A phase II multicenter dose-finding, efficacy and safety trial of ipsapirone in outpatients with generalized anxiety disorder Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. The diagnosis and treatment of generalized anxiety disorder. Predictors of persistence of comorbid generalized anxiety disorder among veterans with major depressive disorder. An open-label trial of risperidone augmentation for refractory anxiety disorders. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. A pilot controlled trial of bupropion XL versus escitalopram in generalized anxiety disorder. Psychopharmacotherapy of somatoform disorders: effects of opipramol on symptoms of somatization, anxiety, and depression. Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder Kava for the treatment of generalised anxiety disorder (K-GAD): study protocol for a randomised controlled trial Efficacy of Agomelatine in Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled Study Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. Efficacy of an acceptance-based behavior therapy for generalized anxiety disorder: evaluation in a randomized controlled trial. Benzodiazepine discontinuation among adults with GAD: A randomized trial of cognitive-behavioral therapy. Protocol for a randomised controlled trial investigating the effectiveness of an online e-health application compared to attention placebo or sertraline in the treatment of generalised anxiety disorder Paroxetine efficacy in the treatment of generalized anxiety disorder Broadening of Generalized Anxiety Disorders Definition Does not Affect the Response to Psychiatric Care: Findings from the Observational ADAN Study Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from 4 randomized, double-blind, placebo-controlled studies. Efficacy and Safety of Lesopitron in Outpatients with Generalized Anxiety Disorder
Benzodiazepines have been prescribed for the treatment of  Generalized Anxiety Disorder ( GAD ) for nearly three decades due to their proven anxiolytic efficacy , despite a considerable side effect and abuse liability profile . A new class of compounds , the azapirones , have been developed as an alternative to benzodiazepine treatment . Ipsapirone is a novel anxiolytic azapirone which has high specificity for the 5-HT1A receptor and which has the potential for offering certain advantages over buspirone . The present 5-week study investigated three doses of ipsapirone ( 2.5 mg , 5.0 mg and 7.5 mg tid ) versus placebo in 267 GAD out patients .  Efficacy was evaluated using the Hamilton Anxiety Rating Scale ( HAM-A ) , Zung Anxiety Scale ( Zung-A ) , and Clinical Global Impression ( CGI ) . The study design consisted of a 1-week placebo run-in , a 4-week double-blind treatment period , and a 1-week placebo washout . The 5.0 mg group demonstrated consistently superior improvement in all efficacy variables during the treatment period , with significant differences ( p < 0.05 ) from placebo and , at times , the 2.5 mg and 7.5 mg groups . Incidence of adverse events , primarily dizziness , nausea , sedation , and asthenia , was found to be dose proportional , with significant increase in the 7.5 mg group , which may account for the diminished effectiveness seen with this dose . Our results suggest that ipsapirone may represent a viable treatment for GAD OBJECTIVE The current study examines whether antidepressants , contrary to current thinking , are safe and effective treatments for generalized anxiety disorder ( GAD ) not complicated by depression or panic disorder . DESIGN R and omized , double-blind , placebo-controlled , flexible-dose , 8-week treatment study comparing imipramine hydrochloride ( mean maximum daily dose , 143 mg ) , trazodone hydrochloride ( 255 mg ) , and diazepam ( 26 mg ) . PATIENTS Two hundred thirty patients with a DSM-III diagnosis of GAD in whom major depression and panic disorder has been excluded , and who had a Hamilton Anxiety Scale total score of at least 18 . SETTING Seventy-five percent of patients were treated in family practice setting s in the community , with the remainder treated in psychiatric practice s , either academic or private . RESULTS Patients treated with diazepam showed the most improvement in anxiety ratings during the first 2 weeks of treatment , with somatic symptoms being most responsive . From week 3 through week 8 trazodone achieved comparable , and imipramine somewhat better , anxiolytic efficacy when compared with diazepam , with psychic symptoms of tension , apprehension , and worry being more responsive to the antidepressants . Among completers , moderate to marked improvement was reported by 73 % of patients treated with imipramine , 69 % of patients treated with trazodone , 66 % of patients treated with diazepam , but only 47 % of patients treated with placebo . Overall , patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients , but attention rates were the same across all treatments . CONCLUSIONS The results of the study need replication , but suggest a potentially important role for antidepressants , particularly imipramine , in patients suffering from GAD BACKGROUND Generalized anxiety disorder  ( GAD ) is a common and serious