World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders.

AIM: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008). METHOD: A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications. RESULT: This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence. CONCLUSION: It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD.

AIM: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008. METHOD: A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments. RESULT: The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders.For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs.Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated.For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option. CONCLUSION: OCD and PTSD can be effectively treated with CBT and medications.

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Efficacy of venlafaxine extended release in major depressive disorder patients: effect of baseline anxiety symptom severity.

Effects of baseline anxiety on the efficacy of venlafaxine extended release versus placebo were examined in a post hoc pooled subgroup analysis of 1573 patients enrolled in eight short-term studies of major depressive disorder. Anxiety subgroups were defined based on baseline 17-item Hamilton Rating Scale for Depression Item 10 score <3 (low) versus ≥3 (high). Change from baseline to final visit in Montgomery-Åsberg Depression Rating Scale total score and Montgomery-Åsberg Depression Rating Scale response and remission rates were analyzed. Change from baseline in Montgomery-Åsberg Depression Rating Scale total score and response and remission rates was significantly greater for venlafaxine extended release versus placebo in both low and high anxiety subgroups (all P < 0.0001). A statistically significant baseline anxiety by treatment interaction was observed for Montgomery-Åsberg Depression Rating Scale total score only (P = 0.0152). The adjusted mean change from baseline in Montgomery-Åsberg Depression Rating Scale total score was significantly greater in the high anxiety subgroup versus low anxiety subgroup for patients treated with venlafaxine extended release (-6.27 versus -3.89; P = 0.0440) but not placebo. These results support the efficacy of venlafaxine extended release for major depressive disorder treatment in patients with anxiety symptoms.

Anxiety as a risk factor in cardiovascular disease.

PURPOSE OF REVIEW: The narrative review covers recent studies of anxiety as a companion in cardiovascular disease. RECENT FINDINGS: Prospective population-based studies and studies of cases with known cardiovascular disease have been conducted, as well as studies of intervention with coronary bypass grafting, heart transplants, and implantable cardioverter-defibrillators, and subsequent rehabilitation programs. Mental stress-induced myocardial ischemia (MSIMI) stands for this emerging research arena. SUMMARY: Anxiety has emerged as perhaps the most important risk factor for cardiovascular disease, determining other known risk factors, such as depression, substance use, overweight, and a sedentary lifestyle. Anxiety also increases the risk of major cardiac events in coronary heart disease. There is a need for elucidating the influence of anxiety in takotsubo and in white-coat hypertension. Managing anxiety is of vital importance in patients who have received heart transplants, to ascertain adherence to immunosuppressants.

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology.

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

Anxiety and cardiovascular disease.

This chapter examines the association of anxiety disorders and anxiety symptoms with cardiovascular disease, focussing on hypertension (an independent risk factor for myocardial infarction and stroke) and coronary heart disease. In both cases, epidemiological data linking the cardiovascular disorder with specific anxiety disorders and anxiety symptoms are examined first, and evidence relating to putative mechanisms that may underlie these associations is explored. For hypertension, an association with panic attacks and panic disorder has been reported most consistently, but the literature relating to other forms of anxiety is inconsistent, especially as some studies have reported an association of anxiety with low blood pressure. Recent work which has attempted to elucidate this confusing situation is presented. Mechanisms which may be responsible for the link between hypertension and panic include autonomic nervous system dysfunction (which may be under serotonergic control), respiratory mechanisms, cytokines, platelet dysfunction and behavioural factors. While an association of depression with coronary heart disease has been studied extensively, the association with anxiety disorders has been slower to emerge. Studies contributing to this evidence base are examined, and as for hypertension putative mechanisms are discussed.

Pharmacotherapy of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is chiefly characterized by a cognitive focus on threats and risks towards the individual and/or the immediate family. It is accompanied by a sense of tension, worry, muscle pain, disturbed sleep and irritability. The condition impairs work capacity, relations, and leisure activities, and aggravates concurrent somatic diseases. Due to its chronic course, GAD increases costs for the individual, the family, and health care services, and reduces work and educational performance. In cardiovascular or cerebrovascular disease, pulmonary disease, diabetes and neurological diseases, GAD is a risk factor for somatic complications and for lowered adherence to somatic treatments. There is evidence that GAD can be treated with cognitive behavioural therapy (CBT), and/or with medications. First-line pharmacotherapies are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and pregabalin. If such therapies fail, one may reconsider the diagnosis, question adherence with the prescribed schedule, and determine the adverse influence of comorbidity (such as depression, substance use, and physical ill-health) as well as the influence of social stressors. Second-line pharmacotherapies are largely not supported by controlled trials, and so leave much to clinical judgment and careful monitoring. One may attempt treatments with benzodiazepine anxiolytics, with quetiapine, or with pregabalin as an adjunct therapy in patients with partial response to SSRI or SNRI treatment. CBT is a valid alternative to pharmacotherapy, depending on patient preference.

