Pharmacological treatment of generalized anxiety disorder

INTRODUCTION: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging. AREAS COVERED: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: 'generalized anxiety disorder AND treatment' and 'generalized anxiety disorder AND therapy'. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD). EXPERT OPINION: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.     

Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability

Abstract

Objective:

Short-term clinical trials have demonstrated the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder (GAD). This study examined long-term safety and tolerability of pregabalin in patients with GAD, social anxiety disorder (SAD), or panic disorder (PD).     

Pharmacological treatment for generalized anxiety disorder in adults: an update

Introduction: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature.

Areas covered: A literature search was conducted in the MedLine database with search terms ‘generalized anxiety disorder’ and ‘treatment’ for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD.

Expert opinion: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician.     

Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review

Introduction: Generalized anxiety disorder (GAD) is a common form of anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines (BZs) are the most commonly prescribed medications for GAD, but little is known about the relative efficacy of these pharmacological treatments.

Areas covered: This study provides a meta-analytic review of the efficacy of these medications in the treatment of adults with GAD. A comprehensive literature search yielded 54 articles reporting 56 unique studies with 12,655 participants treated with either pill placebo (6,191 participants), SSRIs (16 trials, 2,712 participants), SNRIs (17 trials, 2,603 participants), or BZs (23 trials, 1,149 participants). The overall combined effect size was modest to moderate (Hedges’ g = 0.37, p < 0.0001). Effect sizes decreased significantly over time. SSRIs (Hedges’ g = 0.33) and SNRIs (Hedges’ g = 0.36) demonstrated significantly lower effect sizes than BZs (Hedges’ g = 0.50). These findings were not due to differences in treatment length or publication year.

Expert opinion: The results of this study suggest that the most common forms of pharmacotherapy for adult GAD are moderately effective, with BZs being the most effective drug.     

Pharmacotherapy of generalized anxiety disorder: results of duloxetine treatment from a pooled analysis of three clinical trials

ABSTRACT

Objective: Duloxetine is a serotonergic noradrenergic reuptake inhibitor with demonstrated efficacy in each of three independent studies for treatment of adults with generalized anxiety disorder (GAD). A pooled dataset from all completed trials is provided here to show the most likely clinical outcomes associated with duloxetine treatment for GAD.

Research design and methods: Data were summed at the individual patient level from three double-blind, placebo-controlled trials of duloxetine treatment: two were 10-week flexible-dose 60–120?mg/day and one was 9-week fixed dose 60 or 120?mg/day. Inclusion/exclusion criteria were consistent across studies.

Main outcome measures: Efficacy measures included the Hamilton Anxiety Scale (HAMA) and Sheehan Disability Scale (SDS). Adverse events were queried at every visit in each study.

Results: Patients were randomly assigned to duloxetine (n = 668) or placebo (n = 495) treatment. Mean age was 42.4 years; 65% were female. Duloxetine-treated patients improved significantly more from baseline to endpoint on HAMA total score (mean = –11.1 points) compared with placebo-treated patients (mean = –8.0 points, p ≤ 0.001). On the SDS global functioning score, patients in the duloxetine group had a mean improvement from baseline of 46% compared with 25% in the placebo group (?p ≤ 0.001). Nausea was the most common of twelve treatment-emergent adverse events that occurred in the duloxetine group.

Limitations: Pooled studies were not for long-term treatment and did not include patients with comorbid psychiatric conditions.

Conclusions: In this sample of more than 1100 patients, duloxetine was efficacious for reducing anxiety severity and for increasing patients’ overall role functioning in GAD.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.     

Agomelatine in treating generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 – 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet-based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT_2C antagonist indicated in the treatment of major depressive episodes.

Areas covered: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study.

Expert opinion: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation.     

The failure of anxiolytic therapies in early clinical trials: what needs to be done

Introduction: Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials.

Areas covered: Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation.

Expert opinion: In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases.     

Use of duloxetine in patients with an anxiety disorder,or with comorbid anxiety and major depressive disorder: a review of the literature

Importance of the field: Except for generalized anxiety disorder, few reports have been published on the efficacy, safety and tolerability of duloxetine in patients with anxiety disorders individually or in comorbidity with major depressive disorder (MDD).

