy group at the 9-month follow-up . CONCLUSION The addition of brief dynamic psychotherapy to treatment with clomipramine significantly reduces the relapse rate of panic disorder compared with clomipramine treatment alone 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 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 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 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 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 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 Recent studies have suggested that most patients treated for panic disorder receive forms of psychotherapy other than cognitive behavior therapy , even though there is little information about the efficacy of such treatments or how they compare to proven active treatments . The authors compared one of these other forms , emotion-focused psychotherapy ( given to 30 patients with panic disorder ) , to results obtained with recommended st and ard treatment ( either cognitive behavior therapy [ N=36 ] or imipramine [ N=22 ] ) . The authors also compared emotion-focused psychotherapy to results obtained in subjects given pill placebo ( N=24 ) . METHOD Subjects met DSM-IV criteria for panic disorder with no more than mild agoraphobia . Treatment consisted of approximately 3 months of weekly visits followed by 6 monthly maintenance visits . Assessment s were conducted after each treatment phase and at a follow-up visit after 6 months of no treatment . RESULTS Emotion-focused psychotherapy  was less effective for symptoms of panic disorder than treatment with either cognitive behavior therapy or imipramine ; results obtained with emotion-focused psychotherapy after the acute and maintenance phases were similar to those seen with placebo .  Treatment expectations were not different among the different groups . Patients receiving emotion-focused psychotherapy had the highest completion rate . CONCLUSIONS The results suggest that emotion-focused psychotherapy ( a supportive form of psychotherapy ) has low efficacy for the treatment of panic disorder . However , emotion-focused psychotherapy may be superior to medical management in helping patients stay in treatment BACKGROUND It is a common view that psychodynamic treatment does not help much to ameliorate the symptoms of panic and agoraphobia . The effects of an insight-oriented treatment on central anxiety symptoms are the subject of the present controlled study . METHODS Forty patients with severe panic and agoraphobia were admitted to an inpatient anxiety treatment program . Most of the patients had been treated by pharmacological means unsuccessfully . The patients were r and omly assigned to pure client-centered therapy or to additional behavioral exposure treatment . Client-centered and behavioral agoraphobia manuals were used . The patients were examined on admission , at discharge and at 3 , 6 , and 12 months follow-up for panic ( Structured Clinical Interview for DSM III-R -- SCID ) , anxiety ( Hamilton Anxiety Scale ) , agoraphobia ( SCID , Fear Survey Schedule ) , and depressive ( Hamilton Depression Scale ) symptoms . RESULTS Both client-centered treatment and a combination with exposure treatment reduced panic , avoidance and depressive symptoms significantly . For a short period the combined treatment was superior in patients ' coping actively with anxiety and improving agoraphobic symptoms . However , at 1-year follow-up there was no further difference in the reduction of anxiety and depressive symptoms . CONCLUSIONS The results are discussed with regard to the combination of these forms of therapy and to widespread skepticism about the efficacy of insight-oriented treatment 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 BACKGROUND In 2001 , the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments ( CANMAT ) partnered to produce evidence -based clinical guidelines for the treatment of depressive disorders .  A revision of these guidelines was undertaken by CANMAT in 2008 - 2009 to reflect advances in the field . This article , one of five in the series , review s new studies of psychotherapy in the acute and maintenance phase of MDD , including computer-based and telephone-delivered psychotherapy . METHODS The CANMAT guidelines are based on a question -answer format to enhance accessibility to clinicians . Evidence -based responses are based on up date d systematic review s of the literature and recommendations are grade d according to the Level of Evidence , using pre-defined criteria . Lines of Treatment are identified based on criteria that included evidence and expert clinical support . RESULTS Cognitive-Behavioural Therapy ( CBT ) and Interpersonal Therapy ( IPT ) continue to have the most evidence for efficacy , both in acute and maintenance phases of MDD , and have been studied in combination with antidepressants . CBT is well studied in conjunction with computer-delivered methods and bibliotherapy . Behavioural Activation and Cognitive-Behavioural Analysis