A possible association between panic disorder and a polymorphism in the preproghrelingene.

The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin. In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was significantly associated with panic disorder, while there were no significant associations with the two other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the preproghrelin gene may be associated with increased risk of panic disorder. It will be important to confirm these findings in additional panic disorder patient groups.

Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study.

OBJECTIVE: This study evaluated the efficacy and tolerability of agomelatine in the prevention of relapse in patients with generalized anxiety disorder (GAD). METHOD: Patients with GAD (Hamilton Anxiety Rating Scale [HARS] ≥ 22, with items 1 and 2 ≥ 2, item 1 + 2 ≥ 5; Montgomery-Asberg Depression Rating Scale [MADRS] ≤ 16; and < 20% decrease in HARS total score between screening and baseline) who responded to a 16-week course of agomelatine 25-50 mg/d treatment were randomly assigned to receive continuation treatment with agomelatine (n = 113) or placebo (n = 114) for 26 weeks. The main outcome measure was time to relapse during this maintenance period. The estimated risk of relapse was calculated using the Kaplan-Meier method, and groups were compared using a log-rank test stratified for country. The study was undertaken in 31 clinical centers in Canada, Denmark, Estonia, Finland, Hungary, and Sweden from November 2007 to September 2009. RESULTS: During the 6-month maintenance period, the proportion of patients that relapsed during the double-blind period in the agomelatine group (22 patients, 19.5%) was lower than in the placebo group (35 patients, 30.7%). The risk of relapse over time was significantly lower for patients who continued treatment than for those switched to placebo (P = .046, log-rank test stratified for country). Agomelatine was also superior to placebo in preventing relapse in the subset of more severe patients with baseline HARS total score ≥ 25 and CGI-S score ≥ 5. The tolerability of agomelatine was good throughout the study, and there were no differences in discontinuation symptoms after withdrawal of agomelatine in comparison to maintenance on agomelatine. CONCLUSIONS: The present study extends the positive findings of an earlier short-term study of agomelatine in GAD, demonstrating that agomelatine is effective and well-tolerated in the longer-term treatment of this chronic disorder. TRIAL REGISTRATION: www.isrctn.org identifier: ISRCTN38094599.

An international survey of reported prescribing practice in the treatment of patients with generalised anxiety disorder.

OBJECTIVE: To gain insight into the experience and practice of psychiatrists in the pharmacological management of patients with generalized anxiety disorder (GAD). METHODS: Multiple-choice questionnaire completed by 501 psychiatrists (representing a 45% response rate) from 18 countries, selected by pharmaceutical company representatives to attend a scientific meeting, through having an interest in anxiety disorders. RESULTS: Use of screening tools, routine structured diagnostic interviews, and practice guidelines was infrequent. Over one-third of patients did not receive their initial psychiatric consultation within a month after referral. A total of 45% of patients had symptoms for 2 years or longer before being diagnosed and treated. Most patients had been treated with benzodiazepines before referral. 80% of respondents always or often prescribed selective serotonin reuptake inhibitors (SSRIs), 43% serotonin-norepinephrine reuptake inhibitors (SNRIs), or pregabalin (35%) as first-line treatments. The most frequently recommended second-line treatments were SNRIs (41%) and pregabalin (36%). Concentration difficulties, fatigue, excessive worrying and pain were reported as the symptoms most difficult to manage. CONCLUSIONS: Patients with GAD have frequently been treated with benzodiazepines before referral to a psychiatrist. SSRIs were the preferred first-line treatment, and SNRIs and pregabalin preferred second-line treatments. Reported practice in this sample appears largely consistent with recent evidence-based treatment guidelines.

Cost of disorders of the brain in Europe 2010.

BACKGROUND: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. AIMS: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. METHODS: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. RESULTS: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. DISCUSSION: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. RECOMMENDATIONS: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene.

