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.     

The selective serotonin reuptake inhibitor paroxetine is effective in more generalized and in less generalized social anxiety disorder

RATIONALE: The DSM-IV includes the specifier "generalized" to refer to social anxiety disorder (social phobia) patients if the fears include "most social situations". The focus on interventions such as the selective serotonin reuptake inhibitors (SSRIs) for generalized social anxiety disorder arguably runs the risk that inadequate treatment will be provided to patients with the non-generalized or discrete subtypes. There are, however, few data to address whether more generalized and less generalized subgroups of social anxiety disorder differ in response to medication. OBJECTIVE: To compare response of more generalized and less generalized social anxiety disorder to pharmacotherapy. METHODS: Data from three randomized placebo-controlled double-blind multicenter trials of the SSRI paroxetine in social anxiety disorder were pooled. Response on the Clinical Global Impression Global Improvement item was analyzed using logistic regression, and change in total Liebowitz Social Anxiety Score was analyzed using analysis of variance, with both models incorporating treatment (paroxetine vs placebo), subgroup (more generalized vs less generalized), demographic, and clinical variables. RESULTS: The prevalence of more generalized social anxiety disorder was higher in females than in males. However, there was no significant difference in terms of age or clinical characteristics (duration of condition, baseline pulse, mean arterial blood pressure). At treatment endpoint there were significant treatment effects (for paroxetine vs placebo), but no significant subgroup effects (for more generalized vs less generalized). CONCLUSIONS: Although the current database is limited insofar as few patients with discrete social anxiety disorder would have been included, it is helpful in addressing the value of medication for patients lying on the spectrum from generalized to non-generalized and discrete social anxiety disorder. Paroxetine was effective in both more generalized and in less generalized social anxiety disorder.     

Recognizing the patient with social anxiety disorder

Social anxiety disorder is a prevalent and highly disabling condition, affecting 7-13% of the population at some point in their lives. Most sufferers are not diagnosed however, even after visiting a healthcare professional. Social anxiety disorder need not be a difficult condition to diagnose. Characteristic features of the disorder include blushing as the principal symptom and an early age of onset. Social anxiety disorder is also easily distinguished from other anxiety disorders by the situations in which patients experience fear and avoidance; for the patient with social anxiety disorder, these situations always involve social interaction or scrutiny by other people. The consequences of untreated social anxiety disorder include social isolation, impaired educational attainment and career progression, depression, and alcohol abuse. Rating scales such as the Liebowitz Social Anxiety Scale (LSAS) give a consistent measure of severity of social anxiety disorder and so help physicians assess their patients' need for treatment and their improvement. Social anxiety disorder is an eminently treatable condition, as demonstrated by treatment-induced reduction in LSAS scores in clinical trials and by individual case histories. Appropriate therapy can give patients relief from their distressing and disabling symptoms and allows them to make substantial improvements to their quality of life.     

Citalopram 20 mg, 40 mg and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder

Serotonin reuptake inhibitors appear to be uniquely effective treatments for obsessive-compulsive disorder (OCD). This double-blind, placebo-controlled study was the first trial to assess the efficacy of the most selective of the serotonin reuptake inhibitors, citalopram, in OCD. A total of 401 patients were randomized to receive citalopram 20, 40 or 60 mg/day or placebo for 12 weeks. All three doses of citalopram were significantly more effective than placebo measured on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) change score (P < 0.01). The highest response rate, defined as 25% improvement in Y-BOCS entry score, was observed in the 60 mg group (65%). This compared with 52% and 57.4% in the 40 mg and 20 mg groups. Response rate on placebo was 36.6% (P < 0.05 for all three doses of citalopram compared to placebo). There was no significant difference between the individual doses of citalopram. An advantage was seen for citalopram on the Sheehan Disability Scale compared with placebo (P < 0.05 on all three citalopram groups versus placebo for both the work situation and the family life and home responsibilities and P < 0.05 on citalopram 60 mg and 20 mg versus placebo for the social life and home activities). Citalopram was well tolerated; only 4 to 6 patients in each dose group discontinued the study prematurely due to adverse events.     