System of Psychotherapy have significant evidence , but need replication . Newer psychotherapies including Acceptance and Commitment Therapy , Motivational Interviewing , and Mindfulness-Based Cognitive Therapy do not yet have significant evidence as acute treatments ; nor does psychodynamic therapy . LIMITATIONS Although many forms of psychotherapy have been studied , relatively few types have been evaluated for MDD in r and omized controlled trials . Evidence about the combination of different types of psychotherapy and antidepressant medication is also limited despite widespread use of these therapies concomitantly . CONCLUSIONS CBT and IPT are the only first-line treatment recommendations for acute MDD and remain highly recommended for maintenance . Both computer-based and telephone-delivered psychotherapy -- primarily studied with CBT and IPT -- are useful second-line recommendations . Where feasible , combined antidepressant and CBT or IPT are recommended as first-line treatments for acute MDD OBJECTIVE Benzodiazepines , other anxiolytics , or sedative hypnotics are prescribed for 30%-50 % of posttraumatic stress disorder ( PTSD ) patients . Prior data and theory suggest that these medications may inhibit response to exposure therapy , one of the most effective PTSD treatments . The present post hoc study reanalyzed results from a psychotherapy trial to assess whether benzodiazepine use was associated with reduced response to exposure therapy . METHOD Between August 2002 and October 2005 , 283 female veterans and soldiers meeting DSM-IV criteria for PTSD were r and omly assigned to 10 weekly 90-minute sessions of either prolonged exposure ( n = 140 ) or present-centered psychotherapy ( n = 143 ) . Benzodiazepine use ( n = 57 ) or non-use ( n = 226 ) at intake was not r and omly assigned . Multilevel modeling was used to assess the effects of benzodiazepine status , psychotherapy condition , and their interaction on changes on the Clinician-Administered PTSD Scale and the PTSD Checklist during the treatment and 6-month follow-up periods . RESULTS Consistent with prior reports from these data , prolonged exposure psychotherapy produced greater reductions per week in PTSD symptoms than did present-centered psychotherapy ( b = -0.48 , P = .02 ) . Patients prescribed benzodiazepines did not have weaker response to prolonged exposure , but demonstrated poorer posttreatment maintenance of gains from present-centered psychotherapy ( b = -0.78 , P < .001 ) . CONCLUSIONS Prolonged exposure is a sufficiently robust treatment that patients who are taking benzodiazepines  can benefit from it . It is unclear whether benzodiazepine use or other patient factors accounted for benzodiazepine recipients ' poorer maintenance of gains in  present-centered psychotherapy .  TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00032617 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 Objective : This study examined the relationship between reduced anxiety level by therapeutic interventions and cell-mediated immunity ( CMI ) in patients with panic disorder . Methods : The subjects consisted of 42 patients with panic disorder and 42 normal gender- and age-matched controls . Among the patients , 21 were r and omly assigned to a combined treatment of cognitive-behavioral therapy and the benzodiazepine antianxiety agent ethyl loflazepate ( 2 mg daily ) , and 21 were assigned to the antianxiety agent only . The treatment lasted for 6 weeks . Cell-mediated immune function was measured by the lymphocyte proliferative response to phytohemagglutinin ( PHA ) and interleukin-2 ( IL-2 ) production . The anxiety level was assessed by the Hamilton Rating Scale for Anxiety and the anxiety subscale of the Symptom Checklist-90 Revised . Results : Prior to treatment , the panic disorder patients had significantly lower IL-2 production and blastogenic response to PHA than the normal controls . However , no significant differences in CMI were found between the pretreatment and posttreatment period in either the patient group receiving medication only or the combined treatment group , though after treatment , patients were significantly less anxious than before treatment in both intervention groups . The delta change ( posttreatment value minus pretreatment value ) in the self-reported anxiety level was significantly associated with the delta change in the blastogenic response in the combined treatment group . Conclusion : These findings suggest that panic disorder may be associated with decreased CMI , and the reduced level of self-reported anxiety in the patients who underwent combined therapeutic intervention is likely to increase the blastogenic response . Further studies are needed to evaluate the long-term effects of treatment on immune function 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 Past episodes of depressive or anxiety disorders and subthreshold symptoms have both been reported to predict the occurrence of depressive or anxiety disorders . It is unclear to what extent the two factors interact or predict these disorders independently . AIMS To examine the extent to which history , subthreshold symptoms and their combination predict the occurrence of depressive ( major depressive disorder , dysthymia ) or anxiety disorders ( social phobia , panic disorder , agoraphobia , generalised anxiety disorder ) over a 2-year period . METHOD This was a prospect i ve cohort study with 1167 participants : the Netherl and s Study of Depression and Anxiety . Anxiety and depressive disorders were determined with the Composite International Diagnostic Interview , subthreshold symptoms were determined with the Inventory of Depressive Symptomatology-Self Report  and the  Beck Anxiety Inventory .  