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 Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Heart rate and heart rate variability in panic, social anxiety, obsessive-compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation. Transdiagnostic versus disorder-specific and clinician-guided versus self-guided internet-delivered treatment for generalized anxiety disorder and comorbid disorders: A randomized controlled trial. 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. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Sensitivity to 35% carbon dioxide in patients with generalized anxiety disorder. Paradoxical cardiovascular effects of implementing adaptive emotion regulation strategies in generalized anxiety disorder. A randomized clinical trial comparing an acceptance-based behavior therapy to applied relaxation for generalized anxiety disorder. Relation of Serotonin Transporter Genetic Variation to Efficacy of Escitalopram for Generalized Anxiety Disorder in Older Adults Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder Are Attentional Control Resources Reduced by Worry in Generalized Anxiety Disorder? Efficacy and Safety of Lesopitron in Outpatients with Generalized Anxiety Disorder A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder. A randomized clinical trial of cognitive-behavioral therapy and applied relaxation for adults with generalized anxiety disorder. Internet Treatment for Generalized Anxiety Disorder: A Randomized Controlled Trial Comparing Clinician vs. Technician Assistance Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: A double-blind placebo-controlled trial
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 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 It remains unclear if diminished high frequency heart rate variability ( HF-HRV ) can be found across anxiety disorders .  HF-HRV and heart rate ( HR ) were examined in panic ( PD ) , generalized anxiety ( GAD ) , social anxiety ( SAD ) , and obsessive-compulsive disorder ( OCD ) relative to healthy controls at baseline and during anxiety stressors . All disorders evidence d diminished baseline HF-HRV relative to controls . Baseline HRV differences were maintained throughout relaxation . For hyperventilation , PD and GAD demonstrated greater HR than controls . Psychotropic medication did not account for HF-HRV differences except in OCD . Age and sex evidence d multiple main effects . Findings suggest that low baseline HF-HRV represents a common index for inhibitory deficits across PD , GAD , and SAD , which is consistent with the notion of autonomic inflexibility in anxiety disorders . Elevated HR responses to hyperventilation , however , are specific to PD and GAD Generalized anxiety disorder ( GAD ) can be treated effectively with either disorder-specific cognitive behavior therapy ( DS-CBT ) or transdiagnostic CBT ( TD-CBT ) . The relative benefits of DS-CBT and TD-CBT for GAD and the relative benefits of delivering treatment in clinician guided ( CG-CBT ) and self-guided ( SG-CBT ) formats have not been examined . Participants with GAD ( n=338 ) were r and omly allocated to receive an internet-delivered TD-CBT or DS-CBT intervention delivered in either CG-CBT or SG-CBT formats . Large reductions in symptoms of GAD ( Cohen 's d ≥ 1.48 ; avg . reduction ≥ 50 % ) and comorbid major depressive disorder ( Cohen 's d ≥ 1.64 ; avg . reduction ≥ 45 % ) , social anxiety disorder ( Cohen 's d ≥ 0.80 ; avg . reduction ≥ 29 % ) and panic disorder ( Cohen 's d ≥ 0.55 ; avg . reduction ≥ 33 % ) were found across the conditions . No substantive differences were observed between DS-CBT and TD-CBT or CG-CBT and SG-CBT , highlighting the public health potential of carefully developed TD-CBT and SG-CBT 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 ) Escitalopram has been shown in clinical trials to improve anxiety symptoms associated with depression , panic disorder , and social anxiety disorder . This study was design ed to evaluate the efficacy and tolerability of escitalopram in the treatment of generalized anxiety disorder ( GAD ) . Out patients ( 18 years or older ) who met DSM-IV criteria for GAD , with baseline Hamilton Rating Scale for Anxiety ( HAMA ) scores > or = 18 , were r and omly assigned to double blind treatment with escitalopram ( 10 mg/day for the first 4 weeks and then flexibly dosed from 10 - 20 mg/day ) or placebo for 8 weeks , following a 1-week , single-blind , placebo lead-in period . The primary efficacy variable was the mean change from baseline in total