A Comparison of the Efficacy and Safety of Alprazolam and Desipramine in Depressed Outpatients Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. A double-blind clinical trial of alprazolam, imipramine, or placebo in the depressed elderly. A DOUBLE-BLIND EVALUATION OF ALPRAZOLAM AND IMIPRAMINE IN THE TREATMENT OF MAJOR DEPRESSION Alprazolam and amitriptyline in the treatment of major depressive disorder: a double-blind clinical and sleep EEG study. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study Adinazolam, diazepam, imipramine, and placebo in major depressive disorder: a controlled study. Alprazolam: An Antidepressant? Alprazolam, Desipramine, and an Alprazolam‐Desipramine Combination in the Treatment of Adult Depressed Outpatients A Comparison of the Safety and Efficacy of Alprazolam and Desipramine in Moderately Severe Depression * Alprazolam vs amitriptyline in depressions with reduced REM latencies. Antidepressant or antianxiety? A study of the efficacy of antidepressant medication Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Challenging the amphetamine challenge test: report of an antidepressant treatment study. A double-blind comparative study of alprazolam and dothiepin hydrochloride in the treatment of anxiety associated with depression. Alprazolam versus imipramine in depressed out-patients with neurovegetative signs. Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies. Risperidone for Treatment-Refractory Major Depressive Disorder Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind placebo-controlled study A cluster randomized trial comparing two interventions to improve treatment of major depression in primary care. Treatment of depressive outpatients with lorazepam, alprazolam, amytriptyline and placebo Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. An evaluation of alprazolam in the treatment of reactive or neurotic (secondary) depression. Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety. Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure: ARGOS study. Psychopharmacological treatment of panic disorder and related states: A Placebo controlled study of alprazolam Is the Comparison between Exercise and Pharmacologic Treatment of Depression in the Clinical Practice Guideline of the American College of Physicians Evidence-Based? Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. Improving patients' beliefs about antidepressants in primary care: a cluster-randomized controlled trial of the effect of a depression care program. Comparative efficacy of alprazolam, imipramine, and placebo administered once a day in treating depressed patients. Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.
Fifty-two adult depressed out patients fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine .  Twenty-nine patients completed the seven week ( one week placebo followed by six weeks of active drug ) study . The mean daily dose of alprazolam and desipramine at study termination was 3.34 mg and 192 mg respectively . Based on psychometric ratings of depression ( Hamilton Scale ) and severity of illness ( Clinical Global Impressions ) there was no significant difference between alprazolam and desipramine at the end of six weeks of active drug treatment . Both medications were well tolerated with drowsiness being the most common side effect of alprazolam , and insomnia , dry mouth , and constipation , the complaints most associated with desipramine Five hundred four out patients suffering from a major depressive episode were r and omly assigned to receive either amitriptyline , doxepin , alprazolam , or placebo . The study was conducted in three treatment centers during a six-week period . All three active medications produced significantly more clinical improvement than did placebo , irrespective of the patient 's initial anxiety , depression , and psychomotor retardation and irrespective of the patient 's assignment to various subtypes of depression , including the DSM-III melancholia subtype . Compared with placebo , sedation was reported more frequently with all three medications , whereas anticholinergic effects were reported more frequently only for the two tricyclic antidepressants , but not for alprazolam The efficacy and safety of alprazolam as compared to imipramine or a placebo added to weekly interpersonal psychotherapy was compared in a 6-week double-blind r and omized clinical trial of 35 ambulatory elderly patients with major depression . The average maximum dosage of alprazolam was 2.2 mg and the average maximum dosage of imipramine was 97.5 mg . The findings showed a rapid onset of action of alprazolam within 1 week on symptoms of depression and anxiety . The effects for imipramine were seen later in the study . There were no serious side effects that interfered with treatment . The anticholinergic effects of imipramine were the ones that most commonly interfered with treatment . Alprazolam produced the greatest number of symptoms with discontinuation , most of which were alleviated within a week . We conclude that alprazolam may be useful as an antidepressant for the elderly . More clinical trials are needed to test its efficacy in the depressed elderly with concomitant medical problems , using plasma levels . A double-blind discontinuation study of alprazolam is needed to determine the degree of symptom return SUMMARY This report describes the results of a multicentre collaborative study comparing the safety and efficacy of alprazolam with imipramine in patients suffering from major depressive disorder . Two hundred and eight patients diagnosed as major depression as per DSM-III criteria were r and omly allocated to alprazolam ( N= 105 ) or imipramine ( N = 103 ) in a double-blind fashion . Detailed assessment s were carried out for a period of six weeks . Results revealed that alprazolam was as effective as imipramine as an antidepressant . Side effects were less frequently reported with alprazolam This study was design ed to compare the antidepressant effects of alprazolam and amitriptyline in a group of 30 in patients suffering from a severe major endogenous depression , diagnosed by Research Diagnostic Criteria and the Newcastle Rating scale , and to examine the effects of alprazolam and amitriptyline on two biological markers of depression , the dexamethasone suppression test and sleep EEG parameters . The 6-week study was double-blind with a r and om allocation of treatment . Patients were treated with flexible doses of 4 - 9 mg of alprazolam and 100 - 225 mg of amitriptyline . After 4 weeks of treatment the antidepressant effects of amitriptyline significantly exceeded those of alprazolam , as measured on the Hamilton Rating Scale for Depression . There was a high drop-out rate in the alprazolam group because of ineffectiveness of treatment . Alprazolam showed similar effects on sleep parameters as amitriptyline : lengthening of the REM latency and a tendency to shorten stages 3 and 4 and stage REM . These negative clinical results should be interpreted with caution , because of the severity of our selection criteria , and should not be extended to all depressive disorders BACKGROUND Although transcranial magnetic stimulation ( TMS ) can be an effective acute antidepressant treatment , few studies systematic ally examine persistence of benefit . OBJECTIVE We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder ( MDD ) using protocol -specified maintenance antidepressant monotherapy . METHODS Three hundred one patients were r and omly assigned to active or sham TMS in a 6-week , controlled trial . Nonresponders could enroll in a second , 6-week , open-label study . Patients who met criteria for partial response ( i.e. , > 25 % decrease from the baseline HAMD 17 ) during either the sham-controlled or open-label study ( n = 142 ) were tapered off TMS over 3 weeks , while simultaneously starting maintenance antidepressant monotherapy . Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS . During this durability study , TMS was readministered if patients met prespecified criteria for symptom worsening ( i.e. , a change of at least one point on the CGI-S scale for 2 consecutive weeks ) . Relapse was the primary outcome measure . RESULTS Ten of 99 ( 10 % ; Kaplan-Meier survival estimate = 12.9 % ) patients relapsed . Thirty-eight ( 38.4 % ) patients met criteria for symptom worsening and 32/38 ( 84.2 % ) reachieved symptomatic benefit with adjunctive  TMS . Safety and tolerability were similar to acute TMS monotherapy . CONCLUSIONS These initial data suggest that the therapeutic effects of  TMS  are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse In summary , the clinical results of this double-blind study clearly show that imipramine , as expected , demonstrated significant antidepressive properties in out patients suffering from major depressive disorders . In contrast , adinazolam showed rather mild and weak antidepressive properties , and in no measures did its response differ significantly from that of diazepam . These findings are quite in contrast to those obtained by the authors in an earlier study with alprazolam ( Rickels et al. , 1987 ) in which alprazolam and imipramine produced rather similar results and both were significantly better than placebo , while diazepam was not . While the rather high dropout rate may well be considered a limitation of the study , the dropout rate is equally distributed between all four treatments . And since both decreasing sample size and endpoint analyses which include all patients with at least one week data , provide rather similar results , the findings can be considered as robust despite the high dropout rate . While the authors consider those findings the most robust in which endpoint and completer analyses results are rather similar , when high dropout rates occur , endpoint analyses should be given more weight than completer analyses as they are more representative of actual clinical practice . The present findings therefore suggest that adinazolam clearly possesses less antidepressive properties than imipramine and not more than diazepam and these findings are in agreement with other studies which found lack of significant antidepressant activity for such benzodiazepines as diazepam ( Covi et al. , 1974 ) and chlordiazepoxide ( Lipman et al. , 1986 ) . The presence of only borderline antidepressive effects combined with rebound symptoms occurring already after only 6 weeks of therapy does not recommend adinazolam for use in depression . ( ABSTRACT TRUNCATED AT 250 WORDS The antidepressant efficacy of alprazolam ( ALP ) was tested in a double-blind controlled comparison with desipramine ( DMI ) and an ALP-DMI combination in out patients diagnosed with major depressive disorder by Research Diagnostic Criteria ( 90 % met criteria for endogenous subtype ) . Following a placebo period of at least 1 week , subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale ( HDRS ) scores were administered oral doses of the active medication ( N = 79 ) , in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI . Treatment continued for 6 weeks , and all subjects who completed at least 2 weeks ( N = 69 ) were included in endpoint analyses . Following the placebo baseline , symptoms were rated again at day 5 and at the end of weeks 1 , 2 , 4 , and 6 . Final doses averaged 4.6 ± 1.3 mg for the ALP group , 230 ± 61 mg for the DMI group , and 4.6 ± 1.2 mg ALP + 229.5 ± 1.2 mg DMI for the combination group . The final outcome was a comparable degree of improvement at the end-point among the three treatment groups on measures of depression ( HDRS and Beck Depression Inventory ) , anxiety ( Hamilton Anxiety Rating Scale ) , and global improvement ( Global Assessment Scale , and Physician and Patient Global Impressions ) . A similar outcome was found for the subgroup of patients who completed all 6 weeks ( N = 56 ) . Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression , anxiety , and global status . These results suggest that ALP alone is as effective as a st and ard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication . Side effect profiles were compared among treatment groups and are discussed , as are other clinical studies that have investigated ALP 's  potential antidepressant efficacy . ( J Clin Psychopharmacol 1987;7:295—310 Fifty-four patients ( 34 out patients , 20 in patients ) fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine . The mean daily dose of alprazolam and desipramine at study termination was 3.78 mg and 208 mg respectively . As there were no significant demographic or clinical differences between out patients and in patients , both groups were combined in data analysis . Using the Hamilton Depression Rating Scale ( HAM-D ) both drug groups showed highly significant improvement beginning with the first week of active drug treatment . HAM-D scores continued to decrease through study termination ( six weeks of active drug ) . There were no significant differences when comparing alprazolam and desipramine ( out patients , in patients , or both groups combined ) on any of the subjective or objective psycho-metrics used in this study . Clinical ly , only twelve of thirty-four out patients ( 35.3 % ) were felt to be “ markedly or moderately ” improved , suggesting that neither the outpatient alprazolam nor desipramine patients did particularly well with drug treatment . In terms of drug safety there was no difference between the alprazolam and desipramine in the number of excessive or serious drug side effects . However , five of twenty-nine alprazolam patients had to discontinue therapy because of excessive drowsiness , and two of the alprazolam out patients had motor vehicle accidents directly related to this adverse event . Alprazolam appeared as effective as desipramine in the pharmacotherapy of this group of depressed outpatient and in patients .  