BACKGROUND: Orexin A and B are neuropeptides influencing, for example, arousal and respiration. Although panic disorder is characterized by both enhanced proneness for arousal and by respiratory abnormalities, the possible influence of orexin-related genes on the risk of developing this disorder has not been studied until now. METHODS: We have analyzed the Ile408Val polymorphism in the hypocretin receptor 1 (HCRTR1) gene and the Val308Iso (G1246A) polymorphism in the hypocretin receptor 2 (HCRTR2) gene in a sample of 215 panic disorder patients and 454 controls. RESULTS: Although the polymorphism in the HCRTR1 did not differ between groups, the Iso allele of the HCRTR2 polymorphism was significantly more frequent in patients than in controls. After the population was divided according to sex, the association between the Iso allele of the Val308Iso polymorphism and panic disorder was observed only in female patients. CONCLUSION: Our results suggest that the HCRTR2 polymorphism may be of importance for the pathophysiology of panic disorder. The results should be regarded as preliminary until replicated in an independent sample. This indicates that further research on the possible role of orexin in panic disorder may prove rewarding.

Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder.

OBJECTIVE: Data from a relapse prevention study of duloxetine treatment for adults with generalized anxiety disorder (GAD) were examined to identify predictors of relapse. METHODS: Patients responding to 6 months of open-label duloxetine treatment were randomized to continuation with duloxetine or withdrawal to placebo for a 6-month double-blind continuation phase (duloxetine, N= 216; placebo, N= 213). Post hoc analyses compared time to GAD relapse during continuation phase by using predictor variables that included patient demographics, symptom severity measures (Hamilton Anxiety Scale Scores [HAMA], Hospital Anxiety and Depression Scale), functional outcomes, and visual analogue scale (VAS) pain measures. Univariate and multivariate analyses were performed using predictor variables from time of randomization into the continuation, withdrawal phase. RESULTS: Severity of anxiety symptoms, degree of functional impairment, and severity of pain at time of randomization were significantly predictive of likelihood of relapse during the continuation phase. Multivariate backwards elimination analysis of significant univariate predictors identified HAMA item one (anxious mood) ≥ 1 and severity of pain while awake (≥ 30 on VAS) as the strongest predictors of GAD relapse. CONCLUSIONS: For patients with GAD responding to open-label treatment with duloxetine, residual symptoms related to anxious mood, pain severity, and psychosocial function were associated with increased relapse risk, although the greatest risk was associated with anxious mood and increased severity of pain while awake.

Evidence-based pharmacological treatment of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is common in community and clinical settings. The associated individual and societal burden is substantial, but many of those who could benefit from treatment are not recognized or treated. This paper reviews the pharmacological treatment of GAD, based on findings of randomized placebo-controlled studies. Particular attention is paid to response rates to acute treatment, treatment tolerability, prediction of response, duration of treatment, and further management of patients who do not respond to initial treatment approaches. On the basis of their proven efficacy and reasonable tolerability in randomized placebo-controlled trials, recent evidence-based guidelines for pharmacological management have recommended initial treatment with either a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor, although there is also good evidence for the efficacy of pregabalin and quetiapine. It is difficult to predict reliably which patients will respond well to pharmacological treatment, but response to antidepressants is unlikely if there is no evidence of an onset of effect within 4 wk. The small number of placebo-controlled relapse-prevention studies causes uncertainty about the optimal duration of treatment after a satisfactory initial response, but continuing treatment for at least 12 months is recommended. There have been few investigations of the further management of patients who have not responded to first-line treatment, but switching to another evidence-based treatment, or augmentation approaches may be beneficial.

Psychiatric caseness is a marker of major depressive episode in general practice.

OBJECTIVE: Screening for a major depressive episode (MDE) in high-risk groups of patients within the primary care setting has been suggested by several Central Health Organizations. The objective of this study was to investigate whether patients rated as "psychiatric cases" by their general practitioner (GP) were likely to suffer from MDE and therefore qualified for systematic diagnostic screening. DESIGN: Cross-sectional survey of primary care patients assessed through depression screening questionnaires and GP consultations. SETTING: A total of 676 general practices in Denmark, Finland, Norway, and Sweden. Subjects. A total of 8879 unselected primary care patients. MAIN OUTCOME MEASURES: sensitivity, specificity, and Youden Index of the GPs' diagnoses of depression and psychiatric caseness versus patients' MDE status. RESULTS: The proportion of primary care patients receiving a false-positive diagnosis of depression by their GP ranged from 12.4% to 25.2% depending on country. The corresponding numbers for the false-negative diagnoses were 0.9-2.5% [corrected]. Among patients with MDE, GPs recognize the disease in 56-75% of cases. However, GPs recognize as many as 79-92% of patients with MDE as "psychiatric cases". CONCLUSIONS: This report confirms that misclassifications of MDE are common in the primary care setting. In addition, it shows that psychiatric caseness is a valid marker for the presence of MDE in primary care patients. This relationship should be considered in future screening recommendations.