Treatment-resistant Anxiety Disorders Research Articles

Treatment resistance in anxiety disorders-Definition and treatment options

Treatment resistance in anxiety disorders represents aclinical challenge, contributes to the chronicity of the diseases as well as sequential comorbidities, and is associated with asignificant individual and socioeconomic burden. This narrative review presents the operational definition of treatment resistance in anxiety disorders according to international consensus criteria (< 50% reduction in the Hamilton Anxiety Scale, HAM‑A, score or < 50% reduction in the Beck Anxiety Inventory, BAI, score or a clinical global impression-improvement, CGI‑I, score > 2). At least two unsuccessful guideline-based treatment attempts with pharmacological monotherapy or at least one unsuccessful treatment attempt with adequately delivered cognitive behavioral therapy are required. Pharmacotherapeutically, after excluding pseudo-resistance, switching the medication within one class or to another class and augmentation strategies with other antidepressants (mirtazapine, agomelatine), antipsychotics (quetiapine) or anticonvulsants (valproate) are recommended. Psychotherapeutically, third-wave therapies, psychodynamic therapy, systemic therapy and physical exercise can be considered for therapy resistance. In cases of no response to psychotherapy or pharmacotherapy, the respective other form of therapy or acombination of both should be offered. Compounds targeting the glutamatergic and endocannabinoid systems as well as neuropeptides are being tested as potential innovative pharmaceuticals for treatment-resistant anxiety disorders. There is an urgent need for further research to identify predictive markers and mechanisms as well as to develop innovative pharmacological and psychotherapeutic interventions for treatment-resistant anxiety disorders.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

Schema therapy with cognitive behaviour day-treatment in patients with treatment-resistant anxiety disorders and obsessive-compulsive disorder: an uncontrolled pilot study

Treatment resistance in patients with anxiety disorders and obsessive-compulsive disorder (OCD) might be caused by dysfunctional personality traits or, more specifically, early maladaptive schemas (EMSs) and schema modes, that can be treated with schema therapy (ST). To explore possible effectiveness of ST-CBT day-treatment in patients with treatment-resistant anxiety disorders and OCD in an uncontrolled pilot study. Treatment-resistant patients with anxiety disorders or OCD (n = 27) were treated with ST-CBT day-treatment for 37 weeks on average including 11.5 therapy hours per week. The Symptom Questionnaire-48, Young Schema Questionnaire-2 and Schema Mode Inventory were completed before and after treatment. General psychopathology, EMSs and schema modes significantly improved after treatment. Spearman's correlations between pre- to post-treatment difference scores of general psychopathology, EMSs and schema modes were significant and high. The level of pre-treatment EMSs and schema modes did not predict post-treatment general psychopathology. Symptom reduction was strongly correlated with improvement of EMSs and schema modes. Stronger pre-treatment EMSs and schema modes did not hinder improvement of symptoms. ST-CBT day-treatment is promising for patients with treatment-resistant anxiety disorders and OCD. Further controlled research is needed to substantiate evidence for schema therapy in patients with treatment-resistant anxiety disorders and OCD.

Efficacy of right sided low frequency repetitive transcranial magnetic stimulation in treatment resistant anxiety disorders