disease with a lifetime prevalence of 4.3 % to 5.9 % . It is underdiagnosed in primary care . METHODS Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent r and omized trials , retrieved by a selective search of the literature . RESULTS Among psychotherapeutic techniques , various kinds of cognitive behavioral therapy ( CBT ) have been found useful in controlled trials . The drugs of first choice include selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-norepinephine reuptake inhibitors ( SNRIs ) , and the calcium-channel modulator pregabalin . Tricyclic antidepressants are also effective but have more adverse effects than SSRIs . Although benzodiazepines are effective anxiolytic agents for short-term use , they should not be given over the long term because of the danger of addiction . Buspirone , an azapirone , was found to be effective in a small number of trials , but the findings across trials are inconsistent . The response rate of GAD to CBT in published studies lies between 47 % and 75 % , while its response rate to drug treatment lies between 44 % and 81 % . CONCLUSION The treatment of GAD with CBT and drugs is evidence -based and has a good chance of improving the manifestations of the disorder OBJECTIVE A limited number of r and omized clinical trials show that efficacious pharmacologic treatments exist for comorbid major depressive disorder ( MDD ) and generalized anxiety disorder ( GAD ) . The aims of this effectiveness study were to describe the impact of a depression care management intervention on the persistence of comorbid GAD symptoms in a sample of primary care patients with MDD and to identify risk factors for persistent GAD . METHOD Data were collected from April 2003 to September 2005 for the Telemedicine-Enhanced Antidepressant Management ( TEAM ) study , a multisite , r and omized effectiveness trial targeting US Department of Veterans Affairs ( VA ) primary care patients with depression . Veterans aged 26.59 - 88.36 years received either the  TEAM intervention or usual care in small VA community-based outpatient clinics . The TEAM care management intervention focused on optimizing antidepressant therapy through patient education and activation , symptom monitoring , adherence promotion , and side-effect management .  Veterans who screened positive for MDD using the Patient Health Question naire-9 ( based on DSM-IV criteria ) and who met the Mini-International Neuropsychiatric Interview criteria ( maintaining consistency with DSM-IV-TR ) for comorbid GAD at baseline were selected for the present study ( N = 168 ) . The primary outcome was persistence of GAD at 6 months and 12 months . All predictors available in the TEAM study data that were described in the literature to be associated with influencing GAD outcomes were examined . RESULTS Persistence of depression was the strongest predictor of persistence of comorbid GAD at both 6 months ( OR = 5.75 ; 95 % CI , 2.38 - 13.86 ; P < .05 ) and 12 months ( OR = 15.56 ; 95 % CI , 6.10 - 39.68 ; P < .05 ) . Although the TEAM intervention significantly reduced depression symptom severity , it was not significantly associated with GAD persistence . Insomnia was a significant protective factor for persistence of GAD at 6 months ( OR = 0.66 ; 95 % CI , 0.44 - 0.99 ; P < .05 ) . CONCLUSIONS Early screening for presence of comorbid GAD among those with MDD may be valuable both for further research and for enhancing clinical management of GAD and MDD comorbidity BACKGROUND There is a paucity of data to support " next-step " treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy . METHOD Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder ( PD ) , social anxiety disorder ( SAD ) , or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate ( or maximally tolerated ) antidepressant and /or benzodiazepine trial of at least 8 weeks ' duration prior to study initiation received open-label augmentation with  flexibly dosed risperidone for 8 weeks . Participants were diagnosed using the Structured Clinical Interview for DSM-IV . RESULTS Risperidone augmentation at a mean + /- SD dose of 1.12 + /- 0.68 mg/day ( range , 0.25 - 3.00 mg/day ) result ed in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety ( HAM-A ) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale , the Liebowitz Social Anxiety Scale , and HAM-A-in the intent-to-treat sample . Seventy percent ( 21/30 ) of participants completed the 8-week trial , with premature discontinuation due primarily to sedation and weight gain . CONCLUSIONS Although conclusions are limited by the open-label , relatively brief nature of this trial , our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD , SAD , or GAD refractory to adequate initial intervention with antidepressants and /or benzodiazepines . Longer-term , controlled safety and efficacy data are needed to underst and the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders BACKGROUND The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder . Although second generation antipsychotics are being used with increasing frequency in bipolar patients , their anxiolytic effects have not been well studied in this population . METHODS The anxiolytic effect of risperidone 0.5 - 4 mg/day was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder ( GAD ) . The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale ( CGI-21 Anxiety ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and the Sheehan Panic Disorder Scale . RESULTS On the last-observation-carried forward analysis of repeated measures analysis of variance ( ANOVA ) , risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures .  Risperidone was well tolerated , with only two patients withdrawing because of adverse events . LIMITATIONS The  risperidone treated group had more patients with mixed states and lifetime panic disorder at r and omization than the placebo group . The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD . The results may not be applicable to risperidone as an add-on treatment to mood stabilizers , or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD . CONCLUSIONS Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5 - 4 mg/day over 8 weeks of treatment . The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind , placebo-controlled studies OBJECTIVE To compare the efficacy and safety of bupropion XL ( 150 to 300 mg/day ) with the selective serotonin reuptake inhibitor escitalopram ( 10 to 20 mg/day ) in out patients diagnosed with generalized anxiety disorder ( GAD ) . METHODS Twenty-four participants with GAD between 18 and 64 years enrolled in a 12-week , double-blind , r and omized trial . The primary efficacy measures were the Clinical Global Impression of Improvement ( CGI-I ) and the Hamilton Anxiety Rating Scale ( HARS ) . RESULTS Bupropion XL demonstrated comparable anxiolytic efficacy to escitalopram in out patients with GAD . Both treatments were well-tolerated . CONCLUSION Findings from this pilot project suggest that bupropion XL may be useful in treating GAD . These preliminary results warrant further research to explore the use of bupropion XL in the treatment of GAD BACKGROUND The psychopharmacotherapy of somatoform disorders ( SD ; ICD-10 : F45 ) has been less frequently investigated and is not as well established as in other ( neurotic ) disorders of ICD-10 section F4 , i.e. generalized anxiety disorder ( GAD ; ICD-10 : F41.1 ) . The atypical compound opipramol is very often used to treat SD and GAD in clinical practice in Germany . However , state-of-the-art controlled clinical trials have not yet been performed . OBJECTIVES Two clinical trials were performed with the aim of confirming the efficacy and tolerability of opipramol in SD and GAD . METHODS Both trials were performed as r and omized , double-blind , placebo-controlled , multicenter studies . While the GAD trial was a three-arm study with opipramol ( 200 mg/day ) vs. placebo and alprazolam ( 2 mg/day ) for 28 days , the SD trial was a placebo-controlled two-arm study with a treatment duration of 42 days . Each group consisted of about 100 patients . RESULTS Significant differences ( alpha = 0.05 ) were found for the primary efficacy criteria ( HAMA total score in GAD , HAMA somatic subscore in SD ) and most of the secondary criteria in favor of the active drug therapies . Considerable differences between the psychopathology of SD and GAD were detected . CONCLUSION The well-tolerated anxiolytic opipramol is the first psychotropic drug with proven efficacy in somatoform disorders with effects on symptoms of somatization , anxiety , and depression . The compound is also effective and safe in GAD BACKGROUND Although generalized anxiety disorder ( GAD ) and major depressive episode ( MDE ) are known to be highly co-morbid , little prospect i ve research has examined whether these two disorders predict the subsequent first onset or persistence of the other or the extent to which other predictors explain the time-lagged associations between GAD and MDE . METHOD Data were analyzed from the nationally representative two-wave panel sample of 5001 respondents who participated in the 1990 - 1992 National Comorbidity Survey ( NCS ) and the 2001 - 2003 NCS follow-up survey .  Both surveys assessed GAD and MDE . The baseline NCS also assessed three sets of risk factors that are considered here : childhood adversities , parental history of mental-substance disorders , and respondent personality . RESULTS Baseline MDE significantly predicted subsequent GAD onset but not persistence . Baseline GAD significantly predicted subsequent MDE onset and persistence . The associations of each disorder with the subsequent onset of the other attenuated with time since onset of the temporally primary disorder , but remained significant for over a decade after this onset . The risk factors predicted onset more than persistence . Meaningful variation was found in the strength and consistency of associations between risk factors and the two disorders . Controls for risk factors did not substantially reduce the net cross-lagged associations of the disorders with each other . CONCLUSIONS The existence of differences in risk factors for GAD and MDE argues against the view that the two disorders are merely different manifestations of a single underlying internalizing syndrome or that GAD is merely a prodrome , residual , or severity