RESULTS Occurrence of depressive disorder was best predicted by a combination of a history of depression and subthreshold symptoms , followed by either one alone . Occurrence of anxiety disorder was best predicted by both a combination of a history of anxiety disorder and subthreshold symptoms and a combination of a history of depression and subthreshold symptoms , followed by any subthreshold symptoms or a history of any disorder alone . CONCLUSIONS A history and subthreshold symptoms independently predicted the subsequent occurrence of depressive or anxiety disorder . Together these two characteristics provide reasonable discriminative value . Whereas anxiety predicted the occurrence of an anxiety disorder only , depression predicted the occurrence of both depressive and anxiety disorders OBJECTIVE Major depression occurs with generalized anxiety disorder and panic disorder in up to 60 % of psychiatric and primary care patients . This comorbidity has been associated with greater severity of depression , poorer psychosocial functioning , and poorer treatment outcomes in psychiatric sample s. This study examined the clinical outcomes for depressed primary care patients with and without a lifetime anxiety disorder . METHOD A total of 157 primary care patients who met criteria for major depression were r and omly assigned to st and ardized interpersonal psychotherapy or pharmacotherapy with nortriptyline and were assessed at baseline and at 4 and 8 months on severity of depression , psychosocial functioning , and health-related functioning . RESULTS Depressed patients with a comorbid anxiety disorder presented with significantly more psychopathology and tended to prematurely terminate treatment more frequently than patients with major depression alone . Both st and ardized depression-specific treatments were effective for depressed patients with and without a comorbid generalized anxiety disorder , although time to recovery was longer for the former . Patients with lifetime panic disorder showed poor recovery in response to psychotherapy or pharmacotherapy . CONCLUSIONS St and ardized psychotherapy and pharmacotherapy are effective for patients with major depression with and without a generalized anxiety disorder . However , the longer time to recovery for the former group and lack of response to these treatments by patients with lifetime panic disorder suggest that primary care physicians should carefully assess history of anxiety disorder among depressed patients so as to select a proper intervention 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 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 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 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 BACKGROUND Panic disorder ( PD ) patients have been shown to have reduced heart rate variability ( HRV ) . Low HRV has been associated with elevated risk for cardiovascular disease . Our aim was to investigate the effects of treatment on heart rate ( HR ) in patients with PD through a hyperventilation challenge . METHODS We studied 54 participants , 43 with Diagnostic and Statistical Manual of Mental Disorders ( DSM-IV ) PD and 11 controls . Subjects lay supine with their heads in a plastic canopy chamber , resting for 15 min and then breathing at a rate of 30 breaths per minute for 10 min . HRV was sample d for spectral analysis . Clinical and behavioral measures of anxiety were assessed . Treatment was chosen by patients : either 12 weeks of CBT alone or CBT with sertraline . RESULTS All patients showed significant decrease on clinical measures from baseline and 31 were treatment responders , 8 dropped out of the study before completion of the 12-week treatment phase and 4 were deemed nonresponders after 12 weeks of treatment . Although both treatments led to significant clinical improvement , only CBT alone demonstrated a significant reduction in HR and increase in HRV . CONCLUSIONS Our study replicated the finding that increased HR and decreased HRV occur in PD patients . Given the evidence of cardiac risk related to HRV , CBT appears to have additional benefits beyond symptom reduction . The mechanisms of this difference between CBT and sertraline are unclear and require further study The efficacy of tricyclic antidepressants and various psychotherapies , in comparison with one another or in combination , has not been fully established in r and omized clinical trials . The authors present a r and omized controlled trial comparing the combination of amitriptyline and short-term interpersonal psychotherapy , either treatment alone , and nonscheduled supportive psychotherapy in ambulatory patients with acute depression . They found that pharmacotherapy and psychotherapy alone were equally efficacious and better than nonscheduled treatment . The combination treatment of  psychotherapy and pharmacotherapy was more effective than either treatment alone and delayed the onset of symptomatic failure Two years after completion of a controlled outcome study of treatments for panic disorder with agoraphobia , patients were revisited and interviewed about their complaints . In the initial study , four treatments had been compared : ( i ) fluvoxamine combined with exposure ; ( ii ) placebo medication plus exposure ; ( iii ) psychological panic management plus exposure : and ( iv ) exposure alone . Comparison of the results at post‐test had revealed superior efficacy of fluvoxamine combined with exposure over the other three treatments in reducing agoraphobic avoidance . The current naturalistic follow‐up study investigated the long‐term efficacy of the treatments with regard to abatement of complaints and reduced dem and for further treatment . In addition , we examined whether patients were able to taper off the study medication without a recurrence of complaints . In total , 71 of the 76 patients of the original trial ( 93 % ) were interviewed . Comparison of the mean level of psychopathology at follow‐up revealed no difference between the original treatment groups . The effect in the fluvoxamine plus exposure group was maintained , but was no longer superior , due to further improvements in the other treatment groups . Most patients received additional treatment during the follow‐up period , usually because the 12 treatment sessions in the controlled study had yielded insufficient improvement . There was a trend for patients who received the fluvoxamine plus exposure treatment to require less aftercare than those who received the other treatments . Finally , almost 50 % of the patients who had received medication in the original trial were able to taper off the use of fluvoxamine without a recurrence of complaints BACKGROUND Self-administered cognitive behavior therapy ( SCBT ) has been shown to be an effective alternative to therapist-delivered treatment for panic disorder ( PD ) . However , it is unknown whether combining SCBT and antidepressants can improve treatment . This trial evaluated the efficacy of SCBT and sertraline , alone or in combination , in PD . METHOD Patients ( n=251 ) were r and omized to 12 weeks of either placebo drug , placebo drug plus SCBT , sertraline , or sertraline plus SCBT . Those who improved after 12 weeks of acute treatment received treatment for an additional 12 weeks . Outcome measures included core PD symptoms ( panic attacks , anticipatory anxiety , agoraphobic avoidance ) , dysfunctional cognitions ( fear of bodily sensations , agoraphobic cognitions ) , disability , and clinical global impression of severity and improvement . Efficacy data were analyzed using general and generalized linear mixed models . RESULTS Primary analyses of trends over time revealed that sertraline/SCBT produced a significantly greater rate of decline in fear of bodily sensations compared to sertraline , placebo/SCBT and placebo . Trends in other outcomes were not significantly different over time . Secondary analyses of mean scores at week 12 revealed that sertraline/SCBT fared better on several outcomes than placebo , with improvement being maintained at the end of continuation treatment . Outcome did not differ between placebo and either sertraline monotherapy or placebo/SCBT . Moreover , few differences emerged between the active interventions . CONCLUSIONS This trial suggests that sertraline combined with SCBT may be an effective treatment for PD . The study could not confirm the efficacy of sertraline monotherapy or SCBT without concomitant medication or therapist assistance in the treatment of PD OBJECTIVE This study sought to determine the short- and long-term effects of focused cognitive therapy for  panic disorder . METHOD Thirty-three psychiatric out patients with the DSM-III diagnosis of panic disorder were r and omly assigned to either 12 weeks of individual , focused cognitive therapy or 8 weeks of brief supportive psychotherapy based on principles of client-centered therapy . The patients who received supportive psychotherapy were subsequently given the opportunity to cross over to cognitive therapy for 12 weeks . Patients were rated for panic and depression before therapy , after 4 and 8 weeks of therapy , and at 6-month and 1-year follow-up . RESULTS Clinician ratings and self-ratings of panic frequency and intensity indicated that the focused cognitive therapy group achieved significantly greater