Alprazolam appeared well-tolerated by most subjects although drowsiness was a common — and at times serious — medication side effect This study was design ed to compare the antidepressant effects of alprazolam , a triazolobenzodiazepine , with amitriptyline hydrochloride in a group of patients with nonpsychotic , major depressions diagnosed by Research Diagnostic Criteria . A mean rapid eye movement latency of less than 65 minutes was required to enter this study . Dexamethasone suppression tests were conducted before treatment . By strictly applied Research Diagnostic Criteria , 83.6 % of the subjects were endogenous , and 34.7 % were in patients . A significantly greater percentage of alprazolam-treated patients responded within the first seven days of treatment . By the end of this six-week trial , alprazolam was associated with significant reductions in Hamilton , Beck , Covi , Raskin , and Carroll Rating scores ( pretreatment to posttreatment ) . However , by the end of treatment the effects of  amitriptyline  exceeded those of alprazolam on both the Hamilton and Beck scales . These data indicate that alprazolam is not as effective as amitriptyline in major depressions with a shortened rapid eye movement latency The authors analyzed the relative contributions of improvement in depressive and anxiety symptoms , as measured by the Hamilton Rating Scale for Depression ( HRSD ) and the Hamilton Rating Scale for Anxiety ( HRSA ) , respectively , after 1 week of treatment to the prediction of improvement in HRSD score after 6 weeks of antidepressant pharmacotherapy .  Fifty-six subjects completed 6 weeks of treatment with either desipramine ( n = 20 ) , alprazolam ( n = 18 ) , or a desipramine-alprazolam combination ( n = 18 ) . The results showed that early improvement in the HRSD was a moderately strong predictor of the total 6-week improvement in HRSD score , and a better predictor than early improvement in the HRSA . Partial correlations showed that early HRSD improvement was significantly related to total HRSD improvement within the alprazolam group . This pattern of response differed from those observed for the other treatment groups . Desipramine-treated subjects showed gradual improvement over the course of the study , and the improvement in week 1 was not so strongly predictive of overall improvement . The relationship between early and total HRSD improvement for the combination treatment group was intermediate to the other two groups . These findings are discussed in the context of the relationship between depression and anxiety , and potential implication s for the treatment of these overlapping and often mixed syndromes INTRODUCTION Effective management of  major depressive disorder ( MDD ) continues to be a challenging task for psychiatrists and primary care physicians . This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials . METHODS Patients ( N=1,147 ) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled ( week 0 ) ; 827 received single-blind adjunctive placebo plus open-label antidepressant ( escitalopram , fluoxetine , paroxetine controlled release , sertraline , or venlafaxine extended release ) for 8 weeks to confirm inadequate response to antidepressants ; 349 patients with inadequate response were r and omized ( 1:1 ) to double-blind , adjunctive placebo ( n=172 ) or adjunctive aripiprazole ( n=177 ; 2 - 20 mg/day ) . Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) Total score from baseline ( week 8) to endpoint ( week 14 ) . RESULTS Clinical ly significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole ( -10.1 ) than placebo ( -6.4 ; P<.001 ) . Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo ( week 14 , 36.8 % vs 18.9 % ; P<.001 ) . Completion rates with adjunctive aripiprazole and placebo were high ( 83 % vs. 87 % ) and discontinuations due to adverse events were low ( 6.2 % vs 1.7 % ) . CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy , adjunctive therapies can significantly improve depressive symptoms . As reported , adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo . This , and previous studies , have shown that discontinuations due to adverse events were low and completion rates were high , and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe . This is the third consecutive clinical trial , in the absence of a failed trial , to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to st and ard antidepressant monotherapy ( Clinical Trials.gov study NCT00105196 ) The primary goal of this study was to determine whether the amphetamine challenge test ( ACT ) response , as measured by a subjective rating scale , the How I Feel Scale ( HIF ) , could predict antidepressant treatment outcome . Following a 1-day non-blind ACT with dextroamphetamine ( d-AMPH ) , patients were treated double-blind for 6 weeks with either desipramine , alprazolam , or a desipramine-alprazolam combination . Regression ( true score ) analyses were carried out on pre- and post-ACT HIF scores and on baseline and end of study Hamilton Depression Rating Scale ( HDRS ) scores to determine the magnitudes of improvement measured in response to the ACT and antidepressant treatment , respectively . Regression analyses were performed on the residuals ( true scores of improvement ) to determine the best fitting ( linear ) prediction equation . Improvement in the HIF total score predicted HDRS improvement for the whole sample . Possible sources of error contributing to the outcome are identified and the results are discussed in relation to previous clinical investigations of the potential usefulness of the ACT as a predictor of antidepressant response One hundred patients with mixed symptoms of anxiety and depression were enrolled into a prospect i ve , multi-centre , r and omized , double-blind study comparing the response to , and the side-effects of , alprazolam and dothiepin hydrochloride over 4 weeks of treatment . Mean daily doses were 2.33 mg alprazolam and 115 mg dothiepin . Data on 96 patients were evaluated for tolerance , and data for 