marker of MDE Antidepressant drugs are the preferred choice for the treatment of generalized anxiety disorder ( GAD ) . However , the choice of pharmacotherapy is determined on a trial- and -error basis , as the underlying mechanisms of treatment response are unknown . We examined whether the COMT gene , which has been known to play a role in antidepressant treatment response in major depressive disorder ( MDD ) , has a pharmacogenetic effect in antidepressant treatment response in GAD . In our study , 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study . Genotypes were obtained for the COMT functional variant rs4680 ( Val158Met ) for all patients ; however , pharmacogenetic analysis was only conducted for the European American population ( n=112 ) . We found no significant association between our primary Hamilton Anxiety Scale outcome measure and rs4680 . However , we did find a nominally significant allelic association between this variant and a secondary treatment outcome measure ( CGI-I ) in our European American population ( n=112 ) . Furthermore , we show a slight dominant effect of the A-allele with the CGI-I measure in the European American population indicating a possible pharmacogenetic role of rs4680 in antidepressant treatment outcome in GAD . Further studies in a larger population are needed to confirm this effect Background Generalised anxiety disorder ( GAD ) is a chronic and pervasive condition that generates high levels of psychological stress , and it is difficult to treat in the long term . Current pharmacotherapeutic options for GAD are in some cases only modestly effective , and may elicit undesirable side effects . Through targeted actions on the gamma-aminobutyric acid ( GABA ) pathway , the South Pacific medicinal plant kava ( Piper methysticum ) is a non-addictive , non-hypnotic anxiolytic with the potential to treat GAD . The evidence for the efficacy of kava for treating anxiety has been affirmed through clinical trials and meta-analyses . Recent research has also served to lessen safety concerns regarding the use of kava due to hepatotoxic risk , which is reflected in a recent German court overturning the previous kava ban in that country ( which may in turn influence a reinstatement by the European Union ) . The aim of current research is to assess the efficacy of an ‘ aqueous noble cultivar rootstock extract ’ of kava in GAD in a larger longer term study . In addition , we plan to investigate the pharmacogenomic influence of GABA transporters on response , effects of kava on gene expression , and for the first time , the neurobiological correlates of treatment response via functional and metabolic imaging . Methods / Design This clinical trial is funded by the Australian National Health and Medical Research Council ( APP1063383 ) and co-funded by MediHerb ( Integria Healthcare ( Australia ) Pty . Ltd ) . The study is a phase III , multi-site , two-arm , 18-week , r and omised , double-blind , placebo-controlled study using an aqueous extract of noble kava cultivar ( st and ardised to 240 mg of kavalactones per day ) versus matching placebo in 210 currently anxious participants with diagnosed GAD who are non-medicated . The study takes place at two sites : the Centre for Human Psychopharmacology ( Swinburne University of Technology ) , Hawthorn , Melbourne , Australia ; and the Academic Discipline of Psychiatry ( The University of Queensl and ) based at the Royal Brisbane and Women ’s Hospital , Herston , Brisbane , Australia . Written informed consent will be obtained from each participant prior to commencement in the study . The primary outcome is the Structured Interview Guide for the Hamilton Anxiety Rating Scale ( SIGH-A ) . The secondary outcomes involve a range of scales that assess affective disorder symptoms and quality of life outcomes , in addition to the study of mediating biomarkers of response ( assessed via genomics and neuroimaging ) . Discussion If this study demonstrates positive findings in support of the superiority of kava over placebo in the treatment of GAD , and also is shown to be safe , then this plant-medicine can be considered a ’ first-line ‘ therapy for GAD . Genomic and neuroimaging data may reveal clinical response patterns and provide more evidence of the neurobiological activity of the plant extract . Trial Registration Information Clinical Trials.gov : NCT02219880 Date : 13 August 2014 Background : Agomelatine is a novel agent that acts on melatonergic ( MT1 , MT2 ) receptors and serotonergic ( 5-HT2C ) receptors . Pre clinical data and data from clinical trials in major depression suggest that agomelatine may have anxiolytic properties . A r and omized , double-blind , placebo-controlled trial was design ed to assess the efficacy of agomelatine in generalized anxiety disorder ( GAD ) . Methods : One hundred twenty-one patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition GAD and no comorbid disorders were r and omized to agomelatine ( 25 - 50 mg/d ) or placebo for 12 weeks . The primary outcome measure was the Hamilton Anxiety Rating Scale , whereas secondary outcome measures included the Clinical Global Impression scales , the Leeds Sleep Evaluation