reductions in panic symptoms and general anxiety after 8 weeks of treatment than did the group that received brief supportive psychotherapy . At 8 weeks , 71 % of the cognitive therapy group were panic free , compared to 25 % of the psychotherapy group . Moreover , 94 % of the psychotherapy patients elected to cross over to 12 weeks of cognitive therapy . At 1-year follow-up , 87 % of the group that received cognitive therapy only and 79 % of the group that crossed over into cognitive therapy remained free of panic attacks . CONCLUSIONS Focused cognitive therapy offers a promising nonpharmacological alternative for the treatment of panic disorder Benzodiazepines are frequently long-term prescribed for the treatment of patients with severe mental illness . This prescribing practice is problematic because of well-described side effects including risk of dependence . We examined the efficacy of prolonged-release melatonin on objective and subjective sleep quality during benzodiazepine discontinuation and whether sleep variables were associated with benzodiazepine withdrawal . Eligible patients included adults with a diagnosis of schizophrenia , schizoaffective disorder , or bipolar disorder and long-term use of benzodiazepines in combination with antipsychotics .  All participants gradually tapered the use of benzodiazepines after r and omization to add-on treatment with melatonin versus placebo . Here we report a sub sample of 23 patients undergoing sleep recordings ( one-night polysomnography ) and 55 patients participating in subjective sleep quality ratings .  Melatonin had no effect on objective sleep efficiency , but significantly improved self-reported sleep quality . Reduced benzodiazepine dosage at the 24-week follow-up was associated with a significantly decreased proportion of stage 2 sleep . These results indicate that prolonged-release melatonin has some efficacy for self-reported sleep quality after gradual benzodiazepine dose reduction , and that benzodiazepine discontinuation is not associated with rebound insomnia in medicated patients with severe mental illness . However , these findings were limited by a small sample size and a low retention rate As part of the cross‐national collaborative panic study , a double‐blind comparison of alprazolam , imipramine and placebo was performed in Sc and inavian out patients with panic disorder according to DSM‐III ; 41 patients were r and omly allocated to each drug . Doses were increased for 3 weeks to an average of about 6 mg alprazolam , 150 mg imipramine and a corresponding number of placebo capsules , which were then given for 5 weeks . No more than supportive psychotherapy was given . Key symptoms were rated weekly . The drugs were tapered for 4 or 8 weeks and the patients were followed up for 6 months . Compliance at 3 weeks was 95 % for alprazolam , 83 % for imipramine and 88 % for placebo ; at 8 weeks 95 % for alprazolam , 73 % for imipramine and 46 % for placebo . At 3 weeks plasma determination showed that the proportion taking  diazepam  outside the protocol was 0 % for alprazolam , 19 % for imipramine and 31 % for placebo ; at 8 weeks the corresponding proportions were 3 % , 11 % and 16 % . Intention‐to‐treat analysis showed that freedom from panic attacks was obtained for 68 % with alprazolam , 61 % with imipramine and 34 % with placebo . Alprazolam was more effective than imipramine and placebo on anticipatory anxiety and phobic symptoms . Globally rated by physicians and patients , about 60 % had complete remission  with alprazolam and imipramine and 30 % on placebo .  At least partial remission was obtained in about 85 % with alprazolam , 70 % with imipramine and 40 % with placebo . Alprazolam  had a more rapid onset of action than imipramine on all symptoms . Side effects were generally mild , with a preponderance of drowsiness  for alprazolam and anticholinergic effects for imipramine . Tapering was uneventful without significant discontinuation phenomena . During taper and follow‐up , several patients in remission relapsed , leaving approximately 30 % patients in complete remission in all groups . To obtain more stable improvement , either long‐term drug treatment or combinations of drug treatment and psychotherapy should be evaluated BACKGROUND In the treatment of panic disorder with agoraphobia  , the efficacy of pharmacological , psychological and combined treatments has been established . Unanswered questions concern the relative efficacy of such treatments . AIMS To demonstrate that moclobemide and cognitive-behavioural therapy ( CBT ) are effective singly and more effective in combination . METHOD Fifty-five patients were r and omly assigned to an eight-week treatment of : moclobemide plus CBT ; moclobemide plus clinical management ( ' psychological placebo ' ) ; placebo plus CBT ; or placebo plus clinical management . RESULTS Comparisons between treatments revealed strong effects for CBT . Moclobemide with clinical management was not superior to placebo . The combination of moclobemide