自信心心理训练对社交焦虑症患者社交焦虑症状以及信任影响的干预研究

目的探讨自信心心理训练对社交焦虑症患者社交焦虑症状以及信任的影响。方法将80例16～30岁社交焦虑症患者随机分为自信心训练治疗组(研究组)和对照组,研究组每周进行2次自信心训练,每次3 h,持续5周,共10次;对照组不采取任何治疗手段。干预前与干预结束3个月后分别对2组进行社交焦虑量表(SASS)和信任量表(TS)评定,了解训练对患者社交焦虑症状以及信任的影响。结果社交焦虑与信任呈明显负相关;2组心理干预前、后SASS比较差异有统计学意义(t=-4.30,P<0.01);TS差异有统计学意义(t=5.90,P<0.01)。结论自信心心理训练可以显著改善社交焦虑症患者的社交焦虑症状,并可有效提高患者的信任程度。     

Clinical experience with paroxetine in social anxiety disorder

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with proven efficacy in the treatment of depression, panic disorder and obsessive-compulsive disorder. Evidence that paroxetine may be effective in social anxiety disorder (social phobia) first arose from open-label studies. More recently, three multicentre, randomized, placebo-controlled trials have been performed, each lasting 12 weeks, to assess the efficacy and tolerability of paroxetine in the treatment of social anxiety disorder, and these studies are reviewed here. The data from all three studies consistently demonstrated that paroxetine was effective in reducing both the symptoms of anxiety and the disability and impairment of social anxiety disorder. Paroxetine performed significantly better than placebo on all primary (Liebowitz Social Anxiety Scale, Clinical Global Impression) and secondary (Social Avoidance and Distress Scale, Sheehan Disability Scale) outcome measures. Adverse events were restricted to those already known to be associated with SSRIs, no serious adverse events associated with medication were experienced, and the numbers withdrawing from the studies were not significantly different in the paroxetine and control groups. Taken together, these studies confirm that paroxetine is an effective and well tolerated treatment for patients with social anxiety disorder.     

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment

AIMS

To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX.

METHODS

This was a fixed-dose drug–drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15–25 mg per week).

RESULTS

All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC₁₂ ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC₁₂ ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments.

CONCLUSIONS

Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX.     

Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care

Escitalopram, a selective serotonin reuptake inhibitor (SSRI), was compared to placebo in a study of patients with major depressive disorder (DSM-IV) who had baseline Montgomery-Asberg Depression Rating Scale (MADRS) total scores >or=22 and 相似文献   

A meta-analysis of pharmacotherapy for social anxiety disorder: an examination of efficacy,moderators, and mediators

Introduction: Social anxiety disorder (SAD) is among the most prevalent mental disorders, associated with impaired functioning and poor quality of life. Pharmacotherapy is the most widely utilized treatment option. The current study provides an updated meta-analytic review of the efficacy of pharmacotherapy and examines moderators and mediators of treatment efficacy.

Areas Covered: A comprehensive search of the current literature yielded 52 randomized, pill placebo-controlled trials of pharmacotherapy for adults diagnosed with SAD. Data on potential mediators of treatment outcome were collected, as well as data necessary to calculate pooled correlation matrices to compute indirect effects.

Expert Opinion: The overall effect size of pharmacotherapy for SAD is small to medium (Hedges’ g = 0.41). Effect sizes were not moderated by age, sex, length of treatment, initial severity, risk of study bias, or publication year. Furthermore, reductions in symptoms mediated pharmacotherapy’s effect on quality of life. Support was found for reverse mediation. Future directions may include sustained efforts to examine treatment mechanisms of pharmacotherapy using rigorous longitudinal methodology to better establish temporal precedence.     

Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity

The neurobiology of social anxiety disorder (SAD) is not yet fully understood. Structural and functional neuroimaging studies in SAD have identified abnormalities in various brain areas, particularly the amygdala and elements of the salience network. This study is the first to examine resting-state functional brain connectivity in a drug-naive sample of SAD patients without psychiatric comorbidity and healthy controls, using seed regions of interest in bilateral amygdala, in bilateral dorsal anterior cingulate cortex for the salience network, and in bilateral posterior cingulate cortex for the default mode network. Twelve drug-naive SAD patients and pair-wise matched healthy controls, all drawn from the Netherlands Study of Depression and Anxiety sample, underwent resting-state fMRI. Group differences were assessed with voxel-wise gray matter density as nuisance regressor. All results were cluster corrected for multiple comparisons (Z>2.3, p<.05). Relative to control subjects, drug-naive SAD patients demonstrated increased negative right amygdala connectivity with the left middle temporal gyrus, left supramarginal gyrus and left lateral occipital cortex. In the salience network patients showed increased positive bilateral dorsal anterior cingulate connectivity with the left precuneus and left lateral occipital cortex. Default mode network connectivity was not different between groups. These data demonstrate that drug-naive SAD patients without comorbidity show differences in functional connectivity of the amygdala, and of areas involved in self-awareness, some of which have not been implicated in SAD before.     

Attention to social threat as a vulnerability to the development of comorbid social anxiety disorder and alcohol use disorders: An Avoidance-Coping Cognitive Model

Despite the frequent comorbidity of social anxiety disorder and alcohol use disorders, no theoretical model currently exists to explain the specific mechanisms underlying the comorbidity between these two disorders. An integration of existing theoretical models and empirical evidence across the social anxiety and alcohol use literatures is presented as the Avoidance-Coping Cognitive Model, which proposes that socially anxious individuals may be particularly vulnerable to the anxiolytic effects of alcohol through reductions in attention biases to social threat. The disproportionate reduction in anxiety may then make alcohol an attractive method of avoidance coping. Gaps in the empirical literature are reviewed in light of this model as future directions are suggested.     

度洛西汀与帕罗西汀治疗社交焦虑症对照研究

目的比较度洛西汀与帕罗西汀治疗社交焦虑障碍的疗效及不良反应。方法对86例社交焦虑障碍门诊及住院患者,随机分为两组,度洛西汀组和帕罗西汀组各43例,治疗8周,采用汉密尔顿焦虑量表(HAMA)和临床疗效总评量表,病情严重程度量表(CGI-SI)评定临床疗效,用治疗中出现的症状量表(TESS)评定药物不良反应。结果经过8周治疗,度洛西汀组和帕罗西汀组有效率分别为86.05和83.72两组疗效差异无统计学意义(P>0.05),两组不良反应发生率差异无统计学意义(P>0.05)。结论度洛西汀和帕罗西汀对社交焦虑障碍的疗效相当,不良反应较小,值得临床推广。     

Social anxiety disorder and the neurobiology of social relationships

Social anxiety disorder (SAD) is a prevalent anxiety disorder with the potential for considerable impairment. A patient with SAD is presented and treatment options are discussed. Novel concepts guiding our understanding of the neurobiology of SAD are presented, including the concept of sensory maps of the body, which is used to speculate on the nature of internal representations of relationships and their potential role in triggering anxiety in SAD. Understanding the neural circuitry mediating social relationships and its role in the threat response in SAD may be important for the development of new treatments for this disorder.     