Areas covered in this review: The literature search in Medline (dating back to 1966) and Embase (dating back to 1988) databases was conducted using the OVID interface on 9 April 2009, restricted to any article or abstract in English, per title, reporting any information on the use of duloxetine in patients with any anxiety disorder with or without concomitant MDD. A systematic review approach was taken.

What the reader will gain: The reader will gain knowledge of the current data available on the use of duloxetine to treat patients with anxiety disorders individually or in comorbidity with MDD.

Take home message: Duloxetine could be considered an effective treatment option in the treatment of anxiety disorders individually or in comorbidity with each other, or with MDD; however, apart from the well-demonstrated efficacy, tolerability and safety of duloxetine in the treatment of MDD with or without anxiety and GAD, data on this subject are preliminary and very limited, and more research is warranted.     

Current pharmacological treatments for tinnitus

Introduction: Tinnitus, the phantom perception of sound, is a highly prevalent disorder and treatment is elusive.

Areas covered: This review focuses on clinical research regarding pharmacological treatments for tinnitus. The authors searched PubMed databases for English language articles related to pharmacological treatment of tinnitus, published through August 2012. The keywords "tinnitus AND pharmacological treatment” and “tinnitus AND drugs” were used. The search focused on clinical trials, but was complemented by other articles and information from clinical trial registries.

Expert opinion: Despite the significant unmet clinical need for a safe and effective drug for tinnitus relief, there is currently no EMA- or FDA-approved drug on the market. Even a drug that produces a small but significant effect would have a huge therapeutic impact. At present, evidence-based pharmacological approaches are limited to the treatment of comorbidities such as depression, anxiety, or insomnia. In the last few years there have been significant advances in the understanding of the pathophysiology of the different forms of tinnitus, the establishment of valid animal models, and the development of clinical trial methodology. A glimpse of hope is appearing in the horizon as an increasing number of pharmaceutical industries now have compounds targeting tinnitus in their pipeline.     

An updated review of antidepressants with marked serotonergic effects in obsessive–compulsive disorder

Introduction: Since the recognition of the effectiveness of clomipramine in treating obsessive–compulsive disorder (OCD), a number of recent empirical studies have confirmed a key role of the serotonergic (5-HT) system in the pathophysiology of OCD. The current study presents a review of the existing double-blind studies testing 5-HT antidepressants in OCD.

Areas covered: A systematic review was performed to identify double-blind, placebo-controlled, randomized clinical trials investigating the efficacy of antidepressants with marked 5-HT effects [clomipramine, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine and vilazodone] in the short-term treatment of OCD. The search provided 29 studies investigating eight different 5-HT antidepressants. While the findings show reliable efficacy of clomipramine and SSRIs in the treatment of OCD symptoms, no double-blind studies were identified investigating the efficacy of desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine or vilazodone.

Expert opinion: While our results support the effectiveness of older antidepressants with marked 5-HT effects in OCD, it also suggests that newer agents should be tested more comprehensively.     

Vortioxetine: a New Treatment for Major Depressive Disorder

Introduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug’s effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).

Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance.

Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.     

Treatment of idiopathic generalized epilepsy – a review of the evidence

Introduction: Epilepsy is stratified into idiopathic partial, symptomatic partial, idiopathic generalized (IGE) and symptomatic generalized epilepsies.

Areas covered: The epidemiology and clinical characteristics of IGE are reviewed in this paper. Clinically, IGE is characterized by the occurrence of any of the following three seizure types: absence seizures, myoclonic seizures and primarily generalized tonic-clonic seizures. To assess the presence of evidence-based data on the treatment of IGE, the literature was extensively reviewed for studies evaluating the treatment of IGE with various antiepileptic drugs. These studies were stratified into four classes based on recently described criteria. Class I studies were considered as providing evidence of the efficacy of the drug in patients with IGE. Finally, suggestions to evaluate the efficacy of a study drug in patients with IGE are presented.