85 patients were analyzed for therapeutic response . In each case , the groups were similar in numbers , mean ages and sex ratios . Both groups experienced satisfactory responses to therapy , with highly statistically significant changes ( p less than 0.001 ) in the means of all efficacy measures within each group . No statistical difference was demonstrated in favour of either treatment group . Both dothiepin and alprazolam exhibited a similar profile of mild minor side-effects , but more patients suffered moderate to severe reactions to dothiepin , leading to a greater drop-out rate in the dothiepin-treated group . It is concluded that , as both treatments produced equally satisfactory responses in this study , alprazolam should be considered for the treatment of  anxiety associated with depression in patients for whom tricyclic antidepressant drugs are either contra-indicated or poorly tolerated The purpose of this study was to compare the safety and efficacy of a relatively new antidepressant drug , alprazolam ( a triazolobenzodiazepine ) with imipramine in the treatment of 60 depressed symptomatic volunteers . Eligible patients were r and omly assigned after a 1-week washout to one of the medications and followed for 6 treatment weeks . Contrary to the earlier report of Feighner et al. ( 1983 ) , who found alprazolam superior to imipramine and placebo , but consistent with Rush et al. ( 1985 ) we find imipramine superior in efficacy to alprazolam on a variety of symptoms . Both the present study and Rush 's study employed patients with signs indicative of response to tricyclics . Feighner 's patients may have been the type who tend to be less responsive to tricyclics but may be more responsive to alprazolam .  Some of our data also show that alprazolam may have a more advantageous effect in the early weeks of treatment but is overtaken in subsequent treatment weeks by imipramine BACKGROUND The efficacy , safety , and tolerability of lisdexamfetamine dimesylate ( LDX ) augmentation of antidepressant monotherapy in adults with major depressive disorder ( MDD ) from two phase 3 studies are reported . METHODS Across study 1 (  placebo  , n=201 ; LDX , n=201 ) and study 2 ( placebo , n=213 ; LDX , n=211 ) , most participants ( placebo and LDX ) in the safety analysis set were female ( study 1 : 66.2 % and 64.2 % ; study 2 : 67.1 % and 66.8 % ) ; mean±SD ages were 41.8±12.04 with placebo and 42.2±12.32 with LDX in study 1 and 42.6±11.41 with placebo and 42.0±11.63 with LDX in study 2 . Participants ( 18 - 65 y ) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Åsberg Depression Rating Scale ( MADRS ) total scores ≥24 . Eight-week antidepressant lead-in phases prospect ively assessed antidepressant response . Then , 8 weeks of r and omized ( 1:1 ) , double-blind treatment with dose-optimized LDX ( 20 - 70 mg ) or placebo in participants exhibiting inadequate antidepressant monotherapy responses ( augmentation baseline MADRS total scores ≥18 and < 50 % MADRS total score reductions from lead-in baseline to augmentation baseline ) was initiated . The primary endpoint was MADRS total score change from augmentation baseline to week 16 . Safety and tolerability measures included the occurrence of treatment-emergent adverse events ( TEAEs ) . RESULTS Least squares mean ( 95 % CI ) treatment differences ( LDX-placebo ) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 ( 0.1 [ -1.7 , 2.0 ] , P=0.883 ) or study 2 ( -0.5 [ -2.3 , 1.3 ] , P=0.583 ) . The only TEAE reported by > 5 % of LDX participants at twice the placebo rate in both studies was dry mouth . LIMITATIONS Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders , the inability to assess specific MDD symptom domains ( eg , anhedonia , cognition ) or subtypes , the use of telephone-based depression assessment s , and the potential influence of placebo response . CONCLUSION Contrary to expectations , LDX augmentation was not superior to placebo in reducing depressive symptoms in individuals with MDD exhibiting inadequate responses to antidepressant monotherapy Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy ? Contribution This double-blind r and omized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy . Risperidone , compared with placebo , result ed in more remissions ( 25 % vs. 11 % ) , as well as more cases of somnolence ( 5 % vs. 2 % ) and dry mouth ( 5 % vs. 1 % ) . Caution The trial duration was short , and 19 % of risperidone recipients did not complete treatment . Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy . The Editors Major depressive disorder is the leading cause of disability worldwide ( 1 ) , affecting nearly 121 million people . It is associated with increased overall mortality ( 2 , 3 ) ; premature cardiovascular-related death ( 4 , 5 ) ; and morbidity , including disability , lost productivity , and decreased wages , compared with individuals without depression ( 6 ) . Selective serotonin reuptake inhibitors ( SSRIs ) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression . Despite a sufficient dose and duration of antidepressant treatment , symptoms do not resolve in 30 % to 40 % of patients with major depressive disorder ( 710 ) . Remission , defined as the virtual absence of depressive symptoms , is important because it is associated with improved patient prognosis and functioning relative to response ( generally defined as 50 % reduction in symptoms ) ( 11 , 12 ) . In an effort to improve the therapeutic efficacy of antidepressant monotherapy , several pharmacologic strategies to modulate different or additional neurotransmitters ( 1315 ) are commonly used , despite a paucity of evidence from r and omized clinical trials . These strategies include switching monotherapy within ( 10 , 1618 ) or between antidepressant classes ( 10 , 1921 ) , combination regimens consisting of 2 antidepressants ( 2226 ) , and augmentation of antidepressants with nonst and ard treatmentsfor example , thyroid hormone ( 27 ) ; S-adenosyl-l-methionine ( 28 ) ; lithium ( 29 ) ; cyclooxygenase-2 inhibitors ( 30 ) ; or an atypical antipsychotic ( 3133 ) , such as risperidone . Findings of several open-label studies ( 3135 ) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy . Risperidone , whose activity includes blockade of certain serotonin and dopamine receptors , is considered an atypical antipsychotic . It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses . The efficacy of risperidone has also been studied for various psychoses and behavioral disorders , including treatment-resistant depression and anxiety spectrum disorders ( 34 , 3639 ) . We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder , enhance clinical response and remission rates , and reduce disability and improve quality of life compared with continued antidepressant monotherapy . Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks ( 38 ) . We therefore conducted a large , multicenter , double-blind , placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of st and ard antidepressants . Methods Design Consenting persons entered a 4-week prospect i ve open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling , so that we could confirm an insufficient response to st and ard monotherapy . The run-in period was followed by a 6-week double-blind treatment phase ; during this phase , patients who continued to experience depressive symptoms , defined as a Clinical Global ImpressionSeverity of illness ( CGI-S ) score of 4 or greater and a Carroll Depression Scale ( 40 ) score of 20 or greater , were r and omly assigned to receive risperidone augmentation therapy or placebo . A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment ( results not shown ) . Setting and Participants Out patients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( 41 ) , criteria for unremitting major depressive disorder ( single or recurrent episodes ) and a CGI-S score of 4 or more ( 42 ) at the start of both the open-label and double-blind phases were eligible . The CGI-S is scored on a scale of increasing intensity from 1 to 7 , with 4 representing moderate illness . We recruited participants by using various methods , including media advertisements , and enrolled persons from 75 public and private primary care ( n= 41 ) and psychiatric ( n= 34 ) centers in the United States between 19 October 2004 and 17 November 2005 . Ethical approval was obtained from the institutional review board of each site , and written informed consent was obtained from all patients . Exclusion criteria were pregnancy ; serious suicidal risk or serious medical or neurologic illness ; active substance or alcohol use disorders ; or current treatment with a tricyclic antidepressant , monoamine oxidase inhibitor , mood stabilizer , antiepileptic , or a central ly acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy . R and omization and Interventions Patients who were eligible for r and omization continued their st and ard antidepressant regimen and dosage and were assigned to receive risperidone or placebo . Tablets were identical in appearance . The investigators , study staff , and patients were blinded to the treatment assignment . The r and omization code was central ly generated and administered by a telephone interactive voice response system , was stratified by antidepressant class ( SSRI or non-SSRI ) and center , and occurred in r and om permuted blocks . An independent statistician provided the r and omization codes . The dosing schedule was 0.25 mg for the first 3 days , 0.5 mg on days 4 to 15 , and 1.0 mg on days 16 to 28 . On day 29 , patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage , have the dosage increased to 2 mg/d , or discontinue double-blind treatment . Concomitant medications were allowed as necessary for medical conditions . Sedative agents ( zolpidem , 2.5 to 10 mg/d , or zaleplon , 5 to 20 mg/d , as needed ) were allowed for insomnia . During double-blind treatment , benztropine mesylate was permitted as needed for potential treatment-emergent motor effects . Measurements and Outcomes At each visit ( end of the open-label phase and weeks 1 , 2 , 4 , and 6 ) , trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) ( 43 , 44 ) and the CGI-S ( 42 ) , both clinician-rated instruments . Scores on the HRSD-17 range from 0 to 52 ; higher scores indicate more severe depression . Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter . Other patient-reported outcomes were scores on 3 vali date d instruments : the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) ( 45 ) , the Patient Global Improvement Scale ( 7-point rating from 1 [ very much improved ] to 7 [ very much worse ] ) , and the Sheehan Disability Scale ( SDS ) . Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure . Response ( 50 % reduction in HRSD-17 total score from baseline ) and remission ( HRSD-17 total score 7 ) were assessed at each time point . Secondary measures were changes in the CGI-S , Q-LES-Q , SDS , and Patient Global Improvement Scale scores . Follow-up Patients underwent physical examination , including assessment of vital signs , at regular intervals . Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days . To assess adverse effects , patients were interviewed at each study visit with open-ended questions about potential adverse events ; spontaneous reports were also taken into account . All adverse events were recorded , and the investigator assessed each event for severity and relationship to the study drug ( probable , possible , not related ) . Statistical Analysis A sample of 116 patients per group was anticipated to have 90 % power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units , assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05 . We also assumed that approximately 30 % of the participants would not complete double-blind treatment and planned for 332 persons to undergo r and omization . We further assumed that during the open-label run-in phase , 30 % of participants would discontinue the study and 20 % would respond to st and ard antidepressant treatment and therefore be ineligible for r and omization ; thus , we sought 592 persons for the open-label run-in phase . All analyses were performed by using SAS , version 8.2 ( SAS Institute , Cary , North Carolina ) , and statistical analysis personnel were blinded to patient group assignment . Baseline patient characteristics were summarized by using descriptive statistics . Efficacy and safety analyses were based on the intention-to-treat population ( that is , all persons who underwent r and omization and received at least 1 dose of medication in the double-blind phase ) . In a double-blind controlled study lasting 8 weeks , 50 anxious psychoneurotic out patients with a primary diagnosis of generalized anxiety or panic disorder were r and omly assigned to alprazolam ( n=30 ) , a new benzodiazepine , or placebo ( n=20 ) , after a washout period of 1 week . Alprazolam at dosages between 0.25 and 3 mg/day was found to be significantly better than placebo in the treatment of either disorder . The finding that alprazolam was effective in the treatment of panic disorder is of interest as this diagnostic category is usually treated with tricyclic antidepressants or MAO inhibitors BACKGROUND Many patients with major depression are non-adherent to antidepressant medication and do not receive care according to current guidelines . There is increasing evidence that treatment of depression in primary care can be improved . Comparison between effective interventions may help to establish the active ingredients of such interventions . METHOD In a r and omized trial two interventions to improve treatment of major depression in primary care were compared ( 1 ) a depression care programme , targeting general practitioners ( GPs ) , patients , and systematic follow-up , and ( 2 ) a systematic follow-up programme .  