Introduction: The purpose of this study was to determine the efficacy of right sided low frequency rTMS in Treatment Resistant Anxiety Disorders including but not limited to, Generalized Anxiety Disorder, Social Anxiety & Panic Disorder and Post Traumatic Stress Disorder. Patient selection criteria included any patients between the ages of 18-60, with an Anxiety Disorder as a primary diagnosis and a Generalized Anxiety Disorder – 7 Score of 10 or more. All patients were screened for other differential diagnosis’, evidence based psychotherapy for more than a year, documented trials of 3 or more psychopharmacological agents & had no history of substance abuse which yielded 12 patients that were eligible for this study. All patients underwent 36 rTMS treatments over the course of 9 weeks, with an acute taper at starting week 7. All patients received the 1 Hz, Low frequency protocol, Right Dorsolateral Prefrontal Cortex, 2000 pulses with motor thresholds between 100%-120%. Patients completed GAD-7’s on a biweekly basis with reporting done during the middle of the week. Background: The objective of this study was to measure the outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of the Anxiety Based Disorders including GAD, Panic Disorder, & PTSD. Patient demographics both males & females, ages 18-60 years of age, with a mean score of 17.5 on their GAD-7. Methods: All 12 patients underwent 36 rTMS treatments with NeuroStar ™ TMS on the RDLPFC (80%-120% MT, 1 Hz in a sequence of 1 pulse per second for 33:20 minutes providing 2000 inhibitory pulses). Treatment occurred 5 times weekly for 6 weeks with a taper for 3 weeks. Patients would undergo bi-weekly clinical screening via GAD-7 and patient feedback. Results: 100% of participants completed the full course of 36 treatments with an appropriate taper. Patients who received the low frequency right sided TMS treatments had an average of a 14.0 points reduction on their GAD-7 measures, with a mean starting scale of 17.5 and a mean ending scale of 3.5. Conclusions: The results of low frequency right sided TMS for anxiety-based disorders are indicative of a significant clinical response. Low frequency protocols have been found to be mood stabilizing in theory. The GAD-7 scale is explanatory of the sensitivity of such a treatment protocol. Further investigation is warranted. Funding: None Conflicts of Interest: None

Ketamine As A New Therapeutic Option For The Management Of Mental Disorders

IntroductionKetamine is routinely used for anesthetic induction because of its dissociative properties. Recently, it has attracted attention as a rapid-acting anti-depressant, but other studies have also reported its efficacy in the management of diverse psychiatric pathologies previously resistant to treatment.ObjectivesWe aimed to review the efficacity of ketamine in the management of mental disorders.MethodsWe conducted a litterature review through pubmed database, using the following keywords: “mental illness”; “ketamine”;”depression”;”anxiety disorders”;”eating disorders”;”substance use disorders”.ResultsKetamine has primarily been used in psychiatry for people with treatment-resistant depression. Its efficacy in reducing suicidal ideation has been previously reported. Furthermore, Ketamine may be a potential therapeutic option for patients with treatment-resistant anxiety disorders, especially obsessive compulsive disorder (OCD) and post-traumatic stress disorder. It has recently been reported a rapid onset anxiolytic activity in treatment-resistant social anxiety disorder and generalized anxiety disorder. Besides, Ketamine use in subjects suffering from eating disorders was associated with a complete remission of severe anorexia nervosa with a return to normal weight and a decrease in body preoccupations. The use of ketamine alone or in combination with other therapies was effective in reducing alcohol and substance use, prolonging abstinence, reducing craving and enhancing motivation. ketamine in combination with motivational enhancement therapy may be an effective pharmacotherapy for initiating and sustaining abstinence from alcoholicsConclusionsketamine shows great promise as a treatment for several mental disorders. However, its possible side effects and short duration of efficacy limit its use. Further studies exploring longer-term outcomes and administration protocols are needed.DisclosureNo significant relationships.

Hypothalamic deep brain stimulation as a strategy to manage anxiety disorders

Fear is essential for survival, but excessive anxiety behavior is debilitating. Anxiety disorders affecting millions of people are a global health problem, where new therapies and targets are much needed. Deep brain stimulation (DBS) is established as a therapy in several neurological disorders, but is underexplored in anxiety disorders. The lateral hypothalamus (LH) has been recently revealed as an origin of anxiogenic brain signals, suggesting a target for anxiety treatment. Here, we develop and validate a DBS strategy for modulating anxiety-like symptoms by targeting the LH. We identify a DBS waveform that rapidly inhibits anxiety-implicated LH neural activity and suppresses innate and learned anxiety behaviors in a variety of mouse models. Importantly, we show that the LH DBS displays high temporal and behavioral selectivity: Its affective impact is fast and reversible, with no evidence of side effects such as impaired movement, memory loss, or epileptic seizures. These data suggest that acute hypothalamic DBS could be a useful strategy for managing treatment-resistant anxiety disorders.

Acceptance and commitment therapy for older people with treatment-resistant generalised anxiety disorder: the FACTOID feasibility study.