Expert opinion: Based on the reviewed data, there is strong evidence-based data to support the use of valproate and ethosuximide for the treatment of childhood absence seizures; for the use of topiramate as monotherapy or adjunctive therapy for patients with primarily generalized tonic-clonic seizures; for the use of adjunctive therapy with lamotrigine for the treatment of primarily generalized tonic-clonic seizures; and for the use of levetiracetam as adjunctive therapy for the treatment of myoclonic or primarily generalized tonic-clonic seizures. To evaluate a new drug as a potential treatment for patients with IGE requires a rational methodology, discussed in this review.     

Comprehensive review of generalized anxiety disorder in primary care in Europe

Abstract

Objective:

This review aims to summarize meta-analyses and other relevant data relating to the efficacy and safety of the various treatment options for generalized anxiety disorder (GAD) in Europe. In addition, it will provide an overview of the prevalence, burden, and recognition of the disorder, with a view to raise awareness of GAD and inform primary care practitioners.     

Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review

Introduction: Generalized anxiety disorder (GAD) often begins during adolescence or early adulthood and persists throughout the lifespan. Randomized controlled trials support the efficacy of selective serotonin and selective serotonin norepinephrine reuptake inhibitors (SSRIs and SNRIs, respectively), as well as benzodiazepines, azapirones, anti-adrenergic medications, melatonin analogs, second-generation antipsychotics, kava, and lavender oil in GAD. However, psychopharmacologic treatment selection requires clinicians to consider multiple factors, including age, co-morbidity, and prior treatment.

Areas covered: The authors review the literature concerning pharmacotherapy for pediatric and adult patients with GAD with specific commentary on the efficacy and tolerability of selected agents in these age groups. The authors describe an algorithmic approach to the pediatric and adult patient with GAD and highlight considerations for the use of selected medications in these patients.

Expert opinion: In adults with GAD, SSRIs and SNRIs represent the first-line psychopharmacologic treatment while second-line pharmacotherapies include buspirone, benzodiazepines, SGAs, and pregabalin. In pediatric patients with GAD, SSRIs should be considered the first line pharmacotherapy and psychotherapy enhances antidepressant response.     

Pharmacotherapy of trichotillomania (hair pulling disorder): an updated systematic review

Introduction: Individuals affected by trichotillomania (TTM) (hair-pulling disorder) consciously or non-consciously pull out their own body hair. The disorder has recently been incorporated into a chapter entitled, ‘Obsessive-Compulsive and Related Disorders’ in the diagnostic and statistical manual of mental disorders, fifth edition.

Areas covered: The review describes the literature currently available on the pharmacotherapy for TTM, including both randomized controlled trials and open-label trials of pharmacotherapy for TTM in adults or children.

Expert opinion: Early work focused on the serotonin reuptake inhibitors; however, the majority of the trials have been negative. There is a small body of evidence focused on pharmacotherapy for TTM. In future, larger trials are required to expand on the preliminary evidence available for N-acetylcysteine, olanzapine and dronabinol in recent trials.     

坦度螺酮与丁螺环酮治疗广泛性焦虑症的系统评价

目的 系统评价坦度螺酮与丁螺环酮治疗广泛性焦虑症的疗效与安全性。方法 计算机检索PubMed、中国期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）、万方数据库、中文科技期刊全文数据库（VIP）,收集坦度螺酮与丁螺环酮治疗广泛性焦虑症的随机对照研究（RCT）,检索时限为2000年1月至2016年6月,并追溯纳入研究的参考文献。2位研究者按照纳入与排除标准独立筛选文献、提取资料和评价文献质量后,用RevMan5.0软件对各效应指标进行Meta分析。结果 共纳入7篇RCT,合计615例广泛性焦虑症患者。Meta分析结果显示：坦度螺酮（试验组）与丁螺环酮（对照组）在显效率[P=0.34,OR=1.19,95% Cl（0.83～1.69）]与HAMA评分方面[P=0.80,MD=-0.08,95% Cl（-0.72～0.56）]差异无统计学意义（P>0.05）;2组头晕、口干、便秘、失眠、食欲减退、恶心发生率差异无统计学意义（P>0.05）。结论 坦度螺酮与丁螺环酮治疗广泛性焦虑症疗效相当,常见不良反应发生风险相似。     