HAMA score at Week 8 . The escitalopram group ( N = 158 ) showed a statistically significant , and clinical ly relevant , greater improvement at endpoint compared with placebo ( N = 157 ) in all prospect ively defined efficacy parameters . Significant improvement in HAMA total score and HAMA psychic anxiety subscale score for the escitalopram-treated group vs. the placebo-treated group was observed beginning at Week 1 and at each study visit thereafter . Mean changes from baseline to Week 8 on the HAMA total score using a last-observation-carried-forward ( LOCF ) approach were -11.3 for escitalopram and -7.4 for placebo ( P<.001 ) . Response rates at Week 8 were 68 % for escitalopram and 41 % for placebo ( P<.01 ) for completers , and 58 % for escitalopram and 38 % for placebo LOCF values ( P<.01 ) . Treatment with escitalopram was well tolerated , with low rates of reported adverse events and an incidence of discontinuation due to adverse events not statistically different from placebo ( 8.9 % vs. 5.1 % ; P=.27 ) . Escitalopram 10 - 20 mg/day is effective , safe , and well tolerated in the treatment of patients with GAD BACKGROUND Panic disorder and generalized anxiety disorder ( GAD ) are both characterized by severe anxiety , but there is evidence that indicates a qualitative difference between these 2 anxiety disorders . To investigate the specificity of the association between carbon dioxide ( CO2 ) hypersensitivity and panic disorder and the possible relationships between panic disorder and GAD , the responses to inhalation of a gas mixture of 35 % CO2 and 65 % oxygen ( O2 ) were assessed . METHOD Fifteen patients with panic disorder , 13 patients with GAD , and 10 patients with comorbid GAD and panic disorder according to a consensus diagnosis using Diagnostic Interview Schedule Version III-R ( DIS-R ) and DSM-IV criteria , and 12 healthy controls inhaled 2 vital capacities : 1 of 35 % CO2 and 1 of compressed air . A double-blind , r and omized , crossover design was used . RESULTS GAD patients showed reactions to 35 % CO2  that were similar to those of healthy controls and significantly weaker than that of panic disorder patients . Patients with comorbid panic disorder and GAD had anxiogenic reactions similar to those of subjects with panic disorder . CONCLUSION The results of the present study support the idea that panic disorder and GAD are separate disorders that have at least some differences in pathogenetic mechanisms and suggest that the 35 % CO2 test might be a valid tool for discriminating between these 2 disorders Recent models of generalized anxiety disorder ( GAD ) have exp and ed on Borkovec 's avoidance theory by delineating emotion regulation deficits associated with the excessive worry characteristic of this disorder ( see Behar , DiMarco , Hekler , Mohlman , & Staples , 2009 ) . However , it has been difficult to determine whether emotion regulation is simply a useful heuristic for the avoidant properties of worry or an important extension to conceptualizations of GAD . Some of this difficulty may arise from a focus on purported maladaptive regulation strategies , which may be confounded with symptomatic distress components of the disorder ( such as worry ) . We examined the implementation of adaptive regulation strategies by participants with and without a diagnosis of GAD while watching emotion-eliciting film clips .  In a between-subjects design , participants were r and omly assigned to accept , reappraise , or were not given specific regulation instructions . Implementation of adaptive regulation strategies produced differential effects in the physiological ( but not subjective ) domain across diagnostic groups . Whereas participants with GAD demonstrated lower cardiac flexibility when implementing adaptive regulation strategies than when not given specific instructions on how to regulate , healthy controls showed the opposite pattern , suggesting they benefited from the use of adaptive regulation strategies . We discuss the implication s of these findings for the delineation of emotion regulation deficits in psychopathology OBJECTIVE To examine whether an empirically and theoretically derived treatment combining mindfulness- and acceptance-based strategies with behavioral approaches would improve outcomes in  generalized anxiety disorder ( GAD ) over an empirically supported treatment . METHOD This trial r and omized 81 individuals ( 65.4 % female , 80.2 % identified as White , average age 32.92 ) diagnosed with GAD to receive 16 sessions of either an acceptance-based