Thirty GPs were r and omized and 211 primary -care patients with current major depression were included . All patients were prescribed a selective serotonin reuptake inhibitor . Outcome measures included adherence to antidepressant medication , and depression outcome . RESULTS No significant differences in adherence rates and treatment outcome measures were demonstrated between interventions at week 10 or week 26 . Adherence rates were high and treatment outcome was favourable . CONCLUSIONS The depression care programme was not superior to the systematic follow-up programme . Systematic follow-up in depression treatment in primary care seems to be an intervention per se , having the potential to improve adherence and treatment outcome This r and omized double-blind study in 342 mildly to moderately depressive out patients investigated the antidepressant effectiveness and speed of action of lorazepam , alprazolam and amitriptyline versus placebo . Six weeks of drug treatment were followed by a drug taper period , a control period with placebo and a control period without placebo , of 2 weeks duration each . Clinical improvement was assessed by rating scales ( Clinical Global Impressions , Hamilton Rating Scales for Depression and Anxiety ) and patient 's self-ratings ( Patient 's Global Impressions , Self-rating Depression Scale and Visual Analogue Scale ) . At the end of week 6 all active drugs showed similar efficacy which was significantly superior to placebo . Compared to placebo , onset of efficacy was earlier on benzodiazepines than on amitriptyline . While tapering by decreasing the dosage , replacing drug with placebo and finally discontinuing placebo , clear withdrawal phenomena were not seen , but 20 % of patients , equally distributed to all treatment groups , did not want to stop taking tablets after replacing drug with placebo .  Drop-out rate during the treatment period was very low ( 9 % ) . Significantly interfering adverse effects were seen in 27 patients , without predominance in one of the active drug groups This paper presents findings from a multisite study of 126 subjects meeting DSM-III-R criteria for Panic Disorder who also met criteria for a concurrent Major Depressive Episode , Dysthymia , or Depressive Disorder NOS . The study 's primary aim was to discern the influence of varying degrees of depression on the comparative efficacy of alprazolam , imipramine and placebo on anxiety outcomes . A placebo-controlled , double-blind , parallel r and om assignment design was utilized over a total of 16 weeks . There was no medication effect on panic outcomes . At endpoint , percent of anticipatory anxiety ( i.e. , time spent worrying about having an anxiety attack ) was significantly lower in the patients taking active medications vs. placebo .  Phobic measures were significantly improved by alprazolam , vs. both imipramine and placebo early in the study ; however , by week 8 both active medications were equally superior to placebo in the reduction of phobic symptoms . In addition , both active medications were significantly more effective than placebo in reducing depression . The same efficacy pattern ( i.e. , active medications superior to placebo ) was observed on measures of general functioning . Importantly , there were no significant interactions observed between medication and presence of major depression on the depression measures , indicating that both alprazolam and imipramine were equally efficacious in treating the depression in patients with panic disorder and major depression . Since the patients enrolled in this study suffered from major depressive disorder in the mild to moderate severity range , these results may not be transferrable to patients with panic disorder and severe major depression To investigate the effectiveness of a new benzodiazepine , alprazolam , and to compare this with amitriptyline ( AMT ) and with placebo , a trial was undertaken in 65 patients in whom depression was considered to be the dominating feature but not considered to be the primary cause of their condition ; it was design ed to exclude endogenous depressions . A consistent pattern was found favouring alprazolam over AMT both in rate of response and in total response , as well as significant differences in favour of both alprazolam and AMT over placebo . A comparison of side effects showed a definite trend in favour of alprazolam and placebo over AMT Two hundred forty-one out patients with a DSM-III diagnosis of major depressive disorder participated in a six-week double-blind therapeutic trial of alprazolam , diazepam , imipramine hydrochloride , and placebo .  Side effects were given as a major reason for attrition by patients taking the three active compounds and ineffectiveness was the reason given by patients taking placebo . Imipramine-treated patients reported the most and placebo patients the least number of adverse effects .  Imipramine and alprazolam , but not diazepam , produced significantly more improvement in depressed symptomatology than did placebo . Mean diazepam scores frequently assumed an intermediate position between those of imipramine or alprazolam and placebo . These treatment differences were found to be independent of initial severity levels of anxiety and depression In a multicenter placebo-controlled study , the safety , side effects , and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined . A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were r and omly assigned to receive alprazolam or placebo , which they took for eight weeks . The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily . Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug . These included acute intoxication ( three ) , hepatitis ( two ) , mania ( two ) , amnesia ( one ) , aggressive behavior ( one ) , and depression ( one ) . Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation , fatigue , ataxia , slurred speech , and amnesia . Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug . Patient acceptance of alprazolam , as measured by the rate of completion for study participants , was high . Eighty-four percent of patients receiving active drug completed the study compared with 50 % receiving placebo Serotonin-norepinephrine reuptake inhibitors ( SNRIs ) may be used as an alternative treatment for depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant . This r and omized , open-label , multicenter study compared the effectiveness of the SNRI venlafaxine extended release ( VXR ) with that of conventional antidepressants ( CA ) in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a CA in a primary care setting . Patients with a Hamilton Depression Rating Scale ( HAM-D17 ) score > or = 17 were r and omly assigned to treatment with an alternative CA or VXR .  Remission was defined as a score < or = 7 on the HAM-D17 . Efficacy analyses were carried out on 3,097 patients from the intent-to-treat ( ITT ) population ( 1,632 VXR ; 1,465 CA ) . The antidepressants prescribed most frequently in the CA group were paroxetine ( 21.3 % ) , citalopram ( 20.1 % ) , sertraline ( 19.1 % ) , fluoxetine ( 17.0 % ) , and mirtazapine ( 7.9 % ) . After 24 weeks of treatment , the VXR group demonstrated a significantly higher remission rate than did the CA group ( 59.3 % VXR ; 51.5 % CA ; P<.0001 ; odds ratio : 1.37 ; 95 % CI : 1.19 - 1.58 ; P<.01 ) . Despite the limitations of the open design , the results of this study suggest that venlafaxine extended release may be more effective than the conventional antidepressants used in this study when treating depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant The paper consists of two parts . A review of the relationship of panic disorder to the phobic states and the treatment of these disorders by means of tricyclic antidepressants , MAOIs , beta blocking drugs and benzodiazepines . A double blind study of alprazolam and placebo in 118 patients with agoraphobia and panic is presented . In an eight week study alprazolam was found to be significantly superior to placebo in the treatment of panic attacks , phobic avoidance , anticipatory anxiety and general anxiety Major depression disorder is most commonly treated with antidepressants . However , due to their side effects clinicians seek non-pharmacologic options , and one of these is exercise . The literature on the benefits of exercise for depression is extensive . Nevertheless , two recent review s focusing on antidepressants vs. other therapies as a basis for clinical practice guidelines recommended mainly antidepressants , excluding exercise as a viable choice for treatment of depression . The aim of this perspective is to analyze the literature exploring the reasons for this discrepancy . Two categories of publications were examined : r and omized controlled trials ( RCTs ) and meta-analyses or systematic review s. Based on this re assessment , RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective . RCTs comparing exercise combined with antidepressants to antidepressants only reported a significant improvement in depression following exercise as an adjunctive treatment . Almost all the review s examining exercise vs. other treatments of depression , including antidepressants , support the use of exercise in the treatment of depression , at least as an adjunctive therapy . The two review s examining pharmacologic vs. non-pharmacologic therapies as a basis for clinical practice guidelines examined limited evidence on exercise vs. antidepressants . In addition , it is possible that academics and health care practitioners are skeptical of viewing exercise as medicine . Maybe , there is a reluctance to accept that changes in lifestyle as opposed to pharmacological treatment can alter biological mechanisms . Longitudinal studies are needed for assessing the effectiveness of exercise in real clinical setting s , as well as studies exploring dose-response relationship between exercise and depression OBJECTIVE To determine the efficacy and tolerability of aripiprazole , a dopamine D2 and 5-HT1A receptor partial agonist , as augmentation of antidepressant treatment of partially responding and nonresponding patients with major depressive disorder . METHOD Fifteen patients with major depressive disorder ( diagnosed with a site-generated form described in the text ) and an incomplete response or no response to > or = 8 weeks of antidepressant ( selective serotonin reuptake inhibitor , venlafaxine , or bupropion ) monotherapy  were treated with aripiprazole augmentation in an 8-week , open-label study . Data were gathered from July 2003 to March 2004 . RESULTS The mean duration of antidepressant monotherapy at baseline was 43.1 weeks . At baseline , mean Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Depression ( HAM-D ) scores were 4.3 and 18.9 , respectively . After initiation of aripiprazole augmentation , 6 of 15 patients achieved remission ( HAM-D score < or = 7 ) at week 1 , and 9 of 15 patients remitted by week 2 . All 8 completers achieved remission by study endpoint . Akathisia in 2 patients who withdrew prematurely prompted a reduction in the starting dose of aripiprazole from 10 mg/day to 2.5 mg/day , result ing in a 50 % reduction in attrition due to akathisia ( 2/7 withdrew due to akathisia with the 10-mg starting dose , 1/8 withdrew due to akathisia with the 2.5-mg starting dose ) . Discontinuation rates after 4 weeks of treatment were lower for the 2.5-mg starting dose ( 1/8 patients ) than for the 10-mg starting dose ( 3/7 patients ) . Overall discontinuation rates at endpoint were lower for the 2.5-mg dose ( 3/8 patients ) than the 10-mg dose ( 4/7 patients ) . Response to aripiprazole augmentation did not appear to be related to the antidepressant used at study initiation . CONCLUSION Aripiprazole is an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with st and ard antidepressant therapy . Based on this clinical signal , a double-blind , placebo-controlled trial is warranted OBJECTIVE Many depressed patients have negative beliefs about antidepressants , leading to poor adherence , unfavorable depression outcome , and low perceived well-being , role functioning , and quality of life . Interventions to ameliorate beliefs are therefore needed . METHOD In a cluster-r and omized controlled trial conducted from September 1999 to January 2001 , 2 interventions to improve management of major depressive disorder  in primary care were compared : ( 1 ) a depression care program ( DCP ) , providing enhanced patient education , stimulation of active participation of general practitioners and patients in the treatment process , discussion of benefits and costs of taking antidepressant medication , and systematic follow-up and ( 2 ) a systematic follow-up program ( SFP ) .  