Generalised anxiety disorder, characterised by excessive anxiety and worry, is the most common anxiety disorder among older people. It is a condition that may persist for decades and is associated with numerous negative outcomes. Front-line treatments include pharmacological and psychological therapy, but many older people do not find these treatments effective. Guidance on managing treatment-resistant generalised anxiety disorder in older people is lacking. To assess whether or not a study to examine the clinical effectiveness and cost-effectiveness of acceptance and commitment therapy for older people with treatment-resistant generalised anxiety disorder is feasible, we developed an intervention based on acceptance and commitment therapy for this population, assessed its acceptability and feasibility in an uncontrolled feasibility study and clarified key study design parameters. Phase 1 involved qualitative interviews to develop and optimise an intervention as well as a survey of service users and clinicians to clarify usual care. Phase 2 involved an uncontrolled feasibility study and qualitative interviews to refine the intervention. Participants were recruited from general practices, Improving Access to Psychological Therapies services, Community Mental Health Teams and the community. Participants were people aged ≥ 65 years with treatment-resistant generalised anxiety disorder. Participants received up to 16 one-to-one sessions of acceptance and commitment therapy, adapted for older people with treatment-resistant generalised anxiety disorder, in addition to usual care. Sessions were delivered by therapists based in primary and secondary care services, either in the clinic or at participants' homes. Sessions were weekly for the first 14 sessions and fortnightly thereafter. The co-primary outcome measures for phase 2 were acceptability (session attendance and satisfaction with therapy) and feasibility (recruitment and retention). Secondary outcome measures included additional measures of acceptability and feasibility and self-reported measures of anxiety, worry, depression and psychological flexibility. Self-reported outcomes were assessed at 0 weeks (baseline) and 20 weeks (follow-up). Health economic outcomes included intervention and resource use costs and health-related quality of life. Fifteen older people with treatment-resistant generalised anxiety disorder participated in phase 1 and 37 participated in phase 2. A high level of feasibility was demonstrated by a recruitment rate of 93% and a retention rate of 81%. A high level of acceptability was found with respect to session attendance (70% of participants attended ≥ 10 sessions) and satisfaction with therapy was adequate (60% of participants scored ≥ 21 out of 30 points on the Satisfaction with Therapy subscale of the Satisfaction with Therapy and Therapist Scale-Revised, although 80% of participants had not finished receiving therapy at the time of rating). Secondary outcome measures and qualitative data further supported the feasibility and acceptability of the intervention. Health economic data supported the feasibility of examining cost-effectiveness in a future randomised controlled trial. Although the study was not powered to examine clinical effectiveness, there was indicative evidence of improvements in scores for anxiety, depression and psychological flexibility. Non-specific therapeutic factors were not controlled for, and recruitment in phase 2 was limited to London. There was evidence of high levels of feasibility and acceptability and indicative evidence of improvements in symptoms of anxiety, depression and psychological flexibility. The results of this study suggest that a larger-scale randomised controlled trial would be feasible to conduct and is warranted. Current Controlled Trials ISRCTN12268776. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 54. See the NIHR Journals Library website for further project information.

Circulating cytokine levels in the treatment of comorbid anxiety disorders.

Psychotherapy research aims to investigate predictors and moderators of treatment outcome, but there are few consistent findings. This study aimed to investigate cytokines in patients undergoing treatment for anxiety disorders and whether the level of cytokines moderated the treatment outcome. Thirty-seven patients with comorbid and treatment-resistant anxiety disorders were investigated using multilevel modelling. Serum cytokine levels were measured three times: pretreatment, in the middle of treatment, and at the end of treatment. Anxiety and metacognitions were measured weekly throughout treatment by self-report. The levels of monocyte chemoattractant protein-1, tumour necrosis factor-alpha, and interleukin-1 receptor antagonist did not change during therapy or were not related to the level of anxiety. Metacognitive beliefs predicted anxiety, but the relationship between metacognitions and anxiety was not moderated by cytokines. Limitations of the study include that the patients were not fasting at blood sampling, and we did not assess body mass index, which may affect cytokine levels. The lack of significance for cytokines as a predictor or moderator may be due to a lack of power for testing moderation hypotheses, a problem associated with many psychotherapy studies. Cytokines did not predict the outcome in the treatment of comorbid anxiety disorders in our sample. Furthermore, cytokines did not moderate the relationship between metacognitions and anxiety.