with CBT did not yield significantly better short-term results than CBI with placebo . The CBT results remained stable during a six-month follow-up , although a substantial proportion of patients treated with placebo plus CBT needed additional treatment . CONCLUSIONS CBT was highly effective in the treatment of panic disorder with agoraphobia and reduced agoraphobia to levels that were comparable to those of non- clinical controls OBJECTIVE The authors tested the hypothesis that a lifetime history of panic-agoraphobic spectrum symptoms predicts a poorer response to  depression treatment . METHOD A threshold for clinical ly meaningful panic-agoraphobic spectrum symptoms was defined by means of receiver operating characteristic curve analysis of total scores on the Structured Clinical Interview for Panic-Agoraphobic Spectrum in a group of 88 out patients with and without panic disorder . This threshold was then applied to a group of 61 women with recurrent major depression , who completed a self-report version of the same instrument , in order to compare treatment outcomes for patients above and below this clinical threshold . RESULTS Women with high scores ( > or = 35 ) on the Panic-Agoraphobic Spectrum Self-Report were less likely than women with low scores ( < 35 ) to respond to interpersonal psychotherapy alone ( 43.5 % versus 68.4 % , respectively ) . Women with high scores also took longer ( 18.1 versus 10.3 weeks ) to respond to a sequential treatment paradigm ( adding a  selective serotonin reuptake inhibitor  when depression did not remit with interpersonal psychotherapy alone ) . This effect was only partially accounted for by the higher likelihood that patients with high scores required the addition of antidepressants . Although four domains from the Panic-Agoraphobic Spectrum Self-Report were individually associated with a longer time to remission , only stress sensitivity emerged as significant in multivariate regression analyses . CONCLUSIONS A lifetime burden of panic-agoraphobic spectrum symptoms predicted a poorer response to  interpersonal psychotherapy  and an 8-week delay in sequential treatment response among women with recurrent depression . These results lend clinical validity to the spectrum construct and highlight the need for alternate psychotherapeutic and pharmacologic strategies to treat depressed patients with panic spectrum features 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 Studies to date on the effects of benzodiazepines on neuropsychologic function have yielded conflicting data with respect to the type , severity , and duration of deficits that may be induced by these agents . As part of a placebo-controlled trial of alprazolam-XR ( extended release ) administered in combination with cognitive-behavioral therapy in patients with panic disorder , a battery of tests was used to measure neuropsychologic function .  Thirty-eight out patients were r and omly assigned to receive either alprazolam-XR or placebo . Dosages were titrated up so that the alprazolam group ( N = 18 ) received a mean dose of 4 mg/day ( reduced in two patients because of sedative side effects ) . Neuropsychologic function after 6 weeks of therapy at the target dosage was compared with baseline assessment s in each group . Both groups showed a statistically significant improvement from baseline to repeated assessment s on measures of attention , executive functioning , psychomotor speed , and visual memory ( p < 0.001 ) ; these gains were attributed to a practice effect . No significant changes were noted in measures of learning , verbal memory , or reaction time , and neither group showed any deterioration from baseline to retesting in any aspect of neuropsychologic function . These findings call into question the assumption that long-term benzodiazepine therapy produces significant neuropsychologic deficit in patients with diagnosed anxiety disorders BACKGROUND Patients with chronic forms of major depression are difficult to treat , and the relative efficacy of medications and psychotherapy is uncertain . METHODS We r and omly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with  nefazodone ( maximal dose , 600 mg per day ) , the cognitive behavioral- analysis system of psychotherapy ( 16 to 20 sessions ) , or both . At base line , all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression ( indicating clinical ly significant depression ) . Remission was defined as a score of 8 or less at weeks 10 and 12 . For patients who did not have remission , a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less . Raters were unaware of the patients ' treatment assignments . RESULTS Of the 681 patients , 662 attended at least one treatment session and were included in the analysis of response . The overall rate of response ( both remission and satisfactory response ) was 48 percent in both the nefazodone group and in the psychotherapy group , as compared with 73 percent in the combined-treatment group . ( P<0.001 for both comparisons ) . Among the 519 