A phase II multicenter dose-finding, efficacy and safety trial of ipsapirone in outpatients with generalized anxiety disorder The safety and efficacy of ipsapirone vs. lorazepam in outpatients with generalized anxiety disorder (GAD): single site findings from a multicenter trial. The diagnosis and treatment of generalized anxiety disorder. Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study. Efficacy of an acceptance-based behavior therapy for generalized anxiety disorder: evaluation in a randomized controlled trial. Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder Anxiety Disorders in Primary Care: Prevalence, Impairment, Comorbidity, and Detection Psychopharmacotherapy of somatoform disorders: effects of opipramol on symptoms of somatization, anxiety, and depression. Internet-Based Psychodynamic versus Cognitive Behavioral Guided Self-Help for Generalized Anxiety Disorder: A Randomized Controlled Trial A pilot controlled trial of bupropion XL versus escitalopram 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 Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder. Varying temporal criteria for generalized anxiety disorder: prevalence and clinical characteristics in a young age cohort. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Efficacy of applied relaxation and cognitive-behavioral therapy in the treatment of generalized anxiety disorder. Internet-delivered acceptance-based behaviour therapy for generalized anxiety disorder: A randomized controlled trial. A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder Paroxetine efficacy in the treatment of generalized anxiety disorder Treatment of poststroke generalized anxiety disorder comorbid with poststroke depression: merged analysis of nortriptyline trials. The contributory role of worry in emotion generation and dysregulation in generalized anxiety disorder. Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in 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 We report the findings of a r and omized , double-blind , placebo-controlled , parallel , generalized anxiety disorder ( GAD ) outpatient study . The purpose of the study was to compare the efficacy , safety , and tolerability of ipsapirone , an azapirone and 5-HT1A agonist , given at a total daily dose of 10 mg to 30 mg , with a total daily dose of 2 mg to 6 mg of lorazepam or placebo in 90 out patients with GAD of moderate or greater severity . At baseline , all patients had a Hamilton Anxiety Scale ( HAM-A ) score of > or = 18 and Covi anxiety score of > or = 8 . After a 1-week single-blind washout , patients entered a 4-week double-blind period with an optional extension for another 4 weeks , followed by a 2-week single-blind placebo washout .  Ipsapirone and lorazepam ratings on the HAM-A and Clinical Global Impressions ( CGI ) were significantly ( p < .05 ) superior to placebo at the end of the acute and maintenance periods of the trial , with a 50 percent HAM-A reduction on active drugs vs. 20 percent on placebo . The anxiety of patients receiving lorazepam , but not ipsapirone , rebounded during the final placebo washout 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 Lesopitron , a 5-hydroxytryptamine 1A agonist , is a new potential anxiolytic of the azapirone class . It has greater potency in animal models of anxiety than buspirone , gepirone , or ipsapirone , and it lacks the antidopaminergic effects associated with buspirone . Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers . Forty-two patients with generalized anxiety disorder ( GAD ) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron ( 20 , 25 , 30 , 40 , 45 , 50 , and 60 mg two times a day ) over a 6 1/2-day inpatient administration period . Each of the seven panels included six patients ( four drug/two placebo ) . One patient in the 25-mg , two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms . One patient experienced severe orthostatic hypotension at 60 mg two times a day , and moderate to severe adverse events ( dizziness , lightheadedness , nausea , headache ) occurred in two other patients at this dosage . The most commonly reported adverse events in all the panels were headache , dizziness , and nausea .  Lesopitron is rapidly absorbed in patients , having a time to maximum concentration ( Tmax ) ranging from 0.5 to 1 hour , and its elimination half-life ranged from 1.1 to 5.6 hours . Peak plasma concentrations showed high interindividual variability for lesopitron , but increased linearly with dose for the main metabolite , 5-hydroxylesopitron . We defined the maximum tolerated dose in GAD patients as 50 mg two times a day , twice as high as the highest dose tested in healthy volunteers 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 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 Context Anxiety and depression are both common in primary care patients , but much less attention has been paid to anxiety . Contribution The authors administered a 7-item anxiety scale ( Generalized Anxiety Disorder [GAD]-7 ) to 965 primary care patients , who also had a structured interview , to detect an anxiety disorder . Of these patients , 19.5 % had at least 1 anxiety disorder . Patients with anxiety had worse functional status , more disability days , and more physician visits , but 41 % were not being treated for any anxiety disorder . The GAD-7 had high sensitivity and good specificity for detecting a generalized anxiety disorder , panic disorder , social anxiety disorder , and posttraumatic stress disorder . Implication s Anxiety disorders are common , underrecognized , and undertreated , but they are easy to detect with a brief question naire . The Editors Anxiety and depression are the 2 most common mental health problems seen in the general medical setting ( 15 ) . Although increasing attention has been paid to anxiety , it still lags far behind depression in terms of research as well as clinical and public health efforts in screening , diagnosis , and treating affected individuals . This is unfortunate given the prevalence of anxiety and its substantial impact on patient functioning , work productivity , and health care costs ( 614 ) . More than 30 million Americans have a lifetime history of anxiety ( 15 ) , and anxiety disorders cost an estimated $ 42 billion dollars per year in the United States alone , counting direct and indirect costs ( 16 ) . The 4 most common anxiety disorders ( excluding simple phobias that seldom present clinical ly ) are generalized anxiety disorder , panic disorder , social anxiety disorder , and posttraumatic stress disorder ( PTSD ) ( 1723 ) . However , despite the substantial disability associated with each anxiety disorder and the availability of effective treatments , only a minority of patients ( 15 % to 36 % ) with anxiety are recognized in primary care ( 24 , 25 ) . In our paper , we analyze results from a large primary carebased anxiety study ( 26 ) to answer several questions . First , what is the prevalence of these 4 anxiety disorders , both individually and concurrent with one another ? Second , how do these disorders compare in functional impairment , health care use , and comorbid depressive and somatic symptom burden ? Third , how effective is a brief anxiety measure in screening for each disorder ? Compared with previous research , our study is particularly well-positioned to ascertain commonalities among anxiety diagnoses that are traditionally considered to be discrete and to determine whether a single measure can be used as a first step , common metric . This is especially salient for the busy , complex primary care setting , in which simplifying initial recognition of mental disorders may in fact make wider efforts at recognition more feasible . Methods Patient Sample The Patient Health Question naire ( PHQ ) anxiety study ( 26 ) was conducted to develop a short measure to assess generalized anxiety disorder .  Patients were enrolled from a research network of 15 primary care sites ( 13 family practice and 2 internal medicine sites ) located in 12 states and administered central ly by Clinvest , Inc. , Springfield , Missouri , from November 2004 to June 2005 . The Generalized Anxiety Disorder (GAD)-7 scale was developed and vali date d in 2149 patients . In the original study , 2982 persons were invited to participate ; of these , 2740 ( 92 % ) completed the 4-page question naire and had no or minimal missing data ( 26 ) . To minimize sampling bias , consecutive patients were approached at each site in clinic sessions until the target quota for that week was achieved . Of the 2740 participants , the first 2149 were used for development and validation of the GAD-7 scale , whereas the last 591 were used to determine the testretest reliability of the scale . Of the 2149 patients in the validation group , 1654 agreed to a telephone interview , of whom 965 were r and omly selected to undergo this interview within 1 week of their clinic visit by 1 of 2 mental health professionals : a clinical psychologist ( with a PhD ) or a senior psychiatric social worker . Contact information was sent by fax to each interviewer , who shuffled the fax sheets received each day and then drew from the stack several participants to interview that day . The 965 interviewed patients comprise the study population for this paper , and compared with the 1184 participants who did not undergo a mental health professional interview , these were more often women ( 69 % vs. 63 % ; P= 0.003 ) and had slightly higher GAD-7 anxiety scores ( 5.7 vs. 5.1 ; P= 0.010 ) but were similar in age , race , and education . Of note , we only used data from the 1184 participants not undergoing a mental health professional interview to derive the GAD-7 ( 26 ) . The study was approved by the Sterling Institutional Review Board . Study Question naire Before seeing their physicians , patients completed a 4-page question naire that included the GAD-7 ( Appendix Figure ) . This scale was shown to have good internal and testretest reliability , as well as convergent , construct , criterion , procedural , and factorial validity for the diagnosis of generalized anxiety disorder ( 26 ) . Scores on the GAD-7 range from 0 to 21 ; scores of 5 , 10 , and 15 represent mild , moderate , and severe anxiety symptoms , respectively . The first 2 items of the GAD-7 represent core anxiety symptoms , and scores on this GAD-2 subscale range from 0 to 6 . Appendix Figure . The Generalized Anxiety Disorder (GAD)-7 scale . The first 2 items constitute the GAD-2 subscale . GAD-7 2006 Pfizer Inc. All rights reserved . Used with permission . The study question naire also included questions about age , sex , education , race or ethnicity , and marital status ; the Medical Outcomes Study Short Form-20 ( SF-20 ) , which measures functional status in 6 domains ( 27 ) ; the 10-item anxiety subscale from the Hopkins Symptom Checklist ( 28 ) ; the PHQ-8 depression scale ( 29 ) ; a 3-item version  of the Social Phobia Inventory ( Mini-SPIN ) ( 30 ) ; the 5-item PHQ panic module ( 25 ) ; and the PHQ-15 somatic symptom scale ( 31 ) . Also , single-item global assessment s of anxiety , depression , and pain based on a scale of 0 ( none ) to 10 ( as bad as you can imagine ) were included . Finally , patients reported the number of physician visits and disability days during the previous 3 months . Structured Psychiatric Interview The 2 mental health professionals , while blinded to the results of the self-report research question naire , conducted structured psychiatric interviews by telephone to establish independent criteria -based diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( DSM-IV ) ( 32 ) . The interview consisted of the generalized anxiety disorder , social anxiety disorder , and PTSD sections of the Structured Clinical Interview for DSM-IV ( SCID ) ( 33 ) . Reinterview by telephone was used because of its feasibility in our multisite study and its demonstrated comparability with face-to-face research interviews ( 3436 ) . The 2 mental health professionals based diagnoses of generalized anxiety disorder and PTSD on the SCID interview . For generalized anxiety disorder , some questions were slightly modified to better assess each DSM-IV criterion . They based a diagnosis of social anxiety disorder on whether the patient met SCID diagnostic criteria and had a Mini-SPIN score of 8 or greater , because this improves the accuracy of social anxiety disorder diagnoses ( 37 ) . They based a diagnosis of panic disorder on answering yes to all 5 questions on the PHQ panic module , a threshold that reflects DSM-IV criteria and has been vali date d in both clinical ( 25 ) and population -based ( 38 ) sample s. Statistical Analysis We estimated sample size with respect to sensitivity of the  GAD-7 scale for diagnosing the target disease ( generalized anxiety disorder ) . We needed 60 participants with generalized anxiety disorder to ensure that the total width of the 95 % CI around a sensitivity proportion of 0.80 was no greater than 0.20 . Given that the estimated prevalence of generalized anxiety disorder in the primary care population was 6 % ( 18 ) , we needed a total of 1000 unselected primary care patients to have approximately 60 patients with generalized anxiety disorder . We determined the prevalence of each of the 4 anxiety disorders and compared them in patient demographic characteristics , functional status , psychiatric comorbidity , disability days , and physician visits . Consistent with previous work ( 1 , 26 , 29 , 39 ) , we replaced missing values in a scale with the mean value of the remaining items if 25 % or fewer items were missing . If more than 25 % of items were missing , the sum score was not computed and was counted as missing . The amount of missing data for any individual variable or scale score was very low ( < 1 % ) . The 15 sites did not differ in missing data . In addition to descriptive statistics , we used analysis of covariance to examine associations among each anxiety disorder and the 6 SF-20 functional status scales , self-reported disability days , and physician visitscontrolling for demographic variables ( sex , age , race , and educational level ) and study site . We ran similar models to examine the effect of the number of anxiety disorders . In all models , patients with no anxiety disorder were the reference group . We adjusted pairwise statistical comparisons by using the Bonferroni correction . Because some dependent variables displayed a skewed ( but unimodal ) distribution , we also reran the models using the rank transformation of the dependent variables . We examined the operating characteristics ( sensitivity , specificity , and positive likelihood ratio ) for a range of cutoff scores of the GAD-7 and GAD-2 for each anxiety disorder . We conducted receiver-operating characteristic curve analyses to determine the area under the curve ( AUC ) for each anxiety disorder . We calculated AUCs and performed statistical comparisons ( GAD-7 vs. 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 : Guided Internet-based cognitive behavior therapy ( ICBT ) has been tested in many trials and found to be effective in the treatment of  anxiety and mood disorders .  