What is treatment resistance in psychiatry? A "difficult to treat" concept.

What is treatment resistance in psychiatry? A "difficult to treat" concept.

A Randomized Controlled Trial of Attention Bias Modification Treatment in Youth With Treatment-Resistant Anxiety Disorders.

Randomized clinical trials of augmentation strategies for youth with treatment-resistant anxiety disorders do not exist. This report presents findings from an efficacy trial of attention bias modification treatment (ABMT) as an augment for this population compared with attention control training (ACT). Sixty-four youths (34 boys; mean age 11.7 years) who continued to meet for anxiety diagnoses after completing cognitive-behavioral therapy were randomized to ABMT or ACT. ABMT and ACT consisted of dot-probe attention training trials presenting angry and neutral faces; probes appeared in the location of neutral faces on 100% of trials in ABMT and 50% of trials in ACT. Independent evaluators, youths, and parents completed ratings of youth anxiety severity, and youths completed measures of attention bias to threat and attention control at pretreatment, post-treatment, and 2-month follow-up. The 2 arms showed significant decreases in anxiety severity, with no differences between arms. Specifically, across informants, anxiety severity was significantly decreased at post-treatment and decreases were maintained at follow-up. Primary anxiety disorder diagnostic recovery combined across arms was 50% at post-treatment and 58% at follow-up. Attention control, but not attention bias to threat, was significantly improved at post-treatment in the 2 arms. This is the first study to show anxiety can be decreased in youth who did not respond to cognitive-behaviorial therapy, and that the anxiety-decreasing effect is found using these 2 attention training contingency schedules. These findings and increases in attention control in the 2 arms raise intriguing questions about mechanisms of decreasing anxiety in treatment-resistant youth with attention training that require further research. Attention Bias Modification Training for Child Anxiety CBT Nonresponders; https://clinicaltrials.gov/; NCT01819311.

Effectiveness of a self-management training for patients with chronic and treatment resistant anxiety or depressive disorders on quality of life, symptoms, and empowerment: results of a randomized controlled trial

BackgroundAnxiety and depressive disorders are common mental disorders. A substantial part of patients does not achieve symptomatic remission after treatment in specialized services. Current care as usual (CAU) for these patients consists of long-term supportive contacts. Termination of CAU is often not considered to be an option due to persistent symptoms, a low level of functioning, and the absence of further treatment options. A new intervention, ZemCAD, offers a program focused on rehabilitation and self-management, followed by referral back to primary care.MethodsThis multicenter randomized controlled trial was carried out in twelve specialized outpatient mental health care services in the Netherlands. Consenting and eligible patients were invited for the MINI interview and the baseline questionnaire. Assessments were done at 6 (T1), 12 (T2) and 18 (T3) months post baseline. We used linear mixed model analysis (LMM) to ascertain the effectiveness of the ZemCAD group relative to the CAU group on quality of life, symptom severity and empowerment.ResultsIn total 141 patients were included. The results at 18-month follow-up regarding to quality of life and symptom severity, showed no significant differences between the ZemCAD group and the CAU group, except on the ‘social relationships’-domain (d = 0.37). With regard to empowerment a significant difference between both groups was observed in the total empowerment score and one empowerment dimension (d = 0.45 and d = 0.39, respectively). After the ZemCAD intervention, more patients went from specialized outpatient mental health services back to a less specialized health care setting with less intensive treatment, such as primary care.ConclusionThe findings in this study suggest that patients with chronic and treatment-resistant anxiety and depression using the ZemCAD intervention improve on empowerment but not on symptom severity or quality of life. Since little is known about the effects of rehabilitation and self-management in patients with chronic and treatment resistant anxiety and depressive disorders, this is a first attempt to provide a proof-of-concept study in this under-researched but important field.Trial registrationNetherlands Trial Register: NTR3335, registered 7 March 2012.

Effectiveness and cost-effectiveness of a self-management training for patients with chronic and treatment resistant anxiety or depressive disorders: design of a multicenter randomized controlled trial.