Thirty general practitioners were r and omly assigned , and 211 patients with current major depressive disorder ( diagnosed according to DSM-IV ) were included . All patients were prescribed a selective serotonin reuptake inhibitor .  Beliefs were assessed at baseline , at week 10 , and at week 26 . Differences in change of beliefs between DCP and SFP groups were analyzed . RESULTS Changes in patients ' beliefs were more favorable in the DCP condition at week 10 and week 26 , compared with SFP only ( beliefs concerning appropriate medication-taking , week 10 : effect size = 0.39 , p = .012 ; week 26 : effect size = 0.55 , p = .001 ; beliefs concerning harmfulness , week 10 : effect size = 0.45 , p = .011 ; week 26 : effect size = 0.62 , p = .002 ) . CONCLUSION The depression care program ameliorates beliefs about antidepressants in primary care patients with major depressive disorder . The study results encourage the implementation of a depression care program in order to improve beliefs about antidepressant medication in primary care patients diagnosed with major depressive disorder Ninety-eight out patients with major depressive disorder were treated with alprazolam , imipramine , or placebo in a 6-week , double-blind study . Average doses were 3.67 mg of alprazolam and 167 mg of imipramine , given at bedtime . Fifty percent of patients taking alprazolam , 38.2 % taking imipramine , and 17.7 % receiving placebo improved their HAM-D scores by more than 50 % . Eight patients on imipramine , 6 on alprazolam , and 1 on placebo dropped out because of side effects . The most common side effects for imipramine were tachycardia , constipation , light-headedness , and sedation ; common side effects of alprazolam were light-headedness , sedation , and unsteadiness UNLABELLED Remission rates for Major Depressive Disorder ( MDD ) are low and unpredictable for any given antidepressant . No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment . Biosignatures developed from the systematic exploration of multiple biological markers , which optimize treatment selection for individuals ( moderators ) and provide early indication of ultimate treatment response ( mediators ) are needed . The rationale and design of a multi-site , placebo-controlled r and omized clinical trial of sertraline examining moderators and mediators of treatment response is described . The target sample is 300 participants with early onset ( ≤30 years ) recurrent MDD . Non-responders to an 8-week trial are switched double blind to either bupropion ( for sertraline non-responders ) or sertraline ( for placebo non-responders ) for an additional 8 weeks . Clinical moderators include anxious depression , early trauma , gender , melancholic and atypical depression , anger attacks , Axis II disorder , hypersomnia/fatigue , and chronicity of depression . Biological moderator and mediators include cerebral cortical thickness , task-based fMRI ( reward and emotion conflict ) , resting connectivity , diffusion tensor imaging ( DTI ) , arterial spin labeling ( ASL ) , electroencephalograpy ( EEG ) , cortical evoked potentials , and behavioral/cognitive tasks evaluated at baseline and week 1 , except DTI , assessed only at baseline . The study is design ed to st and ardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods , and to use advanced data analytic methods to integrate these markers . A Differential Depression Treatment Response Index ( DTRI ) will be developed . The data , including biological sample s ( DNA , RNA , and plasma collected before and during treatment ) , will become available in a public scientific repository . CLINICAL TRIAL REGISTRATION Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression ( EMBARC ) . Identifier : NCT01407094 . URL : http:// clinical trials.gov/show/NCT01407094 OBJECTIVE Few controlled studies have addressed the issue of which antidepressant medications should be recommended for out patients who have not responded to multiple treatment trials . This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant ( nortriptyline ) following two prospect i ve , consecutive , unsuccessful medication treatments for nonpsychotic major depressive disorder . METHOD Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks ( first step ) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone ( second step ) , adult out patients ( N=235 ) with nonpsychotic major depressive disorder were r and omly assigned to 14 weeks of treatment with mirtazapine ( up to 60 mg/day ) ( N=114 ) or nortriptyline ( up to 200 mg/day ) ( N=121 ) . The primary outcome , symptom remission , was defined a priori as a total exit score of < /=7 on the 17-item Hamilton Rating Scale for Depression . The 16-item Quick Inventory of Depressive Symptomatology-Self-Report ( QIDS-SR(16 ) ) , obtained at treatment visits , provided secondary outcomes of remission ( score < /=5 at exit ) and response ( > /=50 % reduction in score from baseline ) . RESULTS For mirtazapine , remission rates were 12.3 % and 8.0 % per the Hamilton and QIDS-SR(16 ) scores , respectively . For nortriptyline , remission rates were 19.8 % and 12.4 % , respectively . QIDS-SR(16 ) response rates were 13.4 % for mirtazapine and 16.5 % for nortriptyline . Neither response nor remission rates statistically differed by treatment , nor did these two treatments differ in tolerability or adverse events . CONCLUSIONS Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials result ed in low remission rates ( < 20 % ) among patients with major depressive disorder
When alprazolam was compared with placebo for reduction in symptoms all estimates indicated a positive effect for alprazolam .
The RD of all-cause withdrawals did not differ between alprazolam and placebo .
Alprazolam appears to reduce depressive symptoms more effectively than placebo and as effectively as tricyclic antidepressants .
Whilst the rate of all-cause withdrawals did not appear to differ between alprazolam and placebo , and withdrawals were less frequent in the alprazolam group than in any of the conventional antidepressants combined group , these findings should be interpreted with caution , given the dependency properties of benzodiazepines
BACKGROUND The ' off-label ' effect of alprazolam on depression has not been systematic ally evaluated .
OBJECTIVES To determine the antidepressant effect , including tolerability and acceptability , of alprazolam as monotherapy for major depression , when compared to placebo and conventional antidepressants in out patients and patients in primary care .