Generalized anxiety disorder ( GAD ) has also been treated with ICBT , but there are no controlled trials on guided Internet-based psychodynamic treatment ( IPDT ) . Since there is preliminary support for psychodynamic treatment for GAD , we decided to test if a psychodynamically informed self-help treatment could be delivered via the Internet . The aim of the study was to investigate the efficacy of IPDT for GAD and to compare against ICBT and a waiting list control group . Method : A r and omized controlled superiority trial with individuals diagnosed with GAD comparing guided ICBT ( n = 27 ) and IPDT ( n = 27 ) against a no treatment waiting list control group ( n = 27 ) . The primary outcome measure was the Penn State Worry Question naire . Results : While there were no significant between-group differences immediately after treatment on the main outcome measure , both IPDT and ICBT result ed in improvements with moderate to large within-group effect sizes at 3 and 18 months follow-up on the primary measure in the completer analyses . The differences against the control group , although smaller , were still significant for both PDT and CBT when conforming to the criteria of clinical ly significant improvement . The active treatments did not differ significantly . There was a significant group by time interaction regarding GAD symptoms , but not immediately after treatment . Conclusions : IPDT and ICBT both led to modest symptom reduction in GAD , and more research is needed 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 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 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 This study questions the 6-month duration criterion for generalized anxiety disorder ( GAD ) used in DSM-III-R and DSM-IV . METHOD In adults from age 20/21 to 40/41 in the prospect i ve Zurich Cohort Study , four groups of generalized anxiety syndromes defined by varying duration ( 2 weeks , 1 month , 3 months and 6 months ) were compared . RESULTS Applying DSM-III ( 1979 - 1999 ) and DSM-III-R ( 1986 - 1999 ) criteria , there were no significant differences between the four groups in terms of family history of anxiety , work impairment , distress , treatment rates or co-morbidity with major depressive episodes ( MDEs ) , bipolar disorder or suicide attempts . Only social impairment related to the length of episodes . The 6-month criterion of DSM-III-R and DSM-IV GAD would preclude this diagnosis in about half of the subjects treated for generalized anxiety syndromes . CONCLUSIONS In this epidemiological sample , the 6-month duration criterion for GAD could not be confirmed as clinical ly meaningful . GAD syndromes of varying duration form a continuum with comparable clinical relevance 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 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 Nondirective ( ND ) , applied relaxation ( AR ) , and cognitive behavioral ( CBT ) therapies for generalized anxiety disorder ( GAD ) were compared . The latter 2 conditions were generally equivalent in outcome but superior to ND at post assessment . The 3 conditions did not differ on several process measures , and ND created the greatest depth of emotional processing . Follow-up results indicated losses in gains in ND , maintained gains in the other 2 conditions , especially CBT , and highest endstate functioning for CBT . AR and CBT thus contain active ingredients in the treatment of GAD ; support exists for further development of imagery exposure methods or cognitive therapy because of their likely role in promoting maintenance of change with this disorder . Expectancy for improvement was also associated with outcome , suggesting the need for further research on this construct for underst and ing the nature of GAD and its amelioration Generalized anxiety disorder ( GAD ) is a disabling condition which can be treated with cognitive behaviour therapy ( CBT ) . The present study tested the effects of therapist-guided internet-delivered acceptance-based behaviour therapy on symptoms of GAD and quality of life . An audio CD with acceptance and mindfulness exercises and a separate workbook were also included in the treatment . Participants diagnosed with GAD ( N = 103 ) were r and omly allocated to immediate therapist-guided internet-delivered acceptance-based behaviour therapy or to a waiting-list control condition . A six month follow-up was also included . Results using hierarchical linear modelling showed moderate to large effects on symptoms of GAD ( Cohen 's d = 0.70 to 0.98 ) , moderate effects on depressive symptoms ( Cohen 's d = 0.51 to 0.56 ) , and no effect on quality of life . Follow-up data showed maintained effects . While there was a 20 % dropout rate , sensitivity analyses showed that dropouts did not differ in their degree of change during treatment . To conclude , our study suggests that internet-delivered acceptance-based behaviour therapy can be effective in reducing the symptoms of GAD BACKGROUND Functional magnetic resonance imaging ( fMRI ) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial . Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex ( ACC ) . Here , we sought to determine whether pretreatment amygdala and rostral ACC ( rACC ) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder ( GAD ) . METHODS Fifteen subjects ( 12 female subjects ) with GAD participated in an open-label venlafaxine treatment trial . Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration . In addition , the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects ( 12 female subjects ) who did not have GAD and did not receive venlafaxine treatment .  