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To assess the efficacy of psychiatric treatments, rating scales are essential. In this presentation, methodological and statistical problems associated with the use of rating scales in psychiatry are discussed, by taking the anxiety disorders as an example.
Not only standard symptom-specific rating scales, such as the Hamilton Anxiety Scale (HAMA), but also global measures such as the Clinical Global Impression Scale (CGI) and Quality of Life scales are used, as not only improvement of single symptoms, but also an overall increase of a patient's well-being should be the focus of a clinical trial. However, due to high placebo response rates in anxiety disorders, the use of rating scales is determined by the need for an instrument, which is sensitive enough to detect differences between active drugs and placebo (or between a certain psychological treatment and a psychological placebo). Quality of Life scales often do not detect such differences, as domains such as partnership or employment do not show rapid changes within the 8-12 weeks of a clinical study. Moreover, when using too many different scales, problems of multiple testing occur.
The outcome of a clinical study is often described by the number of patients who responded or remitted, as these endpoints are easily understood by patients. “Response” is commonly defined as a ≥ 50% reduction on these standard scales. However, this definition is arbitrary, and cut-off points should rather be founded on empirical data than on a thumb rule. The definition of “remission” on standard scale scores varies from study to study and is also very subjective. An analysis of available treatment studies in patients with anxiety disorders revealed that these definitions do not necessarily reflect clinical reality. Also, “number needed to treat” is an endpoint, which may lead to inaccurate assessments from a statistical point of view, because it is based on a subjective definition of remission. The adequate use of rating scales also touches ethical questions.
– Earlier studies on the influence of pregnancy and postpartum period on the course of panic disorder have been inconsistent. The present study aims to quantify panic manifestations in these periods in large sample of women.
– Panic manifestations, including exacerbations and new manifestations of panic disorder, were assessed retrospectively in a sample of 128 women with panic disorder with or without agoraphobia, 93 of whom had had 195 pregnancies.
– Panic manifestations were fewer during pregnancy and more frequent in the postpartum period when compared with the control period. Women who had never been pregnant had significantly more panic manifestations than women with prior pregnancies. Breastfeeding and miscarriages did not have a significant effect. Women with postpartum panic reported more psychosocial stress events during this period.
– Possible reasons for postpartum panic and the protective effects of pregnancy are discussed, including psychosocial or hormonal factors and other neurobiological changes. Postpartum panic coincides with a sudden drop of hormones after delivery.
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.
We conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.
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.
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 1.08–1.30) 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).
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 interest
In 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.
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.
We aimed to provide evidence on whether enduring effects of psychotherapy differ from control groups.
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).
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.
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 interest
In 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.
Anxiety disorders are the most prevalent mental disorders and are associated with substantial healthcare costs and a high burden of disease. In this article, changes in the new Diagnostic and Statistical Manual for Mental Disorders (the DSM–5) with respect to panic disorder/agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and selective mutism are compared with the International Classification of Diseases (ICD–10) system.
What are the latest psychotherapeutic and pharmacotherapeutic treatment recommendations for obsessive-compulsive disorder (OCD)? OCD is a relatively common disorder with a lifetime prevalence of ~2% in the general population. It often has an early onset, usually in childhood or adolescence, and frequently becomes chronic and disabling if left untreated. High associated healthcare utilization and costs, and reduced productivity resulting in loss of earning, pose a huge economic burden to OCD patients and their families, employers, and society. OCD is characterized by the presence of obsessions and compulsions that are time-consuming, cause marked distress, or significantly interfere with a person's functioning. Most patients with OCD experience symptoms throughout their lives and benefit from long-term treatment. Both psychotherapy and pharmacotherapy are recommended, either alone or in combination, for the treatment of OCD. Cognitive-behavioral therapy is the psychotherapy of choice. Pharmacologic treatment options include the tricyclic antidepressant clomipramine and the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. These have all shown benefit in acute treatment trials; clomipramine, fluvoxamine, fluoxetine, and sertraline have also demonstrated benefit in long-term treatment trials (at least 24 weeks), and clomipramine, sertraline, and fluvoxamine have United States Food and Drug Administration approvals for use in children and adolescents. Available treatment guidelines recommend first-line use of an SSR1 (ie, fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram) in preference to clomipramine, due to the latter's less favorable adverse-event profile. Further, pharmacotherapy for a minimum of 1–2 years is recommended before very gradual withdrawal may be considered.
Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy treatments for obsessive-compulsive disorder (OCD). Clomipramine is effective in OCD but associated with more adverse events. Typically, higher doses of antidepressants are required for OCD. Up to 50% of patients do not respond to initial treatment of OCD. Treatment options for nonresponders include augmentation of antidepressants with atypical antipsychotics, among other strategies. First-line treatments for anxiety disorders include SSRIs, serotonin norepinephrine reuptake inhibitors, and pregabalin. Tricyclic antidepressants are equally effective as SSRIs, but are less well tolerated. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of dependency and tolerance. Other treatment options include irreversible and reversible monoamine oxidase inhibitors, the atypical antipsychotic quetiapine, and other medications. Cognitive-behavioral therapy has been sufficiently investigated in controlled studies of OCD and anxiety disorders and is recommended alone or in combination with the above medications.
What are the current recommendations for the long-term treatment of generalized anxiety disorder (GAD)? GAD is a common disorder with a lifetime prevalence of 4% to 7% in the general population. GAD is characterized by excessive, uncontrollable worry or anxiety about a number of events or activities that the individual experiences on more days than not over a 6-month period. Onset of GAD symptoms usually occurs during an individual's early twenties; however, high rates of GAD have also been seen in children and adolescents. The clinical course of GAD is often chronic, with 40% of patients reporting illness lasting >5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Patients with GAD tend to be high users of outpatient medical care, which contributes significantly to healtcare costs. Currently, benzodiazepines and buspirone are prescribed frequently to treat GAD. Although both show efficacy in acute treatment trials, few long-term studies have been perform Benzodiazepines are not recommended for long-term treatment of GAD, due to associated development of tolerance, psychomotor impairment, cognitive and memory changes, physical dependence, and a withdrawal reaction on discontinuation. The antidepressant venlafaxine extended-release (XR) has received approval for the treatment of GAD in the United States and many other countries. Venlafaxine XR has demonstrated efficacy over placebo in two randomized treatment trials of 6 months' duration as well as in other acute trials. Paroxetine is the first of the selective serotonin reuptake inhibitors (SSRIs) to receive US approval for the treatment of GAD. Paroxetine demonstrated superiority to placebo in short-term trials, and investigations into the use of other SSRIs are ongoing. This suggests that other SSRIs, and serotonin and noradrenaline reuptake inhibitors, are likely to be effective in the treatment of GAD. Of the psychological therapies, cognitive-behavioral therapy (CBT) shows the greatest benefit in treating GAD patients. Treatment gains after a 12-week course of CBT may be maintained for up to 1 year. Currently, no guidelines exist for the long-term treatment of GAD.
What is the best approach for treating patients with social phobia (social anxiety disorder) over the long term? Social phobia is the most common anxiety disorder, with reported prevalence rates of up to 18.7%. Social phobia is characterized by a marked and persistent fear of being observed or evaluated by others in social performance or interaction situations and is associated with physical, cognitive, and behavioral (ie, avoidance) symptoms. The onset of social phobia typically occurs in childhood or adolescence and the clinical course, if left untreated, is usually chronic, unremitting, and associated with significant functional impairment. Social phobia exhibits a high degree of comorbidity with other psychiatric disorders, including mood disorders, anxiety disorders, and substance abuse/dependence. Few people with social phobia seek professional help despite the existence of beneficial treatment approaches. The efficacy, tolerability, and safety of the selective serotonin reuptake inhibitors (SSRIs), evidenced in randomized clinical trials, support these agents as first-line treatment. The benzodiazepine clonazepam and certain monoamine oxidase inhibitors (representing both reversible and nonreversible inhibitors) may also be of benefit. Treatment of social phobia may need to be continued for several months to consolidate response and achieve full remission. The SSRIs have shown benefit in longterm treatment trials, while long-term treatment data from clinical studies of clonazepam are limited but support the drug's efficacy. There is also evidence for the effectiveness of exposure-based strategies of cognitive-behavioral therapy, and controlled studies suggest that the effects of treatment are generally maintained at long-term follow-up. In light of the chronicity and disability associated with social phobia, as well as the high relapse rate after short-term therapy, it is recommended that effective treatment be continued for at least 12 months.
