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.

The relationship of separation anxiety with the age of onset of panic disorder.

AIM: This study aimed to investigate whether separation anxiety (SA) constitutes a dimension related to age at onset of panic disorder (PD), in homogeneous subgroups of outpatients with PD, based on their age of onset and symptom severity. METHODS: A sample of 232 outpatients with PD was assessed with the Panic Disorder Severity Scale (PDSS) and the Sheehan Disability Scale (SDS) for functional impairments. Separation anxiety was evaluated using structured interviews and questionnaires. We applied a K-Means Cluster Analysis based on the standardized "PD age of onset" and "the PDSS total score" to identify distinct but homogeneous groups. RESULTS: We identified three groups of patients: group 1 ("PD early onset/severe", N = 97, 42%, onset 23.2 ± 6.7 years), group 2 ("PD early onset/not severe", N = 76, 33%, onset 23.4 ± 6.0 years) and group 3 ("PD adult onset/not severe", N = 59, 25%, onset 42.8 ± 7.0 years). Patients with early onset/severe PD had significantly higher scores on all SA measures than PD late-onset/not severe. Regression analyses showed that SA scores, but not PDSS scores, were predictive of impairment in SDS work/school, social life, and family functioning domains. CONCLUSIONS: Our data indicate a significant relationship between SA and PD with an earlier age of onset and an impact on individual functioning. This may have important implications for implementing preventive interventions targeting early risk factors for the subsequent onset of PD.

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.

Internet psychotherapeutic interventions for anxiety disorders - a critical evaluation.

BACKGROUND: During the COVID-19 pandemic, internet-delivered psychotherapeutic interventions (IPI) move increasingly into the focus of attention. METHOD: We reviewed 39 randomized controlled studies of IPIs with 97 study arms (n = 4122 patients) for anxiety disorders (panic disorder/agoraphobia, generalized anxiety disorder, and social anxiety disorder) and performed a meta-analysis. Most studies were conducted with cognitive behavioural approaches (iCBT). Results were compared with a previous meta-analysis examining medications and face-to-face (F2F) psychotherapy. RESULTS: In direct comparisons, IPIs were as effective as F2F-CBT and superior to waitlist controls. Programs with more intensive therapist contact yielded higher effect sizes (ES). We compared the obtained ES with a previous comprehensive meta-analysis of 234 studies. In this comparison, iCBT was less effective than individual F2F-CBT and medications, not different from pill placebos, and more effective than psychological placebo and waitlist (p > .0001 for all comparisons). ES of IPIs may be overestimated. Treatments were only compared to waitlist, which is not a sufficient control condition. 97% of the studies were not blinded with regard to the main outcome measure. 32% of the participants received antianxiety drugs during the trials. In 89%, participants were recruited by advertisements rather than from clinical settings, and 63% of the participants had an academic background (students or university employees) which might affect the generalizability of the findings. Remote diagnoses were often made by students without completed training in psychotherapy. In only 15% of the studies, diagnoses were made in personal contact with a psychiatrist or psychologist. In 44% of the studies, the 'therapists' maintaining remote contact with the participants were mostly students without completed psychotherapy education. CONCLUSIONS: IPIs may be a useful tool when face-to-face psychotherapy is not easily available, or as an add-on to standard psychotherapeutic or psychopharmacological treatments but should perhaps not be used as monotherapy. We have suggested standards for future research and the practical use of IPIs.

Chronic Pain and the Endocannabinoid System: Smart Lipids - A Novel Therapeutic Option?

The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).

The German Guidelines for the treatment of anxiety disorders: first revision.

Starting in 2019, the 2014 German Guidelines for Anxiety Disorders (Bandelow et al. Eur Arch Psychiatry Clin Neurosci 265:363-373, 2015) have been revised by a consensus group consisting of 35 experts representing the 29 leading German specialist societies and patient self-help organizations. While the first version of the guideline was based on 403 randomized controlled studies (RCTs), 92 additional RCTs have been included in this revision. According to the consensus committee, anxiety disorders should be treated with psychotherapy, pharmacological drugs, or their combination. Cognitive behavioral therapy (CBT) was regarded as the psychological treatment with the highest level of evidence. Psychodynamic therapy (PDT) was recommended when CBT was not effective or unavailable or when PDT was preferred by the patient informed about more effective alternatives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are recommended as first-line drugs for anxiety disorders. Medications should be continued for 6-12 months after remission. When either medications or psychotherapy were not effective, treatment should be switched to the other approach or to their combination. For patients non-responsive to standard treatments, a number of alternative strategies have been suggested. An individual treatment plan should consider efficacy, side effects, costs and the preference of the patient. Changes in the revision include recommendations regarding virtual reality exposure therapy, Internet interventions and systemic therapy. The recommendations are not only applicable for Germany but may also be helpful for developing treatment plans in all other countries.

Efficacy of naltrexone in borderline personality disorder, a retrospective analysis in inpatients.