BackgroundMany patients with anxiety or depressive disorders achieve no remission of their symptoms after evidence-based treatment algorithms. They develop a chronic course of the disorder. Current care for these patients usually consists of long-term supportive contacts with a community psychiatric nurse and pharmacological management by a psychiatrist. Data on the effectiveness of these treatments is lacking. A psychosocial rehabilitation approach, where self-management is an increasingly important part, could be more suitable. It focuses on the restoration of functioning and enhancement of patients’ autonomy and responsibility. Treatment with this focus, followed by referral to primary care, may be more (cost-)effective.MethodsA multicenter randomized controlled trial is designed for twelve participating specialized outpatient mental health services in the Netherlands. Patients with chronic and treatment resistant anxiety or depressive disorders, currently receiving supportive care in specialized outpatient mental health care, are asked to participate. After inclusion, patients receive the baseline questionnaire and are randomized to the intervention group or the usual care control group. The intervention focuses on rehabilitation and self-management and is provided by a trained community psychiatric nurse, followed by referral to primary care. Measurements take place at 6, 12, and 18 months after baseline. This study evaluates both the effectiveness (on quality of life, symptom severity, and empowerment), and cost-effectiveness of the intervention compared to usual care. In addition, a questionnaire is designed to get insight in which self-management strategies patients use to manage their disorder, and in the experiences of patients with the change of care setting.DiscussionIn this study we evaluate the effectiveness and cost-effectiveness of a self-management intervention for patients with chronic and treatment resistant anxiety or depressive disorders in specialized outpatient mental health care. The results of this study may provide a first ‘proof-of-concept’ in this under-researched but important field, and might be relevant for a large group of patients in the context of a transition of the Dutch health care system.Trial registrationNetherlands Trial Register: NTR3335, registered 7 March 2012.

AUGMENTATION STRATEGIES FOR TREATMENT-RESISTANT ANXIETY DISORDERS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

A systematic review and meta-analysis was conducted to explore the efficacy of medication augmentation strategies compared to control treatments in patients who have had a partial or no response to initial treatment for generalized anxiety disorder, social anxiety disorder, and panic disorder. Double-blind controlled trials of medication augmentation in adult treatment-resistant anxiety disorders conducted between January 1990 and January 2015 were systematically reviewed and evaluated by two independent raters. The search identified 625 articles; 610 were excluded following abstract review and 15 had full-text screening. Studies had to include a definition of treatment resistance, exclude concomitant medications, and have a parallel or crossover design. Data extraction forms were completed in duplicate. Six studies were included in the meta-analysis. Effect estimates were calculated using random effects modeling; heterogeneity was assessed and subgroup and sensitivity analyses were completed. Primary outcome was response, defined by Clinical Global Impression-Improvement score of ≤2. Augmentation was not associated with an increased risk of response, as compared with placebo (RR = 1.08, 95% CI = 0.94-1.24). A small significant effect was found in reduction in symptom severity: standard mean difference = -0.32, 95% CI = -0.56 to -0.08. No significant differences between augmentation with medication versus placebo were found in ratings of functional impairment and dropouts due to adverse events. Augmentation does not appear to be beneficial in treatment-resistant anxiety disorders. These results may be limited by small study samples, and a small number of overall studies in the analysis.

ID 8 – Repetitive transcranial magnetic stimulation in chronic anxiety and depression

Objective Presenting the case of a gentleman with chronic treatment resistant depression (TRD) and social anxiety disorder, who first failed ECT and left sided high frequency repetitive transcranial magnetic stimulation (rTMS) but then responded to right sided low frequency rTMS in order to highlight the therapeutic potential of right sided rTMS for the treatment of TRD with co-morbid anxiety. Methods 44 year old married mixed race male with primary symptoms of chronic sadness, deep sense of worthlessness and hopelessness, irritability, anergia, poor concentration, intermittent suicidal ideation and anxiety. Since the mid 1990s, he’s had adequate trials of multiple psychotropic medications and psychotherapy. Twenty sessions of bilateral ECT offered no therapeutic benefit. He thus began left unilateral, high frequency (10 Hz) rTMS. Results Using the Montgomery–Asberg Depression Rating Scale (MADRS), his initial score was 28. He received 32 left sided treatments, but failed to respond. He was switched to right sided rTMS and after 20 sessions his MADRS score decreased to 9. He has been continued on maintenance rTMS therapy monthly and remains in remission. Conclusion This case illustrates that if left sided high frequency rTMS proves ineffective, then right sided, low frequency treatment should be considered in patients suffering with chronic depression and anxiety.