Posttraumatic stress disorder (PTSD) is a common and disabling condition. In addition to combat-related PTSD, the disorder occurs in civilians exposed to severe traumatic events, with the community prevalence rate for the combined populations reaching as high as 12%. If left untreated, PTSD may continue for years after the stressor event, resulting in severe functional and emotional impairment and a dramatic reduction in quality of life, with negative economic consequences for both the sufferer and society as a whole. Although PTSD is often overlooked, diagnosis is relatively straight-forward once a triggering stressor event and the triad of persistent symptoms—reexperiencing the traumatic event, avoiding stimuli associated with the trauma, and hyperarousal—have been identified. However, comorbid conditions of anxiety and depression frequently hamper accurate diagnosis. Treatment for PTSD includes psychotherapy and pharmacotherapy. The latter includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Only SSRls have been proven effective and safe in long-term randomized controlled trials. Current guidelines from the Expert Consensus Panel for PTSD recommend treatment of chronic PTSD for a minimum of 12–24 months.
Response and remission rates are commonly used to evaluate the efficacy of treatments for anxiety disorders and other psychiatric illnesses. Response is generally regarded as a clinically meaningful improvement in symptoms, while remission, the goal of treatment, is generally thought of as the absence or near absence of symptoms following illness, accompanied by a return to premorbid levels of functioning. Response and remission are often defined using psychiatric rating scales, based on score cutoffs or the magnitude of score changes from baseline. While no universally accepted criteria exist, a commonly used threshold for response is a >50% improvement in the total score, while for remission, various cutoff points have been used. Comparison of cutoffs or change scores for disease-specific scales with Clinical Global Impressions ratings is a useful way of evaluating response and remission criteria across disorders. To illustrate the use of disease-specific and global measures, this article summarizes data from randomized, placebo-controlled studies of adult patients with generalized anxiety disorder, social anxiety disorder, or panic disorder treated with the serotonin norepinephrine reuptake inhibitor venlafaxine extended release, for which acute-phase data are available (a total of 13 trials).
A substantial number of patients with panic disorder and agoraphobia may remain symptomatic after standard treatment (including selective serotonin reuptake inhibitors, tricyclic antidepressants, benzodiazepines, or irreversible monamine oxidase inhibitors). In this review, recommendations for the treatment of patients with panic disorder and agoraphobia who do not respond to these drugs are provided. Nonresponse to drug treatment could be defined as a failure to achieve a 50% reduction on a standard rating scale after a minimum of 6 weeks of treatment in adequate dose. When initial treatments have failed, the medication should be changed to other standard treatments. In further attempts at treatment, drugs should be used that have shown promising results in preliminary studies, such as venlafaxine. Combination treatments may be used, such as the combination of an selective serotonin reuptake inhibitor and a benzodiazepine. Psychological treatments such as cognitive-behavioral therapy have to be considered in all patients, regardless whether they are nonresponders or not. According to existing studies, a combination of pharmacologic treatment with cognitive-behavioral therapy can be recommended.
Background: Many randomized controlled trials of the pharmacotherapy and psychotherapy of obsessive-compulsive disorder (OCD) have been undertaken. Several meta-analyses of these trials, and a number of expert consensus guidelines, have been published. This article summarizes these works, and suggests future research directions.
Methods: Meta-analyses of OCD were assessed with the QUORUM statement and the Oxman and Guyatt rating scale, and consensus guidelines on the treatment of OCD were assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument. Current principles in the treatment of OCD, and gaps in our knowledge, were reviewed.