behavior therapy ( ABBT ) or applied relaxation ( AR ) . Assessment s at pretreatment , posttreatment , and 6-month follow-up included the following primary outcome measures : GAD clinician severity rating , Structured Interview Guide for the Hamilton Anxiety Rating Scale , Penn State Worry Question naire , Depression Anxiety Stress Scale , and the State-Trait Anxiety Inventory . Secondary outcomes included the Beck Depression Inventory-II , Quality of Life Inventory , and number of comorbid diagnoses . RESULTS Mixed effect regression models showed significant , large effects for time for all primary outcome measures ( ds = 1.27 to 1.61 ) but nonsignificant , small effects for condition and Condition × Time ( ds = 0.002 to 0.20 ) , indicating that clients in the 2 treatments improved comparably over treatment . For secondary outcomes , time was significant ( ds = 0.74 to 1.38 ) , but condition and Condition × Time effects were not ( ds = 0.004 to 0.31 ) . No significant differences emerged over follow-up ( ds = 0.03 to 0.39 ) , indicating maintenance of gains . Between 63.3 and 80.0 % of clients in ABBT and 60.6 and 78.8 % of clients in AR experienced clinical ly significant change across 5 calculations of change at posttreatment and follow-up . CONCLUSION ABBT is a viable alternative for treating GAD . ( PsycINFO Data base Record ( c ) 2013 APA , all rights reserved ) Objective : Generalized anxiety disorder ( GAD ) is common in older adults and can be treated with selective serotonin reuptake inhibitors ( SSRIs ) . Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy : 2 polymorphisms ( 5-HTTLPR S/L and rs25531 g/a ) form a haplotype with the La combination having higher transcription activity than other haplotypes . We hypothesized that GAD patients with no La haplotypes ( La− ) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes ( La+ ) . Method : The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week , r and omized trial of escitalopram versus placebo . One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La− and La+ genotype groups ; the primary analyses were done in European Americans only ( n = 125 ; n = 59 with escitalopram and n = 66 with placebo ) . Results : Escitalopram  had no efficacy in the La− group versus moderate efficacy in the La+ group . This genetic moderation of SSRI efficacy was due to a higher placebo response in La− subjects , compared with La+ subjects . Drug concentration did not affect the genetic results . Exploratory analyses suggest that La− subjects had greater variability of anxiety symptoms unrelated to treatment . Conclusions : The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD . The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment , rather than a pharmacodynamic effect that has been previously assumed . Further research is needed to underst and the pharmacogenetic mechanism of this haplotype 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 Abstract Objective : Short-term clinical trials have demonstrated the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder ( GAD ) . This study examined long-term safety and tolerability of pregabalin in patients with GAD , social anxiety disorder ( SAD ) , or panic disorder ( PD ) . Research design and methods : Patients ( n = 528 ) completing one of four r and omized , double-blind , placebo-controlled trials of pregabalin for GAD , SAD , or PD were treated , open label , with flexible-dose pregabalin ( 150–600 mg/day ) for 1 year . Clinical trial registration : NCT00150449 . Main outcome measures : The primary outcomes were safety and tolerability . Illness severity was assessed at baseline and Weeks 27/52 using the Clinical Global Impression of Severity ( CGI-S ) scale . Patients were characterized as ‘ responders ’ or ‘ non-responders ’ based on CGI-S scores ≤2 and > 2 , respectively . Analyses were performed on the total anxiety ( GAD , SAD and PD ) and GAD groups . Results : During 1 year of treatment with pregabalin  , dizziness ( 12.5 % ) was the only treatment-related adverse event ( AE ) occurring ≥10 % . Somnolence , weight gain , headache and insomnia occurred at 7.6 % , 5.5 % , 5.3 % and 4.7 % , respectively . Few treatment-related AEs were rated as severe in the total anxiety ( 5.1 % ) or GAD ( 3.6 % ) groups . Discontinuation rates due to AEs were similar ( 9.7 % and 10.6 % , respectively ) . No clinical ly significant laboratory , electrocardiogram , or other treatment-related safety findings were noted , except for treatment-related weight gain , which occurred in