subjects who completed the study , the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group , as compared with 85 percent in the combined-treatment group ( P<0.001 for both comparisons ) . The rates of withdrawal were similar in the three groups . Adverse events in the nefazodone group were consistent with the known side effects of the drug ( e.g. , headache , somnolence , dry mouth , nausea , and dizziness ) . CONCLUSIONS Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral- analysis system of psychotherapy , the combination of the two is significantly more efficacious than either treatment alone Major depressive disorder is associated with considerable morbidity , disability , and risk for suicide . Treatments for depression most commonly include antidepressants , psychotherapy , or the combination . Little is known about predictors of treatment response for depression . In this study , 681 patients with chronic forms of major depression were treated with an antidepressant ( nefazodone ) , Cognitive Behavioral Analysis System of Psychotherapy ( CBASP ) , or the combination . Overall , the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment . Among those with a history of early childhood trauma ( loss of parents at an early age , physical or sexual abuse , or neglect ) , psychotherapy alone was superior to antidepressant monotherapy . Moreover , the combination of  psychotherapy and pharmacotherapy was only marginally superior to  psychotherapy  alone among the childhood abuse cohort . Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma CONTEXT Panic disorder ( PD ) may be treated with drugs , psychosocial intervention , or both , but the relative and combined efficacies have not been evaluated in an unbiased fashion . OBJECTIVE To evaluate whether drug and psychosocial therapies for PD are each more effective than placebo , whether one treatment is more effective than the other , and whether combined therapy is more effective than either therapy alone . DESIGN AND SETTING R and omized , double-blind , placebo-controlled clinical trial conducted in 4 anxiety research clinics from May 1991 to April 1998 . PATIENTS A total of 312 patients with PD were included in the analysis . INTERVENTIONS Patients were r and omly assigned to receive imipramine , up to 300 mg/d , only ( n=83 ) ; cognitive-behavioral therapy ( CBT ) only ( n=77 ) ; placebo only ( n=24 ) ; CBT plus imipramine ( n=65 ) ; or CBT plus placebo ( n=63 ) . Patients were treated weekly for 3 months ( acute phase ) ; responders were then seen monthly for 6 months ( maintenance phase ) and then followed up for 6 months after treatment discontinuation . MAIN OUTCOME MEASURES Treatment response based on the Panic Disorder Severity Scale ( PDSS ) and the Clinical Global Impression Scale ( CGI ) by treatment group . RESULTS Both imipramine and CBT were significantly superior to placebo for the acute treatment phase as assessed by the PDSS ( response rates for the intent-to-treat [ ITT ] analysis , 45.8 % , 48.7 % , and 21.7 % ; P=.05 and P=.03 , respectively ) , but were not significantly different for the CGI ( 48 . 2 % , 53.9 % , and 37.5 % , respectively ) . After 6 months of maintenance , imipramine and CBT were significantly more effective than placebo for both the PDSS ( response rates , 37.8 % , 39.5 % , and 13.0 % , respectively ; P=.02 for both ) and the CGI ( 37.8 % , 42.1 % , and 13.0 % , respectively ) . Among responders , imipramine produced a response of higher quality . The acute response rate for the combined treatment was 60.3 % for the PDSS and 64.1 % for the CGI ; neither was significantly different from the other groups . The 6-month maintenance response rate for combined therapy was 57.1 % for the PDSS ( P=.04 vs CBT alone and P=.03 vs imipramine alone ) and 56.3 % for the CGI ( P=.03 vs imipramine alone ) , but not significantly better than CBT plus placebo in either analysis . Six months after treatment discontinuation , in the ITT analysis CGI response rates were 41.0 % for CBT plus placebo , 31.9 % for CBT alone , 19.7 % for imipramine alone , 13 % for placebo , and 26.3 % for CBT combined with imipramine . CONCLUSIONS Combining imipramine and CBT appeared to confer limited advantage acutely but more substantial advantage by the end of maintenance . Each treatment worked well immediately following treatment and during maintenance ; CBT appeared durable in follow-up . JAMA . 2000;283:2529 - 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
The review established the paucity of high quality evidence investigating the efficacy of psychotherapy combined with benzodiazepines for panic disorder .
Currently , there is inadequate evidence to assess the clinical effects of psychotherapy combined with benzodiazepines for patients who are diagnosed with panic disorder
BACKGROUND The efficacy of combining psychotherapy and benzodiazepines for panic disorder is unclear , despite widespread use .
OBJECTIVES To examine the efficacy of the combination compared with either treatment alone .