Question naire , and the Sheehan Disability Scale . Safety measures included assessment of spontaneously reported adverse events , laboratory monitoring , and the Discontinuation Emergent Signs and Symptoms Scale to evaluate discontinuation symptoms . Results : Analysis of covariance of change in the last Hamilton Anxiety Rating Scale total score from baseline demonstrated significant superiority of agomelatine 25 to 50 mg as compared with placebo ( E [ SE ] = −3.28 [ 1.58 ] ; 95 % confidence interval = −6.41 to −0.15 ; P = 0.040 ) . Data on secondary outcome measures , including clinical response , symptoms of insomnia , and improvement in associated disability , were consistent with the efficacy of agomelatine . Safety analysis indicated that agomelatine was tolerated as well as placebo and was devoid of discontinuation emergent symptoms . Conclusions : This study suggests that agomelatine is effective in the treatment of GAD and is well tolerated . Additional trials , using an active comparator and extending over a longer period , are needed to delineate the place of agomelatine in the contemporary pharmacotherapy for anxiety disorders CONTEXT Generalized anxiety disorder ( GAD ) is a chronic disorder that is associated with debilitating psychic and somatic symptoms . Venlafaxine extended-release ( XR ) capsules have been shown to be effective in short-term treatment of patients with GAD without major depressive disorder ( MDD ) , but long-term data are needed to establish whether this agent confers persistent benefits . OBJECTIVE To compare the 6-month efficacy and safety of a flexible dosage of venlafaxine XR in out patients with GAD without associated MDD . DESIGN Six-month , r and omized , double-blind , placebo-controlled , parallel-group trial conducted May 1996 to October 1997 . SETTING Fourteen outpatient clinics and private psychiatric practice s in the United States . PARTICIPANTS A total of 251 out patients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ( DSM-IV ) criteria for GAD , had sufficient symptoms to require treatment , and did not have coexisting MDD . INTERVENTIONS Participants were r and omly assigned to receive either placebo ( n=127 ) or venlafaxine XR ( 75 , 150 , or 225 mg/d , as required to control symptoms ; n=124 ) for 28 weeks . MAIN OUTCOME MEASURES Changes from baseline in the Hamilton Rating Scale for Anxiety ( HAM-A ) total score , the HAM-A psychic anxiety factor score , and the Clinical Global Impressions ( CGI ) scale Severity of Illness and Global Improvement scores , compared by intervention group . RESULTS During weeks 6 through 28 , response rates in the venlafaxine XR group were 69 % or higher compared with rates of 42 % to 46 % in the placebo group ( P<.001 ) . By an evaluable-patient analysis , venlafaxine XR compared with placebo significantly improved anxiety scores from week 1 or 2 through week 28 on all primary efficacy measures , including the HAM-A total ( P<.001 ) , the HAM-A psychic anxiety factor ( P<.001 ) , and the CGI scale scores ( P<.001 ) . Adjusted mean changes from baseline to week 28 using last-observation-carried-forward methods were for HAM-A , venlafaxine XR -13.4 , placebo -8.7 ( P<.001 ) ; for HAM-A psychic anxiety score , venlafaxine XR -7.4 , placebo -4.2 ( P<.001 ) ; and for CGI-Improvement , venlafaxine XR 2.2 , placebo 3.0 ( P<.001 ) . The most common treatment-emergent adverse event was nausea , followed by somnolence and dry mouth . CONCLUSIONS This study is the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating out patients with DSM-IV-diagnosed GAD .  Venlafaxine XR is an effective , rapidly acting , safe , once-daily agent for both the short- and long-term treatment of anxiety and may provide an important alternative to currently available anxiolytics . JAMA . 2000 BACKGROUND Conventional drug treatments for Generalized Anxiety Disorder ( GAD ) are often accompanied by substantial side effects , dependence , and /or withdrawal syndrome . A prior controlled study of oral chamomile ( Matricaria chamomilla L. ) extract showed significant efficacy versus placebo , and suggested that chamomile may have anxiolytic activity for individuals with GAD . HYPOTHESIS We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings , and would be associated with a favorable adverse event and tolerability profile . STUDY DESIGN We report on the open-label phase of a two-phase r and omized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD . METHODS Subjects with moderate to severe GAD received open-label treatment with pharmaceutical- grade chamomile extract 1500mg/day for up to 8 weeks . Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8 . Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety , the Beck Anxiety Inventory , and the Psychological General Well Being Index . Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined . RESULTS Of 179 subjects , 58.1 % ( 95 % CI : 50.9 % to 65.5 % ) met criteria for response , while 15.6 % prematurely discontinued treatment . Significant improvement over time was also observed on the GAD-7 rating ( β=-8.4 [ 95 % CI=-9.1 to -7.7 ] ) . A similar proportion of subjects demonstrated statistically significant and clinical ly meaningful reductions in secondary outcome ratings of anxiety and well-being . Adverse events occurred in 11.7 % of subjects , although no serious adverse events occurred . CONCLUSION Chamomile extract produced a clinical ly meaningful reduction in GAD symptoms over 8 weeks , with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile . Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD BACKGROUND The objective of this r and omized , double-blind study was to compare the efficacy and safety of venlafaxine extended release ( XR ) and buspirone in out patients with generalized anxiety disorder ( GAD ) but without concomitant major depressive disorder . METHOD Male and female out patients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety ( HAM-A ) were r and omly assigned to treatment with either venlafaxine XR ( 75 or 150 mg/day ) , buspirone ( 30 mg/day in 3 divided doses ) , or placebo for 8 weeks . The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale ( CGI ) scores . Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale ( HAD ) . RESULTS The efficacy analysis included 365 patients and the safety analysis , 405 . At week 8 , adjusted mean HAM-A psychic anxiety , anxious mood , and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients . On the HAD anxiety subscale , venlafaxine XR , 75 or 150 mg/day , was significantly more efficacious than placebo at all time points except weeks 1 ( both dosages ) and 2 ( 150-mg/day dosage only ) and significantly more efficacious than buspirone at all time points except week 1 . On the CGI-Improvement scale , scores for venlafaxine XR ( both dosages ) and buspirone were numerically superior to those for placebo at all time points , and statistical significance was observed at weeks 3 , 4 , 6 , and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone . The adverse events were not essentially different between treatment groups . CONCLUSION Venlafaxine XR is an effective , safe , and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder . This agent was significantly superior to buspirone on the HAD anxiety subscale . Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response Generalized anxiety disorder ( GAD ) is a chronic anxiety disorder , associated with comorbidity and impairment in quality of life , for which improved psychosocial treatments are needed . GAD is also associated with reactivity to and avoidance of internal experiences . The current study examined the efficacy of an acceptance-based behavioral therapy aim ed at increasing acceptance of internal experiences and encouraging action in valued domains for GAD . Clients were r and omly assigned to immediate ( n = 15 ) or delayed ( n = 16 ) treatment .  Acceptance-based behavior therapy led to statistically significant reductions in clinician-rated and self-reported GAD symptoms that were maintained at 3- and 9-month follow-up assessment s ; significant reductions in depressive symptoms were also observed . At posttreatment assessment 78 % of treated participants no longer met criteria for GAD and 77 % achieved high end-state functioning ; these proportions stayed constant or increased over time . As predicted , treatment was associated with decreases in experiential avoidance and increases in mindfulness This study evaluated the specific effectiveness of cognitive-behavior therapy ( CBT ) combined with medication tapering for benzodiazepine discontinuation among generalized anxiety disorder ( GAD ) patients by using a nonspecific therapy control group . Sixty-one patients who had used benzodiazepines for more than 12 months were r and omly assigned to the experimental conditions . Nearly 75 % of patients in the CBT condition completely ceased benzodiazepine intake , as compared with 37 % in the control condition . Results of the 3- , 6- , and 12-month follow-ups confirmed the maintenance of complete cessation . Discontinuation rates remained twice as high in the CBT condition . The number of patients who no longer met GAD criteria was also greater in the CBT condition . The addition of specific CBT components thus seemed to facilitate benzodiazepine tapering among patients with GAD Background Generalised anxiety disorder ( GAD ) is a high prevalence , chronic psychiatric disorder which commonly presents early in the lifespan . Internet e-health applications have been found to be successful in reducing symptoms of anxiety and stress for post traumatic stress disorder ( PTSD ) , panic disorder , social phobia and depression . However , to date , there is little evidence for the effectiveness of e-health applications in adult GAD . There are no studies which have directly compared e-health applications with recognised evidence -based medication . This study aims to determine the effectiveness of a  web-based program for treating GAD relative to sertraline and attention placebo . Methods / Design 120 community-dwelling participants , aged 18 - 30 years with a clinical diagnosis of GAD will be recruited from the Australian Electoral Roll . They will be r and omly allocated to one of three conditions : ( i ) an online treatment program for GAD , E-couch ( ii ) pharmacological treatment