OBJECTIVE: The endogenous opioid system is assumed to be involved in the pathophysiology of borderline personality disorder (BPD), and opioid antagonists may improve core features of BPD. The aim of this retrospective chart analysis was to evaluate the relative contribution of the opioid antagonist naltrexone and other psychotropic drugs in the improvement of overall symptomatology in BPD. METHODS: One hundred sixty-one inpatients with BPD treated between January 2010 and October 2013 were classified as either treatment responders or non-responders. Treatment responders were defined as subjects with significant improvements in four or more symptoms from a defined symptom list. The relative contribution of all psychotropic drugs to improvement of BPD symptomatology was assessed by means of a stepwise logistic regression. RESULTS: None of the drugs applied contributed significantly to improvement, with the exception of naltrexone (odds ratio [OR] 43.2, p ≤ 0.0001). Patients treated with naltrexone (N = 55, 34%) recovered significantly more often. Higher doses of naltrexone were more effective (OR 791.8, p ≤ 0.0001) than lower doses (OR 26.6, p ≤ 0.0001); however, even low-dose treatment was better than any other pharmacological treatment. CONCLUSIONS: Naltrexone was associated with improvement in BPD in a dose-dependent manner. The present study provides additional evidence that dysregulation of the endogenous opioid system is implicated in the pathophysiology of BPD symptoms.

Separation Anxiety and Measures of Suicide Risk Among Patients With Mood and Anxiety Disorders.

BACKGROUND: Separation anxiety disorder may be important when considering risk of suicide. The aim of this study was to examine the association between both childhood and adult separation anxiety (disorder) and measures of suicide risk in a large cohort of outpatients with anxiety and mood disorders. METHODS: The sample included 509 consecutive adult psychiatric outpatients with DSM-IV mood disorders or anxiety disorders as a principal diagnosis recruited at the Department of Psychiatry, University of Pisa, Italy, between 2015 and 2018. Suicide risk was evaluated by the Hamilton Depression Rating Scale (HDRS) item 3. Patients were classified in 2 groups: those with a score ≥ 1 and those with a score of 0 on HDRS item 3. Suicide risk was also evaluated by specific items within the Mood Spectrum, Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms. Separation anxiety (disorder) was assessed based on the Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C), the Separation Anxiety Symptom Inventory (SASI), and the Adult Separation Anxiety Scale (ASA-27). RESULTS: Of the 509 patients, 97 had an HDRS item 3 score ≥ 1, and 412 had a score of 0. Adult separation anxiety disorder was more frequent among individuals who had suicidal thoughts (53.6%) than those who did not (39.6%) (P = .01). Dimensional separation anxiety symptoms on all scales were elevated in patients with suicidality when compared to patients without (SASI: P = .02; SCI-SAS-C: P < .001; SCI-SAS-A: P < .001; ASA-27: P = .002). Logistic regression found that adult separation anxiety disorder (odds ratio [OR] = 1.86, 95% CI = 1.16-2.97), major depression (OR = 7.13, 95% CI = 3.18-15.97), bipolar I disorder (8.15, 95% CI = 3.34-19.90), and bipolar II disorder (OR = 8.16, 95% CI = 3.50-19.05) predicted suicidal thoughts. Linear regression found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk. Mediation analysis found that separation anxiety significantly mediated the association between depression and suicide risk. CONCLUSIONS: This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms (evaluated by HDRS item 3) and as longitudinal dimensional symptoms (as evaluated by MOODS-SR). Greater understanding of the influence of separation anxiety in patients with affective disorders may encourage personalized interventions for reducing suicide risk.

Current and Novel Psychopharmacological Drugs for Anxiety Disorders.

Anxiety disorders, including panic disorder/agoraphobia (PDA), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and others, are the most prevalent mental disorders. In this paper, recommendations are given for the psychopharmacological treatment of these disorders which are based on comprehensive treatment guidelines, meta-analyses, and systematic reviews of available randomized controlled studies. Anxiety disorders can effectively be treated with psychotherapy, pharmacotherapy, or a combination of both. First-line drugs are the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Benzodiazepines are not recommended for routine use due to their possible addiction potential. Other treatment options include the calcium modulator pregabalin, tricyclic antidepressants, buspirone, moclobemide, and others. Drug treatment can be combined with psychological treatments. Novel treatment strategies include medications that act on GABA, glutamate, and other neurotransmitter systems. After remission, medications should be continued for 6 to 12 months.

A neurobiological framework of separation anxiety and related phenotypes.

In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes. SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity. The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions.

Mean age and gender distribution of patients with major mental disorders participating in clinical trials.