both the total ( 24.4 % ) and GAD ( 19.4 % ) groups . Mean CGI-S scores were similar at baseline in the total ( n = 528 ; score , 3.4 ) and GAD groups ( n = 330 ; score , 3.6 ) , and CGI-S responder rates were similar at last-observation-carried-forward endpoint ( 51.3 % and 48.1 % , respectively ) . Conclusions : Pregabalin was generally well tolerated in the long-term treatment of anxiety disorders . Improvement in illness severity was maintained over time . The key limitations of this study were that it was not r and omized and neither placebo- nor active-comparator-controlled 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 This is the first study to examine attentional control capacities in generalized anxiety disorder ( GAD ) . GAD is characterized by uncontrollable worry . Individuals diagnosed with GAD and healthy participants ( HPs ) performed a r and om key-pressing task while thinking about a worrisome or a positive future event , to assess the extent to which attentional control re sources are used by worry . Attentional control was also assessed when participants were not instructed to think about a specific topic using the N-back task , which varies in task difficulty , and therefore is sensitive to subtle differences in ability to h and le increasing dem and s on attentional control within the same paradigm . GAD participants ( but not HPs ) were less r and om while worrying than thinking about a positive event during the key-pressing task , suggesting that worry consumed more attentional control re sources in this population . During the N-Back task , GAD participants performed worse than HPs during the high load conditions only , indicating greater difficulty in sustaining focus on conditions requiring a higher degree of attentional control , even without concurrent task activity . Poor attentional control might underpin the difficulty of GAD individuals to stop worrying and switch to thinking more benign information . Further research could investigate whether worry consumes attentional control re sources in other psychological disorders with high rates of worry ( e.g. , panic disorder , psychosis ) , as well as the extent to which attentional control is used by other forms of repetitive thinking , such as depressive rumination 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 BACKGROUND Repetitive transcranial magnetic stimulation ( rTMS ) is a noninvasive method that holds promise for treating several psychiatric disorders . Yet the most effective location and parameters for treatment need more exploration . Also , whether rTMS is an effective treatment for individuals with a DSM-IV diagnosis of generalized anxiety disorder ( GAD ) has not been empirically tested . The goal of this pilot study was to evaluate whether functional magnetic resonance imaging (fMRI)-guided rTMS is effective in reducing symptoms of GAD . METHOD Ten participants with a DSM-IV diagnosis of GAD , recruited from the UCLA Anxiety Disorders Program , and between the ages of 18 and 56 years were enrolled in the study from August 2006 to March 2007 . A pretreatment symptom provocation fMRI experiment was used to determine the most active location in the prefrontal cortex of the participants . Ten participants completed 6 sessions of rTMS over the course of 3 weeks , stereotactically directed to the previously determined prefrontal location . The primary efficacy measures were the Hamilton Rating Scale for Anxiety ( HAM-A ) and the Clinical Global Impressions-Improvement of Illness ( CGI-I ) scale . Response to treatment was defined as a reduction of 50 % or more on the HAM-A and a CGI-I score of 1 or 2 ( " very much improved " or " much improved , " respectively ) . RESULTS Overall , rTMS was associated with significant decreases in HAM-A scores ( t = 6.044 , p = .001 ) indicative of clinical improvement in GAD symptoms . At endpoint , 6 ( 60 % ) of the 10 participants who completed the study showed reductions of 50 % or more on the HAM-A and a CGI-I score of 1 or 2 ; those 6 subjects also had an endpoint HAM-A score < 8 , therefore meeting criteria for remission . CONCLUSION Results of the current study suggest that fMRI-guided rTMS treatment may be a beneficial technique for the treatment of anxiety disorders . Limitations include a small sample size and open-label design with a technology that may be associated with a large placebo response . These limitations necessitate further research to determine whether rTMS is indeed effective in treating anxiety disorders This r and omized clinical