Pharmacologic treatment of obsessive-compulsive disorder comorbidity

Introduction: Obsessive-compulsive disorder (OCD) is clearly a heterogeneous syndrome in which comorbidity is the rule rather than the exception and is often ‘phase-specific’. Comorbid conditions have a negative impact on OCD outcome and may clearly impact the disease trajectory. Nevertheless, in the current literature there is an impressive neglect of comorbidities in clinical trials and treatment approaches for these conditions are still not evidence-based.

Areas covered: In this paper we summarized the available data on the treatment of the main OCD comorbidities (mood and anxiety disorders, ‘bipolar neurosis’, tics and OCD-related disorders, addictions and impulsive disorders, eating disorders, attention deficit hyperactivity disorder, psychoses, and post-infective syndromes).

Expert opinion: To achieve the goals of ‘precision medicine’ there is a critical need for deconstructing current diagnostic groups with biomarkers to predict and improve response to treatment. Despite the continuous efforts of several researchers in subtyping homogeneous samples of OCD patients (for example the comorbidity-based subclassification), current available treatments are still syndrome-based rather than network dysfunctions-based. Identifying the homogenous subgroup, subtyping patients according to comorbidity patterns, symptom dimensions, clinical course, neurocognitive and neurophysiological dysfunctions, could represent an essential first step in the direction of a ‘precision medicine’ approach.     

The Relation Between Moment-to-Moment Mindful Attention and Anxiety Among Young Adults in Substance Use Treatment

Background: A growing body of research has examined the intersection of mindfulness and substance use, and a large body of research has examined the relation between mindfulness and anxiety. Unfortunately, no research has been conducted on the relation between mindfulness and anxiety symptoms among young adults (i.e., 18–25 years old) in treatment for substance use. The purpose of the current study was to examine the relation between one facet of mindfulness, moment-to-moment attention, and anxiety (panic and generalized anxiety) among young adults in treatment for substance use. Methods: Preexisting patient records from a residential substance use treatment center for young adults were reviewed (N = 148). Patient records were examined from May 2012 to August 2013, which represented all young adult patients admitted to the residential treatment facility during this time. Results: Findings demonstrated that moment-to-moment mindful attention was associated with symptoms of panic disorder and generalized anxiety disorder even after controlling for gender, age, education, alcohol use, drug use, and the shared variance in generalized and panic symptoms. There were no gender differences in moment-to-moment mindful attention. Conclusions: These findings provide preliminary evidence that moment-to-moment mindful attention is associated with panic and generalized anxiety in young adults in substance use treatment. Combined with previous research on mindfulness-based interventions among adults in substance use treatment, research should examine the efficacy of mindfulness-based interventions for young adults in substance use treatment.     

Pharmacotherapy to control behavioral symptoms in children with autism

Introduction: Autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) are pervasive developmental disorders (PDDs) frequently associated with behavioral symptoms that may require pharmacotherapy to manage.

Areas covered: Behavioral symptoms in children with autism include interfering repetitive behaviors, irritability, and hyperactivity and inattention, among others. The psychotropic medications examined in this review include: serotonin reuptake inhibitors, typical and atypical antipsychotics, medications used to treat attention-deficit/hyperactivity disorder, naltrexone, buspirone, divalproex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole, pioglitazone, and topiramate.

Expert opinion: For the treatment of interfering repetitive behaviors, serotonin reuptake inhibitors demonstrate less efficacy and are more poorly tolerated in children with autism compared to adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in children with autism and other PDDs. For the treatment of hyperactivity and inattention, psychostimulants demonstrate some benefit. However, they are overall less efficacious and cause more side effects in children with PDDs compared to typically developing children with attention-deficit/hyperactivity disorder. Results from double-blind, placebo-controlled trials of these agents and others for the treatment of the behavioral symptom domains described above will be discussed in this review.