Pharmacotherapy of anxiety. The diagnosis and treatment of generalized anxiety disorder. Long‐term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2‐year naturalistic follow‐up Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability A 15-year follow-up study of patients with panic disorder. Temporal profile of brain response to alprazolam in patients with generalized anxiety disorder Group cognitive-behavioral therapy for generalized anxiety disorder: treatment outcome and long-term follow-up. Treatment outcomes for primary care patients with major depression and lifetime anxiety disorders. Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision Results of a naturalistic longitudinal study of benzodiazepine and SSRI use in the treatment of generalized anxiety disorder and social phobia. Long-term effectiveness of cognitive behavioral therapy for youth with anxiety disorders. A component analysis of cognitive-behavioral therapy for generalized anxiety disorder and the role of interpersonal problems. Guidelines for the pharmacological treatment of anxiety disorders, obsessive–compulsive disorder and posttraumatic stress disorder in primary care Randomized controlled trial of false safety behavior elimination therapy: a unified cognitive behavioral treatment for anxiety psychopathology. One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: Outcome and predictors of remission. Protocol for a randomised controlled trial investigating the effectiveness of an online e-health application compared to attention placebo or sertraline in the treatment of generalised anxiety disorder
The pharmacological treatment of anxiety has a long and chequered history , and recent years have seen a rich development in the options available to prescribers . Most of the currently used anxiolytic agents act via monoaminergic ( chiefly serotonin ) or amino acid ( GABA or glutamate ) neurotransmitters , and this chapter describes the pharmacology of the major drug groups . Clinical applications are discussed with respect to the five major anxiety disorders , as well as simple phobia and depression with concomitant anxiety . Prospect i ve future developments in the field are considered 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 Two years after completion of a controlled outcome study of treatments for panic disorder with agoraphobia , patients were revisited and interviewed about their complaints . In the initial study , four treatments had been compared : ( i ) fluvoxamine combined with exposure ; ( ii ) placebo medication plus exposure ; ( iii ) psychological panic management plus exposure : and ( iv ) exposure alone . Comparison of the results at post‐test had revealed superior efficacy of fluvoxamine combined with exposure over the other three treatments in reducing agoraphobic avoidance . The current naturalistic follow‐up study investigated the long‐term efficacy of the treatments with regard to abatement of complaints and reduced dem and for further treatment . In addition , we examined whether patients were able to taper off the study medication without a recurrence of complaints . In total , 71 of the 76 patients of the original trial ( 93 % ) were interviewed . Comparison of the mean level of psychopathology at follow‐up revealed no difference between the original treatment groups . The effect in the fluvoxamine plus exposure group was maintained , but was no longer superior , due to further improvements in the other treatment groups . Most patients received additional treatment during the follow‐up period , usually because the 12 treatment sessions in the controlled study had yielded insufficient improvement . There was a trend for patients who received the fluvoxamine plus exposure treatment to require less aftercare than those who received the other treatments . Finally , almost 50 % of the patients who had received medication in the original trial were able to taper off the use of fluvoxamine without a recurrence of complaints 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 BACKGROUND Panic disorder ( PD ) is generally regarded as a chronic condition with considerable variation in severity of symptoms . AIMS To describe the long-term outcome of naturalistically treated PD . METHODS Fifty-five out patients with PD , who participated in a placebo-controlled drug trial of the efficacy of alprazolam and imipramine 15 years ago were reassessed with the same instruments used in the original study . RESULTS Complete recovery ( no panic attacks and no longer on medication during the last 10 years ) was seen in 18 % of patients , and an additional 13 % recovered but were still on medication . Fifty-one percent experienced recurrent anxiety attacks whereas 18 % still met diagnostic criteria for PD . The incidence of agoraphobia decreased from 69 % to 20 % . Patients with agoraphobia at admission tended to have a poorer long-term outcome according to daily functioning compared with patients without agoraphobia at admission , although both groups reported improved daily functioning at follow-up . Maintenance medication was common . No benzodiazepine abuse was reported . CONCLUSION PD has a favourable outcome in a substantial