右佐匹克隆合并艾司西肽普兰治疗广泛性焦虑伴失眠的对照研究简

目的：比较广泛性焦虑伴失眠患者在抗焦虑治疗（艾司西酞普兰）初期合用或不用右佐匹克隆对患者失眠、焦虑症状的疗效与安全性。方法：将100例符合“中国精神障碍分类与诊断标准（第三版）”（CCMD-3）广泛性焦虑伴有失眠的患者随机分为试验组（52例）和对照组（48例）。试验组给予艾司西酞普兰合并右佐匹克隆治疗,对照组单用艾司西酞普兰治疗,观察期为8周。用汉密尔顿焦虑量表（HAMA）评定患者焦虑症状及疗效,用睡眠障碍量表（SDRS）评定失眠症状和疗效,同时用不良反应量表（TESS）和实验室检查评估治疗安全性。结果：试验组在治疗第1周末HAMA评分明显下降（P〈0．01）,对照组在第2周末HAMA评分明显下降（P〈0．01）,试验组在治疗后第1、2、4、6周末HAMA总分均低于对照组（P〈0．05）,第8周末差异无统计学意义（P〉0．05）。2组在治疗后第1、2、4周末SDRS总分均低于治疗前（P〈0．01）。试验组在第1、2、4周末SDRS总分均低于对照组（P〈0．01）。试验组较对照组更易发生头痛、口苦、口干、恶心及困倦感（P〈0．05）。结论：艾司西酞普兰合并右佐匹克隆治疗广泛性焦虑伴失眠,有助于快速改善患者的失眠和焦虑症状,但副反应相对明显。     

Pregabalin for the treatment of social anxiety disorder

Introduction: Social anxiety disorder (SAD) is one of the most common psychiatric disorders, causing a reduction of in the quality of life by impairing functioning in social situations. The lifetime prevalence of SAD is estimated to be 12%. Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are considered first-line drugs for SAD. However, new effective therapeutic options are still needed. Pregabalin is a novel anxiolytic, which seems to be a promising therapy for SAD.

Areas covered: This review presents the results of three randomized controlled trials (RCTs) comparing the efficacy and safety of pregabalin with placebo in patients with generalized SAD. The authors also discuss the long-term safety and tolerability data from an extension study.

Expert opinion: The results of the RCTs have demonstrated efficacy and safety with pregabalin at doses of 600 mg or 450 mg/d for treating generalized SAD. Thus, pregabalin may be an effective therapeutic option, especially for patients who cannot tolerate the adverse effects or who demonstrate a lack of efficacy with SSRIs or SNRIs. In addition to being an alternative therapy to SSRIs or SNRIs, it may also have value as an add-on therapy, either to augment pharmacotherapy or in addition to cognitive-behavioral therapy.     

Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI

Individuals with social phobia (SP) fear and avoid a wide variety of social and performance situations in which they are exposed to unfamiliar persons or to possible scrutiny by others. The lifetime prevalence of SP is estimated to be as high as 13%. It is frequently co-morbid with and usually precedes the onset of other psychiatric illnesses and is associated with significant occupational and social impairment, including academic and vocational underachievement. Fortunately, there are effective treatments for this common and debilitating condition. There is currently considerable evidence for the efficacy of pharmacotherapy and especially the monoamine oxidase inhibitors (MAOIs) and selective serotonin re-uptake inhibitors (SSRIs) in the treatment of this disorder. However, SSRIs are generally preferred as the first-line treatment of choice due to the advantages of SSRIs over MAOIs in terms of safety and tolerability. Despite encouraging results, current treatments most often produce partial symptomatic improvement, rather than high end-state functioning. While current first line treatments for social phobia target the serotonergic system, it is important to remember that different social fears are likely to have different developmental roots and may be based on quite different neurobiological systems. In this article we provide a review of current pharmacotherapeutic options for SP, current knowledge of the neurobiology of SP, and a review of new and promising directions in pharmacological research. It is increasingly clear that serotonin (5-HT) is unlikely to be the whole story in SP and that other brain chemical systems, especially the dopaminergic, noradrenaline-corticotropin releasing hormone and gamma-aminobutyric acid (GABA) dependent systems, most probably have an important role to play in a substantial percentage of cases. A number of new and novel agents, including the substance P antagonists, GABA agonists and CRF antagonists show considerable promise in the treatment of SP. However, in order to enhance the understanding of the neurobiology and treatment response of SP, we need to develop more sophisticated theory-driven typologies of SP.