with a selective serotonin re-uptake inhibitor ( SSRI ) , sertraline ( a fixed-flexible dose of 25 - 100 mg/day ) or ( iii ) an attention control placebo , HealthWatch . The treatment program will be completed over a 10 week period with a 12 month follow-up . Discussion As of February 2010 , there were no registered trials evaluating the effectiveness of an e-health application for GAD for young adults . Similarly to date , this will be the first trial to compare an e-health intervention with a pharmacological treatment . Trial Registration Current Controlled Trials IS RCT Recently , there has been a renewed interest in alternatives to the benzodiazepines for the treatment of  generalized anxiety disorder ( GAD ) . The aim of the present study was to compare the efficacy of paroxetine vs. imipramine and 2′‐chlordesmethyldiazepam in 81 patients with a DSM‐IV diagnosis of GAD . Approximately two‐thirds of the patients who completed the study improved greatly or moderately on all three active drugs . During the first 2 weeks of treatment , 2′‐chlordesmethyldiazepam treatment result ed in the greatest improvement in anxiety ratings . Both paroxetine and imipramine treatment result ed in more improvement than 2′‐chlordesmethyldiazepam by the fourth week of treatment . Paroxetine and imipramine affect predominantly psychic symptoms , whereas 2′‐chlordesmethyldiazepam affects predominantly somatic symptoms . Our results suggest that paroxetine is effective for the treatment of GAD Objective : To eluci date the consequences of broadening DSM-IV criteria for generalized anxiety disorder ( GAD ) , we examined prospect ively the evolution of GAD symptoms in two groups of patients ; one group diagnosed according to DSM-IV criteria and the other , according to broader criteria . Method : Multicentre , prospect i ve and observational study conducted on outpatient psychiatric clinics . Patients were selected from October 2007 to January 2009 and diagnosed with GAD according to DSM-IV criteria ( DSM-IV group ) or broader criteria . Broader criteria were considered 1-month of excessive or non-excessive worry and only 2 of the associated symptoms listed on DSM-IV for GAD diagnosis . Socio-demographic data , medical history and functional outcome measures were collected three times during a 6-month period . Results : 3,549 patients were systematic ally recruited ; 1,815 patients in DSM-IV group ( DG ) and 1,264 in broad group ( BG ) ; 453 patients did not fulfil inclusion criteria and were excluded . Most patients ( 87.9 % in DG , 82.0 % in BG ) were currently following pharmacological therapies ( mainly benzodiazepines ) to manage their anxiety symptoms . The changes observed during the study were : 49.0 % and 58.0 % , respectively of patients without anxiety symptoms as per HAM-A scale at the 6 month visit ( p=0.261 ) and 59.7 % and 67.7 % , respectively ( p=0.103 ) of responder rates ( > 50 % reduction of baseline scoring ) . Conclusion : Broadening of GAD criteria does not seem to affect psychiatric care results in subjects with GAD , is able to identify the core symptoms of the disease according to the DSM-IV criteria and could lead to an earlier diagnosis LY354740 , a potent and selective mGlu ( metabotropic glutamate receptor)2/3 agonist , has shown efficacy in the treatment of generalized anxiety disorder ( GAD ) . LY544344 is a LY354740 prodrug that increases LY354740 bioavailability . This 8-week study was design ed to evaluate the efficacy , safety , and tolerability of LY544344 in the treatment of GAD . Participants had a diagnoses of GAD , baseline Hospital Anxiety and Depression Scale anxiety subscale scores ⩾10 , and moderate illness severity . Patients were r and omized to double-blind treatment with LY544344 16 mg b.i.d . ( n=28 ) , LY544344 8 mg b.i.d . ( n=36 ) , or placebo ( n=44 ) . LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression — Improvement scores , as well as response and remission rates compared with placebo-treated patients . LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups . However , the trial was discontinued early based on findings of convulsions in pre clinical studies . In conclusion , the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD . Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344 OBJECTIVE These studies were design ed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b ) receptor antagonist , SSR149415 , in the treatment of major depressive disorder ( MDD ) and generalized anxiety disorder ( GAD ) . METHOD Studies were r and omized 8-week , double-blind , placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415 , placebo , and escitalopram 10 mg/day or paroxetine 20 mg/day , conducted from August 2006 through February 2008 . Participants met the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , Text Revision criteria for MDD or GAD .  