Troubles anxieux résistants : revue des stratégies de traitements médicamenteux

Anxiety disorders are widespread psychiatric conditions with significant social and professional disability, poor quality of life, an increased risk of suicide, and frequent attendance of medical services. Serotonin reuptake inhibitors (SRI) and serotonin and norepinephrine reuptake inhibitors (SNRI) have demonstrated a rather robust efficacy for the treatment of most of anxiety disorders. Nevertheless a substantial number of patients are resistant or still suffer from residual symptoms despite this first line treatment. The objective of our paper is to review relevant studies for the pharmacologic management of anxiety disorders resistant to the first line treatment. For this purpose, we conducted a pubmed/medline search for double-blind placebo-controlled trials of treatment-resistant anxiety disorders. An adequate trial for a SRI in the treatment of obsessive-compulsive disorder (OCD) should continue for at least 12 weeks. Special considerations of the comorbidities and symptom profile could help in the choice of an appropriate pharmacotherapy. Several trials have highlighted the efficacy of antipsychotics as an add-on to SRI in treatment-resistant OCD such as haloperidol more so when comorbid with a tic disorder, or risperidone that can reduce OCD as well as depressive symptoms. Aripiprazole has been shown efficacious in two placebo-controlled double-blind trials, while the efficacy of quetiapine and olanzapine remains controversial. Other trials showed some efficacy of anticonvulsants (lamotrigine, topiramate), pindolol, memantin and N-acetylcystein as an adjunctive treatment to SRI for resistant OCD. Few trials have investigated selective serotonin reuptake inhibitors (SSRI) or SNRI resistant generalized anxiety disorder showing a failure of adjunctive therapy with olanzapine, quetiapine, ziprasidone and risperidone. These studies were underpowered and very limited in number. Adjunctive risperidone for resistant post-traumatic stress disorder (PTSD) showed benefit in some but not all trials. Olanzapine was beneficial for the reduction of the CAPS score in addition to the improvement of sleep disturbances. Furthermore, prazosin was efficacious by reducing PTSD symptoms, sleep disturbances, nightmares, and psychological distress. One double-blind placebo-controlled study was conducted to investigate treatment-resistant social phobia showing no benefit of pindolol add-on paroxetine. Our results demonstrate that the pharmacological management of treatment-resistant anxiety disorders is not sufficiently investigated in double-blind placebo-controlled trials, despite a growing evidence in favor of antipsychotics and some other pharmacological agents in resistant OCD and, to a lesser extent, PTSD. Hence, there is a crucial need for larger double-blind placebo-controlled trials for resistant anxiety disorders. Finally, being out of the scope of our review, we omitted studies of non-pharmacologic therapies.

P.4.c.001 The use of augmentation strategies in treatment resistant anxiety disorders: a meta-analysis and systematic review

P.4.c.001 The use of augmentation strategies in treatment resistant anxiety disorders: a meta-analysis and systematic review

Clinical effectiveness of interventions for treatment-resistant anxiety in older people: a systematic review