proportion of patients . However , the illness is chronic and needs treatment . The short-term treatment given in the drug trial had no influence on the long-term outcome This study investigated the temporal pattern of brain response to emotional stimuli during 28 days of alprazolam treatment among patients with generalized anxiety disorder ( GAD ) r and omized 2:1 to drug or placebo in a double-blind design . Functional magnetic resonance imaging scans obtained during an emotion face matching task ( EFMT ) and an affective stimulus expectancy task ( STIMEX ) were performed at baseline , one hour after initial drug administration and 28 days later . Alprazolam significantly reduced scores on the Hamilton Anxiety Scale and the Penn State Worry Question naire after one week and 28 days of treatment . Brain activation in the amygdala during the EFMT and in the insula during the STIMEX was reduced one hour after alprazolam administration but returned to baseline levels at Day 28 . Exploratory analyses revealed significant treatment differences in brain activity during the STIMEX on Day 28 in frontal lobe , cau date nucleus , middle temporal gyrus , secondary visual cortex , and supramarginal gyrus . These results are consistent with the notion that the neural mechanisms supporting sustained treatment effects of benzodiazepines in GAD differ from those underlying their acute effects A recently developed cognitive-behavioral treatment for  generalized anxiety disorder  ( GAD ) targets intolerance of uncertainty by the reevaluation of positive beliefs about worry , problem-solving training , and cognitive exposure . As previous studies have established the treatment 's efficacy when delivered individually , the present study tests the treatment in a group format as a way to enhance its cost-benefit ratio . A total of 52 GAD patients received 14 sessions of cognitive-behavioral therapy in small groups of 4 to 6 participants . A wait-list control design was used , and st and ardized clinician ratings and self-report question naires assessed GAD symptoms , intolerance of uncertainty , anxiety , depression , and social adjustment . Results show that the treatment group , relative to the wait-list group , had greater posttest improvement on all dependent variables and that treated participants made further gains over the 2-year follow-up phase of the study OBJECTIVE Major depression occurs with generalized anxiety disorder and panic disorder in up to 60 % of psychiatric and primary care patients . This comorbidity has been associated with greater severity of depression , poorer psychosocial functioning , and poorer treatment outcomes in psychiatric sample s. This study examined the clinical outcomes for depressed primary care patients with and without a lifetime anxiety disorder . METHOD A total of 157 primary care patients who met criteria for major depression were r and omly assigned to st and ardized interpersonal psychotherapy or pharmacotherapy with nortriptyline and were assessed at baseline and at 4 and 8 months on severity of depression , psychosocial functioning , and health-related functioning . RESULTS Depressed patients with a comorbid anxiety disorder presented with significantly more psychopathology and tended to prematurely terminate treatment more frequently than patients with major depression alone . Both st and ardized depression-specific treatments were effective for depressed patients with and without a comorbid generalized anxiety disorder , although time to recovery was longer for the former . Patients with lifetime panic disorder showed poor recovery in response to psychotherapy or pharmacotherapy . CONCLUSIONS St and ardized psychotherapy and pharmacotherapy are effective for patients with major depression with and without a generalized anxiety disorder . However , the longer time to recovery for the former group and lack of response to these treatments by patients with lifetime panic disorder suggest that primary care physicians should carefully assess history of anxiety disorder among depressed patients so as to select a proper intervention 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 In this report , which is an up date of a guideline published in 2002 ( B and elow et al. 2002 , World J Biol Psychiatry 3:171 ) , recommendations for the pharmacological treatment of anxiety disorder , obsessive-compulsive disorder ( OCD ) and post-traumatic stress disorder ( PTSD ) are presented . Since the publication of the first version of this guideline , a substantial number of new r and omized controlled studies of anxiolytics have been published . In particular , more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs . The recommendations , developed by the World Federation of Societies of Biological Psychiatry ( WFSBP ) Task Force for the Pharmacological Treatment of Anxiety , Obsessive-Compulsive and Post-traumatic Stress Disorders , a consensus panel of 30 international experts , are now based on 510 published r and omized , placebo- or comparator-controlled clinical studies ( RCTs ) and 130 open studies and case reports . First-line treatments for these disorders are selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-noradrenaline