Baseline Montgomery-Asberg Depression Rating Scale ( MADRS ) and Hamilton Depression Rating Scale ( HDRS ) total scores were ≥ 24 and 18 , respectively , and in the GAD trial baseline Hamilton Anxiety Rating Scale ( HARS ) score was ≥ 22 . Primary efficacy variables included changes from baseline in total score on HDRS or HARS and MADRS , and the secondary variable included changes in the Clinical Global Impressions-Severity of Illness score ( CGI-S ) . A 4-week , double-blind , placebo-controlled study evaluating the effect of 100- and 250-mg twice daily doses of SSR149415 on the hypothalamic-pituitary-adrenal ( HPA ) axis in MDD patients was also conducted . RESULTS In the GAD trial , SSR149415 did not separate from placebo on the primary ( HARS-100 mg : P = .29 ; 250 mg : P = .21 ) and secondary ( CGI-S-100 mg : P = .18 ; 250 mg : P = .24 ) outcome measures , while paroxetine  demonstrated efficacy ( HARS : P = .003 ; CGI-S : P = .01 ) . In 2 MDD trials , SSR149415-treated patients did not show significant improvement from baseline on any outcome measure compared with placebo-treated patients ( HDRS-100 mg : P = .21 and .48 , respectively ; 250 mg : P = .22 and P = .46 , respectively ; CGI-S-100 mg : P = .64 and P = .82 , respectively ; 250 mg : P = .33 and P = .08 , respectively ) . In the third MDD study , SSR149415 250 mg ( P = .04 ) , but not escitalopram ( P = .15 ) , demonstrated significant improvement compared to placebo on the HDRS total score at week 8 . SSR149415 had no deleterious effects on the HPA axis . CONCLUSIONS These studies demonstrate that SSR149415 may not be useful for the treatment of GAD and that its antidepressant potential needs to be further evaluated . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00374166 ( Sanofi ID number : DFI5880 ) , NCT00361491 ( Sanofi ID number : DFI5879 ) , NCT00358631 ( Sanofi ID number : DFI5878 ) , NCT01606384 ( Sanofi ID number : PDY5467 ) OBJECTIVE : To compare the relative efficacy and safety of lesopitron 40–80 mg/d versus lorazepam 2–4 mg/d and placebo in a subgroup of patients with anxiety history taken from a larger study of patients with a primary diagnosis of generalized anxiety disorder ( GAD ) . DESIGN : Six-week , r and omized , double-blind , parallel , placebo and lorazepam-controlled , Phase II , single-center , outpatient study . SETTING : Outpatient clinic . PATIENTS : One hundred sixty-one patients with GAD were r and omized in the main study ; 68 with a documented history of GAD or anxiety disorder not otherwise specified were included in the subgroup . METHODS : After a one-week placebo lead-in , patients were r and omized to receive placebo , lesopitron , or lorazepam twice daily for six weeks , followed by a one-week taper period . Efficacy was assessed using the Hamilton Rating Scale for Anxiety ( HAM-A ) and the Clinical Global Impressions scale . Safety was assessed through physical examinations , monitoring of vital signs , 12-lead electrocardiograms , laboratory analyses , and adverse event monitoring . RESULTS : An overall mean improvement in the HAM-A total score between baseline and end point for all three treatment groups was seen , with mean changes of 3.4 ( 95 % CI 2.0 to 4.8 ) , 6.1 ( 95 % CI 4.1 to 8.1 ) , and 6.1 ( 95 % CI 4.6 to 7.6 ) for the placebo , lesopitron , and lorazepam groups , respectively ( omnibus p = 0.044 , uncorrected ) . Positive treatment effects were also observed in the subgroup population on several other measures and suggest that additional therapeutic trials may be warranted . Future trials could be stratified on the basis of referral status ( symptomatic volunteer vs. clinical patient with preexisting illness ) or previous exposure to anxiolytics , and use a fixed-dose rather than flexible-fixed-dose design . CONCLUSIONS : The subgroup analysis represents a comparison of treatment outcome in GAD patients presenting with a history of previous episodes of GAD or anxiety disorder not otherwise specified compared with those who were experiencing their first episode of GAD and reported no anxiety history . Although the overall study analysis was equivocal , for the approximately 40 % of patients with recurrent anxiety disorder , beneficial effects for both lesopitron and lorazepam are suggested
Dropout rates did not differ between antidepressants .
The latter study showed very promising results of  sertraline  in children and adolescents with GAD , which warrants its replication in larger sample s. REVIEW ER 'S CONCLUSIONS The available evidence suggests that antidepressants are superior to placebo in treating GAD .
There is also evidence from placebo-controlled trials suggesting that these drugs are well tolerated by GAD patients .
Further trials of antidepressants for GAD will help to demonstrate which antidepressants should be used for which patients
BACKGROUND Pharmacological treatments have been successfully used to treat  Generalized Anxiety Disorder ( GAD ) .
The mainstay for the pharmacological treatment of GAD in past decades has been the use of benzodiazepine and non benzodiazepine anxiolytics .
Data emerging over the last two decades have shown that antidepressants may be equally effective to anxiolytics for treating GAD .
The use of antidepressants for treating GAD may be advantageous , due to the fact that GAD presents a high co morbidity ratio with major depressive disorder ( 62 % ) and dysthymia ( 37 % ) .
OBJECTIVES To assess the efficacy and acceptability of antidepressants for treating generalized anxiety disorder .