trial compared cognitive-behavioral therapy ( CBT ) , applied relaxation ( AR ) , and wait-list control ( WL ) in a sample of 65 adults with a primary diagnosis of generalized anxiety disorder ( GAD ) . The CBT condition was based on the intolerance of uncertainty model of GAD , whereas the AR condition was based on general theories of anxiety . Both manualized treatments were administered over 12 weekly 1-hour sessions . St and ardized clinician ratings and self-report question naires were used to assess GAD and related symptoms at pretest , posttest , and at 6- , 12- , and 24-month follow-ups . At posttest , CBT was clearly superior to WL , AR was marginally superior to WL , and CBT was marginally superior to AR . Over follow-up , CBT and AR were equivalent , but only CBT led to continued improvement . Thus , direct comparisons of CBT and AR indicated that the treatments were comparable ; however , comparisons of each treatment with another point of reference ( either waiting list or no change over follow-up ) provided greater support for the efficacy of CBT than AR Background Internet-based cognitive behavioural therapy ( iCBT ) for generalized anxiety disorder ( GAD ) has been shown to be effective when guided by a clinician . The present study sought to replicate this finding , and determine whether support from a technician is as effective as guidance from a clinician . Method R and omized controlled non-inferiority trial comparing three groups : Clinician-assisted vs. technician-assisted vs. delayed treatment . Community-based volunteers applied to the VirtualClinic ( www.virtualclinic.org.au ) research program and 150 participants with GAD were r and omized . Participants in the clinician- and technician-assisted groups received access to an iCBT program for GAD comprising six online lessons , weekly homework assignments , and weekly supportive contact over a treatment period of 10 weeks . Participants in the clinician-assisted group also received access to a moderated online discussion forum . The main outcome measures were the Penn State Worry Question naire ( PSWQ ) and the Generalized Anxiety Disorder-7 Item ( GAD-7 ) . Completion rates were high , and both treatment groups reduced scores on the PSWQ ( p<0.001 ) and GAD-7 ( p<0.001 ) compared to the delayed treatment group , but did not differ from each other . Within group effect sizes on the PSWQ were 1.16 and 1.07 for the clinician- and technician-assisted groups , respectively , and on the GAD-7 were 1.55 and 1.73 , respectively . At 3 month follow-up participants in both treatment groups had sustained the gains made at post-treatment . Participants in the clinician-assisted group had made further gains on the PSWQ . Approximately 81 minutes of clinician time and 75 minutes of technician time were required per participant during the 10 week treatment program . Conclusions Both clinician- and technician-assisted treatment result ed in large effect sizes and clinical ly significant improvements comparable to those associated with face-to-face treatment , while a delayed treatment/control group did not improve . These results provide support for large scale trials to determine the clinical effectiveness and acceptability of technician-assisted iCBT programs for GAD . This form of treatment has potential to increase the capacity of existing mental health services . Trial Registration Australian New Zeal and Clinical Trials Registry The objective was to examine duloxetine 60 - 120 mg/day treatment for relapse prevention in adults with generalized anxiety disorder ( GAD ) . Adult patients ( N=887 ; mean age=43.3 years ; 61.0 % female ) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks . Patients who completed open-label phase and were treatment responders ( > or=50 % reduction in Hamilton Anxiety Rating Scale total score to < or=11 and " much"/"very much improved " ratings for the last 2 visits of open-label phase ) were r and omly assigned to receive duloxetine or placebo for a 26-week double-blind continuation phase . Relapse was defined as > or=2-point increase in illness severity ratings or by discontinuation due to lack of efficacy . During the double-blind phase , placebo-treated patients ( N=201 ) relapsed more frequently ( 41.8 % ) than duloxetine-treated patients ( 13.7 % , N=204 , P < or=0.001 ) and worsened on each outcome measure ( P < or=0.001 , all comparisons ) . Duloxetine 60 - 120 mg/day treatment was efficacious and reduced risk of relapse in patients with GAD
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 .