Anxiety and related disorders include generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder and phobic disorders (intense fear of an object or situation). These disorders share the psychological and physical symptoms of anxiety, but each disorder has its own set of characteristic symptoms. Anxiety disorders can be difficult to recognise, particularly in older people (those aged over 65 years). Older people tend to be more reluctant to discuss mental health issues and there is the perception that older people are generally more worried than younger adults. It is estimated that between 3 and 14 out of every 100 older people have an anxiety disorder. Despite treatment, some people will continue to have symptoms of anxiety. People are generally considered to be 'resistant' or 'refractory' to treatment if they have an inadequate response or do not respond to their first treatment. Older adults with an anxiety disorder find it difficult to manage their day-to-day lives and are at an increased risk of comorbid depression, falls, physical and functional disability, and loneliness. To evaluate the effectiveness of pharmacological, psychological and alternative therapies in older adults with an anxiety disorder who have not responded, or have responded inadequately, to treatment. Electronic databases (MEDLINE, MEDLINE In-Process and Other Non-Indexed citations, EMBASE, The Cochrane Library databases, PsycINFO and Web of Science) were searched from inception to September 2013. Bibliographies of relevant systematic reviews were hand-searched to identify additional potentially relevant studies. ClinicalTrials.gov was searched for ongoing and planned studies. A systematic review of the clinical effectiveness of treatments for treatment-resistant anxiety in older adults was carried out. No randomised controlled trial or prospective comparative observational study was identified meeting the prespecified inclusion criteria. Therefore, it was not possible to draw any conclusions on clinical effectiveness. As no study was identified in older adults, there is uncertainty as to which treatments are clinically effective for older adults with an anxiety disorder who have not responded to prior treatment. The comprehensive methods implemented to carry out this review are a key strength of the research presented. However, this review highlights the extreme lack of research in this area, identifying no comparative studies, which is a marked limitation. Specific studies evaluating interventions in older adults with an anxiety disorder who have not responded to first-line treatment are needed to address the lack of evidence. The lack of evidence in this area means that older adults are perhaps receiving inappropriate treatment or are not receiving a particular treatment because there is limited evidence to support its use. At this time there is scope to develop guidance on service provision and, as a consequence, to advance the standard of care received by older adults with a treatment-resistant anxiety disorder in primary and secondary care. Evaluation of the relative clinical effectiveness and acceptability of pharmacological and psychological treatment in older adults with an anxiety disorder that has not responded to first-line treatment is key future research to inform decision-making of clinicians and patients. An important consideration would be the enrolment of older adults who would be representative of older adults in general, i.e. those with multiple comorbid physical and mental disorders who might require polypharmacy. The protocol for the systematic review is registered on PROSPERO (registration number CRD42013005612). The National Institute for Health Research Health Technology Assessment programme.

S23-02 - Evidence-based treatment of anxiety disorders in Europe - an update

Anxiety disorders are chronic, disabling conditions with prevalence rates higher than the ones of schizophrenia or diabetes.Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are standard treatments for anxiety disorders. The calcium-channel modulator pregabalin is a treatment option for generalized anxiety disorder. Tricyclic antidepressants (TCAs) are as effective as modern antidepressants, but less well tolerated. For short-term treatment and in treatment-resistant cases, benzodiazepines like alprazolam may be used when the patient does not have a history of dependency and tolerance. Combining drug treatment with cognitive behaviour therapy is the most successful treatment strategy in anxiety disorders. Strategies of treatment-resistant anxiety disorders and future anxiolytics will be presented in the symposium.

Aripiprazole: A clinical review of its use for the treatment of anxiety disorders and anxiety as a comorbidity in mental illness

Background Although anxiety disorders are common, optimal treatment is elusive. More than half of anxiety patients treated with an adequate course of antidepressants fail to fully improve: treatment resistance, residual symptoms, and recurrence/relapse remain a challenge. Recently, atypical antipsychotics have been considered for treatment-resistant anxiety disorders. This review will explore the available data for the role of aripiprazole in the treatment of anxiety. Methods PubMed and conference abstracts were searched for randomized, double-blind studies that investigated the efficacy of aripiprazole in anxiety; its efficacy in bipolar disorder and depression was also explored for comparison. Results A number of studies have shown atypical antipsychotics to be effective in anxiety, and currently available data suggest that aripiprazole augmentation in patients with anxiety disorders is likely as effective as other atypical antipsychotic drugs. Although there have been no randomized, controlled trials, aripiprazole has been found to be effective in treating anxiety disorders in two open-label trials. This combined with the larger data base demonstrating its utility in bipolar disorder and depression, its safety profile and its unique mechanism of action, make aripiprazole for anxiety an intriguing avenue of exploration. Limitations Data from large randomized, controlled trials on the use of atypical antipsychotics for anxiety in general, and aripiprazole in particular, are currently lacking. Conclusion The results of open-label trials of aripiprazole in anxiety provide enough support to warrant its further study. This, combined with a larger data base demonstrating its utility in bipolar disorder and depression, its safety profile and its unique mechanism of action, make aripiprazole for anxiety an intriguing avenue of exploration.