Results: Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy are currently viewed as the first-line treatments of choice for adult and pediatric OCD.There is also good evidence for the efficacy of atypical antipsychotics in the augmentation of patients refractory to SSRIs. Important questions remain for the field.
Conclusions: There have been significant advances in both the pharmacotherapy and psychotherapy of OCD. Nevertheless, there is a paucity of longer-term trials, data on symptom remission and functional improvement, and data on treatment effectiveness in wider clinical practice. It is hoped that improved understanding of the mechanisms underlying OCD will lead to future advances.
What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants, have also shown antipardc efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. A n integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12–24 months, and in some cases, indefinitely.
Over the last 25 years, the perception of obsessive-compulsive disorder (OCD) has changed; where once it was seen as a rare refractory disorder, it is now viewed as a fairly prevalent, but treatable, medical condition responding to two main therapeutic strategies–serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy (CBT). Given the emergence of new results with SRIs, more data on the role of augmentation strategies with second-generation antipsychotics, and recent genetic and neuroimaging findings with potential for advancing the understanding of the pathogenesis of OCD, it was thought appropriate to revisit OCD in order to identify key developments in this field and examine how they might be translated into the clinical arena. This consensus statement is the product of the International Anxiety Disorders Conference that took place in Cape Town in February 2006, and is referred to as the Cape Town Consensus (CTC).
In the Diagnostic and Statistical Manual of Mental Disorders (DSM) system, OCD has been classified as an anxiety disorder. However, in the International Classification of Diseases (ICD) system, OCD is separated from these conditions. This is consistent with several findings. OCD can begin before puberty, whereas other anxiety disorders, particularly generalized anxiety disorder (GAD), have a later age of onset. OCD is similarly prevalent in men and women, as opposed to depressive and anxiety disorders, which are more common in women. Pharmacologic challenges in some (but not all) studies show exacerbation of symptoms to 5-HT receptor agonists (eg, mCPP, sumatriptan), but not to other anxiogenic challenges such as yohimbine, sodium lactate, caffeine, CO2, cholecystokinin, and pentagastrin, which are known to elicit anxiety symptoms in anxiety disorders.
– Los estudios anteriores sobre la influencia del embarazo y el periodo postparto en el curso del trastorno de angustia (panic disorder) no han sido coherentes. El presente estudio pretende cuantificar las manifestaciones de angustia en estos periodos en una muestra grande de mujeres.
– Se evaluó retrospectivamente las manifestaciones de angustia, incluidas las exacerbaciones y las nuevas manifestaciones del trastorno de angustia, en una muestra de 128 mujeres con trastorno de angustia con o sin agorafobia, 93 de las cuales habían tenido 195 embarazos.
– Las manifestaciones de angustia fueron menores en número durante el embarazo y más frecuentes en el periodo postparto cuando se comparaba con el periodo de control. Las mujeres que nunca habían estado embarazadas tenían significativamente más manifestaciones de angustia que las mujeres con embarazos anteriores. La lactancia materna y los abortos espontáneos no tuvieron un efecto significativo. Las mujeres con angustia postparto comunicaron más acontecimientos de estrés psicosocial durante este periodo.
– Se analizan las posibles razones para la angustia postparto y los efectos protectores del embarazo, incluidos los factores psicosociales u hormonales y otros cambios neurobiológicos. La angustia postparto coincide con una caída repentina de las hormonas después del parto.
There has been increasing interest in intermittent medication as a viable alternative to continuous neuroleptic treatment for chronic schizophrenic patients. Considerations supporting the plausibility of a targeted-medication approach include the fact that long-term medication involves certain risks, and that neither favourable outcome in the long-term nor risk of relapse are necessarily dependent on the continuous administration of neuroleptic drugs. An intermittent-targeted administration strategy was developed by Herz et al (1989) in an attempt to abort relapses at an early stage and to stabilise or to improve the course taken by illness.
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