The mean age and gender distribution of patients seeking help for mental disorders have not yet been investigated systematically. Epidemiological surveys can provide data on gender distribution of disorders and an age range in which a disorder is most frequent, but do not offer data on the average help-seeking patient, and they are usually conducted by lay interviewers with non-clinical subjects. However, this information on age and gender can be simply extracted from randomized clinical trials (RCTs) in which consecutive clinical patients are included. As it can be assumed that the average patient tends to participate in a clinical trial when her/his illness severity has reached its highpoint, the mean age of patients in RCTs is a good estimator of the peak severity of a disorder. In RCTs, diagnoses are made by psychiatrists and only clinical patients fulfilling a minimum degree of severity are included. From 10.465 records found by electronic and hand search, we extracted 832 eligible RCTs with 151,336 patients with the 19 most relevant mental disorders. We provide a table with the mean age, standard deviation and gender distributions of all major mental disorders. These results can be used in scientific articles and educational materials and can help health care providers or researchers planning treatment programs. Patients can be informed about the natural course of the disorder. By determining the reasons why some disorders occur predominantly in a certain age or have an unbalanced gender distribution information the aetiology of these disorders may further be elucidated.

Pharmacotherapy of borderline personality disorder: what has changed over two decades? A retrospective evaluation of clinical practice.

BACKGROUND: The purpose of this study was to assess the pharmacological treatment strategies of inpatients with borderline personality disorder between 2008 and 2012. Additionally, we compared pharmacotherapy during this period to a previous one (1996 to 2004). METHODS: Charts of 87 patients with the main diagnosis of borderline personality disorder receiving inpatient treatment in the University Medical Center of Goettingen, Germany, between 2008 and 2012 were evaluated retrospectively. For each inpatient treatment, psychotropic drug therapy including admission and discharge medication was documented. We compared the prescription rates of the interval 2008-2012 with the interval 1996-2004. RESULTS: 94% of all inpatients of the interval 2008-2012 were treated with at least one psychotropic drug at time of discharge. All classes of psychotropic drugs were applied. We found high prescription rates of naltrexone (35.6%), quetiapine (19.5%), mirtazapine (18.4%), sertraline (12.6%), and escitalopram (11.5%). Compared to 1996-2004, rates of low-potency antipsychotics, tri-/tetracyclic antidepressants and mood stabilizers significantly decreased while usage of naltrexone significantly increased. CONCLUSIONS: In inpatient settings, pharmacotherapy is still highly prevalent in the management of BPD. Prescription strategies changed between 1996 and 2012. Quetiapine was preferred, older antidepressants and low-potency antipsychotics were avoided. Opioid antagonists are increasingly used and should be considered for further investigation.

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.

Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis.

BACKGROUND: Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD. METHOD: Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions. RESULTS: Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52). CONCLUSIONS: Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.

WFSBP guidelines on how to grade treatment evidence for clinical guideline development.

OBJECTIVE AND METHODS: This paper reviews sources of data typically used in guideline development, available grading systems, their pros and cons, and the methods for evaluating risks of bias in publications, and proposes a revised method for grading evidence and recommendations for use in development of clinical treatment guidelines. RESULTS: The new World Federation of Societies of Biological Psychiatry (WFSBP) grading system allows guideline developers to follow a multi-step approach of defining levels of evidence, applying criteria for grading (define the acceptability) and the grading of recommendations. CONCLUSIONS: Further, these updated WFSBP recommendations for rating evidence and treatment recommendations provide a grading system that takes into account potential biases in sources of evidence in arriving at final ratings that are likely more clinically meaningful and pragmatic and thus should be used for the development of future treatment guidelines.

Enduring effects of psychological treatments for anxiety disorders: meta-analysis of follow-up studies.

BACKGROUND: It is a widespread opinion that after treatment with psychotherapy, patients with anxiety disorders maintain their gains beyond the active treatment period, whereas patients treated with medication soon experience a relapse after treatment termination.AimsWe aimed to provide evidence on whether enduring effects of psychotherapy differ from control groups. METHOD: We searched 93 randomised controlled studies with 152 study arms of psychological treatment (cognitive-behavioural therapy or other psychotherapies) for panic disorder, generalised anxiety disorder and social anxiety disorder that included follow-up assessments. In a meta-analysis, pre-post effect sizes for end-point and all follow-up periods were calculated and compared with control groups (medication: n = 16 study arms; pill and psychological placebo groups: n = 17 study arms). RESULTS: Gains with psychotherapy were maintained for up to 24 months. For cognitive-behavioural therapy, we observed a significant improvement over time. However, patients in the medication group remained stable during the treatment-free period, with no significant difference when compared with psychotherapy. Patients in the placebo group did not deteriorate during follow-up, but showed significantly worse outcomes than patients in cognitive-behavioural therapy. CONCLUSIONS: Not only psychotherapy, but also medications and, to a lesser extent, placebo conditions have enduring effects. Long-lasting treatment effects observed in the follow-up period may be superimposed by effects of spontaneous remission or regression to the mean.Declaration of interestIn the past 12 months and in the near future, Dr Bandelow has been/will be on the speakers/advisory board for Hexal, Mundipharma, Lilly, Lundbeck, Pfizer and Servier. Dr Wedekind was on the speakers' board of AstraZeneca, Essex Pharma, Lundbeck and Servier. All other authors have nothing to declare.