reuptake inhibitors ( SNRIs ) and the calcium channel modulator pregabalin . Tricyclic antidepressants ( TCAs ) are equally effective for some disorders , but many are less well tolerated than the SSRIs/SNRIs . In treatment-resistant cases , benzodiazepines may be used when the patient does not have a history of substance abuse disorders . Potential treatment options for patients unresponsive to st and ard treatments are described in this overview . Although these guidelines focus on medications , non-pharmacological were also considered . Cognitive behavioural therapy ( CBT ) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders , OCD , and PTSD to support them being recommended either alone or in combination with the above medicines The past decade has brought major new developments in the psychopharmacologic management of generalized anxiety disorder and social phobia . We examined medication-prescribing patterns for the treatment of these anxiety disorders for 12 years to assess changes in patients ' anti-anxiety psychotropic medication usage during that period of evolving practice guidelines . We examined psychotropic medication use in 305 patients with generalized anxiety disorder and 232 with social phobia enrolled in the Harvard/Brown Anxiety Disorders Research Project ( HARP ) , a prospect i ve , longitudinal study of anxiety disorders .  Psychotropic treatment patterns seem to have remained relatively stable over 12 years with benzodiazepines the medications most commonly used for both generalized anxiety disorder and social phobia . Comparatively , selective serotonin reuptake inhibitor ( SSRI ) and venlafaxine usage as st and -alone medications for these disorders remained low throughout the follow-up period . At the 12-year follow-up , 24 % of patients with generalized anxiety disorder and 30 % of patients with social phobia were utilizing neither an  SSRI/selective norepinephrine reuptake inhibitor ( SNRI ) nor a benzodiazepine . Treatment recommendations for use of SSRIs and venlafaxine in the management of generalized anxiety disorder and social phobia initially promulgated in 1998 had a modest impact on changes in psychopharmacologic practice 4 - 5 years later . Difficulties in the implementation of treatment guidelines are discussed Cognitive behavioral therapy ( CBT ) has demonstrated favorable long-term outcomes in youth with anxiety disorders in efficacy trials . However , long-term outcomes of CBT delivered in a community setting are uncertain . This study examined the long-term outcomes of individual ( ICBT ) and group CBT ( GCBT ) in youth with anxiety disorders treated in community mental health clinics . A total of 139 youth ( mean age at assessment 15.5 years , range 11 - 21 years ) with a principal diagnosis of separation anxiety disorder ( SAD ) , social anxiety disorder ( SOP ) , and /or generalized anxiety disorder ( GAD ) were evaluated , on average , 3.9 years post-treatment ( range 2.2 - 5.9 years ) . Outcomes included loss of all inclusion anxiety diagnoses , loss of the principal anxiety diagnosis and changes in youth- and parent-rated youth anxiety symptoms . At long-term follow-up , there was loss of all inclusion anxiety diagnoses in 53 % , loss of the principal anxiety diagnosis in 63 % of participants as well as significant reductions in all anxiety symptom measures . No statistical significant differences in outcome were obtained between ICBT and GCBT . Participants with a principal diagnosis of SOP had lower odds for recovery , compared to those with a principal diagnosis of SAD or GAD . In conclusion , outcomes of CBT for  youth anxiety disorders delivered in community mental health clinics were improved at nearly 4 years post-treatment , and recovery rates at long-term follow-up were similar to efficacy trials Clients with generalized anxiety disorder ( GAD ) received either ( a ) applied relaxation and self-control desensitization , ( b ) cognitive therapy , or ( c ) a combination of these methods . Treatment result ed in significant improvement in anxiety and depression that was maintained for 2 years . The large majority no longer met diagnostic criteria ; a minority sought further treatment during follow-up . No differences in outcome were found between conditions ; review of the GAD therapy literature suggested that this may have been due to strong effects generated by each component condition . Finally , interpersonal difficulties remaining at posttherapy , measured by the Inventory of Interpersonal Problems Circumplex Scales ( L. E. Alden , J. S. Wiggins , & A. L. Pincus , 1990 ) in a subset of clients , were negatively associated with posttherapy and follow-up improvement , suggesting the possible utility of adding interpersonal treatment to cognitive-behavioral therapy to increase therapeutic effectiveness Abstract Objective . Anxiety disorders are frequently under-diagnosed conditions in primary care , although they can be managed effectively by general practitioners . Methods . This paper is a short and practical summary of the World Federation of Biological Psychiatry ( WFSBP ) guidelines for the pharmacological treatment of anxiety disorders , obsessive – compulsive disorder ( OCD ) and posttraumatic stress disorder ( PTSD ) for the treatment in primary care . The recommendations were developed by a task force of 30 international experts in the field and are based on r and omized controlled studies . Results . First-line pharmacological treatments for these disorders are  selective serotonin reuptake inhibitors  ( for all disorders ) ,  serotonin-norepinephrine reuptake inhibitors  ( for some ) and  pregabalin  ( for generalized anxiety disorder only ) . A combination of  medication and cognitive behavior/exposure therapy  was shown to be a clinical ly desired treatment strategy . Conclusions . This short version of an evidence -based guideline may improve treatment of anxiety disorders , OCD , and PTSD in primary care We tested the efficacy of a unified cognitive-behavioral therapy protocol for anxiety disorders . This group treatment protocol , termed false safety behavior elimination therapy ( F-SET ) , is a cognitive-behavioral approach design ed for use across various anxiety disorders such as panic disorder ( PD ) , social anxiety disorder ( SAD ) , and generalized anxiety disorder ( GAD ) .  F-SET simplifies , as well as broadens , key therapeutic elements of empirically vali date d treatments for anxiety disorders to allow for easier delivery to heterogeneous groups of patients with anxiety psychopathology . Patients with a primary anxiety disorder diagnosis ( N=96 ) were r and omly assigned to F-SET or a wait-list control . Data indicate that F-SET shows good efficacy and durability when delivered to mixed groups of patients with anxieties ( i.e. , PD , SAD , GAD ) by relatively inexperienced clinicians . Findings are discussed in the context of balancing treatment efficacy and clinical utility Non-response to pharmacotherapy for panic disorder ( PD ) is a well-documented problem . However , little information exists to guide next-step strategies for these non-responders . In addition to pharmacologic augmentation strategies , several studies support the efficacy of cognitive-behavior therapy ( CBT ) for these patients , although data on long-term outcomes has been lacking . In this study , we provide one-year outcomes on a sample of 63 patients who completed group CBT for PD after failing to respond adequately to previous pharmacotherapy . Sustained significant benefit was found for all dimensional outcome scores , and nearly two-thirds of the sample met remission criteria . This occurred with reductions in medication use over the follow-up period . Negative predictors of remission status included comorbid dysthymia , social phobia , and generalized anxiety disorder . These results provide additional evidence for the efficacy of CBT for medication non-responders with PD Background Generalised anxiety disorder ( GAD ) is a high prevalence , chronic psychiatric disorder which commonly presents early in the lifespan . Internet e-health applications have been found to be successful in reducing symptoms of anxiety and stress for post traumatic stress disorder ( PTSD ) , panic disorder , social phobia and depression . However , to date , there is little evidence for the effectiveness of e-health applications in adult GAD . There are no studies which have directly compared e-health applications with recognised evidence -based medication . This study aims to determine the effectiveness of a  web-based program for treating GAD relative to sertraline and attention placebo . Methods / Design 120 community-dwelling participants , aged 18 - 30 years with a clinical diagnosis of GAD will be recruited from the Australian Electoral Roll . They will be r and omly allocated to one of three conditions : ( i ) an online treatment program for GAD , E-couch ( ii ) pharmacological treatment with a selective serotonin re-uptake inhibitor ( SSRI ) , sertraline ( a fixed-flexible dose of 25 - 100 mg/day ) or ( iii ) an attention control placebo , HealthWatch . The treatment program will be completed over a 10 week period with a 12 month follow-up . Discussion As of February 2010 , there were no registered trials evaluating the effectiveness of an e-health application for GAD for young adults . Similarly to date , this will be the first trial to compare an e-health intervention with a pharmacological treatment . Trial Registration Current Controlled Trials IS RCT
Our review confirms the usefulness of long-term pharmacological treatments for PD and GAD and suggests that they can provide further improvement over that obtained during short-term therapy .
Paroxetine , escitalopram , and clonazepam can be effective for long-term treatment of PD .
Pregabalin and quetiapine can be effective for long-term treatment of GAD , while preliminary suggestions emerged for agomelatine and vortioxetine .
We did not find any evidence for determining the optimal length and /or dosage of medications to minimize the relapse risk .
Many aspects of long-term pharmacological treatments for  anxiety disorders ( AnxDs ) are still debated .
We undertook an up date d systematic review of long-term pharmacological studies on panic disorder ( PD ) , generalized anxiety disorder ( GAD ) , and social anxiety disorder ( SAD ) .