RESULTS The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala . These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1 ) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2 ) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group . CONCLUSIONS These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD 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 The existence of anxiety disorders plays an important role in the prognosis and associated impairment among patients with poststroke depression . The authors examined the efficacy of nortriptyline treatment for patients with comorbid generalized anxiety disorder ( GAD ) and depression after stroke . METHODS Data from three studies were merged to provide 27 patients with comorbid GAD and depression , who participated in double-blind treatment studies comparing nortriptyline ( N=13 ) and placebo ( N=14 ) . Severity of anxiety was measured with the Hamilton Rating Scale for Anxiety ( Ham-A ) , and severity of depression was measured with the Hamilton Rating Scale for Depression ( Ham-D ) . Activities of daily living were assessed by use of the Johns Hopkins Functioning Inventory ( JHFI ) . RESULTS There were no significant differences between the nortriptyline and placebo groups in demographic characteristics , stroke type , and neurological findings . Patients receiving nortriptyline treatment showed significantly greater improvement on the Ham-A , Ham-D , and JHFI than patients receiving placebo . The anxiety symptoms showed earlier improvement than depressive symptoms in patients treated with nortriptyline . CONCLUSIONS These findings suggest that poststroke GAD comorbid with poststroke depression may be effectively treated with nortriptyline , and data indicate the need for a trial specifically design ed to examine treatment of anxiety disorder The role of worry in generalized anxiety disorder ( GAD ) has been posited to serve as an avoidance of emotional experience , and emotion regulation deficits in GAD have been found in several previous studies . It remains unclear whether those with GAD experience more dysregulated emotions during periods of euthymia and positive affect or whether these deficits occur only during periods of worry . Individuals with GAD ( with and without co-occurring dysphoria ) and non-anxious controls were r and omly assigned to receive a worry , neutral , or relaxation induction . Following the induction , all participants viewed a film clip documented to elicit sadness . Intensity of emotions and emotion regulation were examined following the induction period and film clip . The results revealed that , regardless of co-occurring dysphoria , individuals with GAD in the worry condition experienced more intense depressed affect than GAD participants in the other conditions and controls participants . In contrast , presence of worry appeared to have less impact on indices of emotion dysregulation , which were greater in participants with GAD compared to controls , but largely insensitive to context ual effects of worry or of relaxation . Following film viewing , both GAD participants with and without dysphoria displayed poorer underst and ing , acceptance , and management of emotions than did controls . However , acceptance and management deficits were most pronounced in individuals with both GAD and co-occurring dysphoria . Implication s for the role of emotions in conceptualization and treatment of GAD are discussed Variation in genes involved in serotonergic signaling is thought to be associated with antidepressant treatment response in generalized anxiety disorder ( GAD ) . We examined a possible interaction between the serotonin transporter gene ( SLC6A4 ) 5-HTTLPR/rs25531 haplotype and the serotonin 2A receptor gene ( HTR2A ) single-nucleotide polymorphism ( SNP ) rs7997012 in antidepressant treatment outcome in GAD . Patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study . Genotypes obtained for the 5-HTTLPR/rs25531 ( La/La , La/S or S/S ) haplotype and rs7997012 SNP ( G or A ) in the European American population ( n=112 ) were used for pharmacogenetic analysis . Our data show that subjects with genotypes La/La+G/G or La/La+G/A ( n=28 ) had significantly lower Hamilton Anxiety Scale ( HAM-A ) scores than those with genotypes La/S+A/A or S/S+A/A ( n=12 ) at 6 months ( HAM-A difference=10.7 ; P<0.0001 ) . Single-marker analysis only showed HAM-A differences of 4.3 ( 5-HTTLPR/rs25531 : La/La versus La/S+S/S ) and 4.8 ( rs7997012 : G/G+G/A versus A/A ) , showing for the first time a significant gene – gene interaction between these markers
Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants , kava kava or psychotherapy .
Azapirones appeared to be well tolerated .
Azapirones appeared to be useful in the treatment of GAD , particularly for those participants who had not been on a benzodiazepine .
Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines .
Side effects appeared mild and non serious in the azapirone treated group .
Longer term studies are needed to show that azapirones are effective in treating GAD , which is a chronic long-term illness
BACKGROUND Azapirones are a group of drugs that work at the 5-HT1A receptor and are used to treat patients suffering from generalized anxiety disorder ( GAD ) .
However , several studies have shown conflicting results .
Whether azapirones are useful as first line treatment in general anxiety disorders still needs to be answered .
OBJECTIVES To assess the efficacy and the acceptability of azapirones for the treatment of GAD .