Pharmacologic treatment of generalized anxiety disorder.

GAD is a severe, chronic, and distressing illness that often requires long-term management. Considerable progress has been made in the ability to help these patients. New antidepressants, such as venlafaxine, and the SSRIs provide an important treatment alternative to "traditional" anxiollytic treatments, which include the benzodiazepines, buspirone, and the TCAs; however, comparative efficacy and the effects of psychiatric comorbidity, long-term treatment, and relapse prevention are areas requiring further investigation.

Generalized anxiety disorder in women.

Women have a higher prevalence of GAD than do men. This ratio holds true in most clinical and general-population samples. Some variations exist, with evidence to suggest the strong impact of environment and life events. Women are sensitive to lifetime adversity and exacerbation of symptoms in conjunction with their menstrual cycle. Comorbidity is a crucial diagnostic factor when treating anyone with GAD, especially women. Most notably, high comorbidity with other anxiety disorders, MDD and alcohol-abuse disorder occurs for women. Overall, although the prevalence of women with GAD is greater than that of men with GAD, the course of illness and prognosis are not qualitatively different. Across varied methodology, data suggest gender-related differences in the metabolism and potentially in the effects and side effects of the various benzodiazepines and antidepressant psychopharmacologic treatments of GAD. Additional research is needed to better understand these differences.

Bupropion-SR in treatment of social phobia.

A 12-week, open label flexible dosing study was conducted to evaluate the efficacy of bupropion-SR in the treatment of generalized social phobia. The primary outcome measures include the Clinical Global Impression of Improvement (CGI-I) and the Brief Social Phobia Rating Scale (BSPS). A total of 18 subjects were enrolled. Five of the ten subjects who completed all 12 weeks were considered as responders. Response to treatment was defined as a CGI-I score of 1 or 2, ("much improved" or "very much improved," respectively) and a > 50% decrease in BSPS score. The final doses for the completers ranged between 200 and 400 mg/day (mean 366 +/- 68 mg/day). The medication was generally well tolerated. Findings from this open-label trial suggest that bupropion-SR may be useful in treating generalized social phobia.

Feasibility of using fMRI to study mothers responding to infant cries.

While parenting is a universal human behavior, its neuroanatomic basis is currently unknown. Animal data suggest that the cingulate may play an important function in mammalian parenting behavior. For example, in rodents cingulate lesions impair maternal behavior. Here, in an attempt to understand the brain basis of human maternal behavior, we had mothers listen to recorded infant cries and white noise control sounds while they underwent functional MRI (fMRI) of the brain. We hypothesized that mothers would show significantly greater cingulate activity during the cries compared to the control sounds. Of 7 subjects scanned, 4 had fMRI data suitable for analysis. When fMRI data were averaged for these 4 subjects, the anterior cingulate and right medial prefrontal cortex were the only brain regions showing statistically increased activity with the cries compared to white noise control sounds (cluster analysis with one-tailed z-map threshold of P < 0.001 and spatial extent threshold of P < 0.05). These results demonstrate the feasibility of using fMRI to study brain activity in mothers listening to infant cries and that the anterior cingulate may be involved in mothers listening to crying babies. We are currently replicating this study in a larger group of mothers. Future work in this area may help (1) unravel the functional neuroanatomy of the parent-infant bond and (2) examine whether markers of this bond, such as maternal brain response to infant crying, can predict maternal style (i.e., child neglect), offspring temperament, or offspring depression or anxiety.

Evaluation of the efficacy, safety and physiological effects of fluvoxamine in social phobia.

There is no US Food and Drug Administration (FDA) approved treatment for social phobia although data suggest efficacy for several drug classes, including beta-blockers, benzodiazepines, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). The SSRIs are particularly attractive due to their favourable tolerance and safety profile. An open label trial of fluvoxamine was conducted to evaluate its efficacy and safety in the treatment of social phobia (DSM-III-R) and to assess physiological changes that may accompany treatment. Fifteen non-depressed patients, aged 22-44 years (mean 31.6 years), entered the study. A 5-min performance task (public speaking simulation) preceded and concluded the active treatment period. Cardiovascular monitoring was performed during this time and blood sampled for plasma cortisol and steady-state plasma fluvoxamine concentration (at week 7). Ten patients (5 men and 5 women) completed an active 6 week treatment period of flexible dosing (50-150 mg/day). Five patients failed to complete the study due to drowsiness (n = 2), nausea (n = 1), or were lost to follow-up (n = 2). Analysis of clinical ratings indicated a statistically significant decrease in all scales from baseline to week 7 at the conclusion of the active treatment period. Clinical benefits were still evident at follow-up 1 week after drug discontinuation. Neither physiological effects nor plasma drug concentration correlated with clinical change. Fluvoxamine appeared to be effective and well tolerated in completers. Randomized clinical trials are needed to further demonstrate the efficacy of fluvoxamine in the treatment of social phobia.

Once-weekly dosing of fluoxetine in the maintenance of remission in panic disorder.

BACKGROUND: Fluoxetine and its active metabolite norfluoxetine have long half-lives of 4-6 days and 4-16 days, respectively. We postulated that, owing to the long elimination half-life, patients diagnosed with panic disorder might be maintained on fluoxetine taken once a week, after being treated initially with daily doses of fluoxetine. METHOD: Ten patients with DSM-III-R panic disorder were treated openly with fluoxetine, 20-40 mg daily. Once panic free, these patients were switched to once-weekly dosing of fluoxetine, and dosage was titrated as needed. RESULTS: All 10 patients successfully switched to once-weekly dosing. One patient reported recurrence of panic attacks 18 months after the switch. After a brief treatment for 4 weeks with benzodiazepines and daily fluoxetine, the patient was once again maintained on once-weekly dosing when rechallenged. Patients have been maintained in a panic-free state for up to 26 months with a single weekly dose of fluoxetine ranging from 10 to 60 mg. The medication was well tolerated. CONCLUSION: Fluoxetine at doses ranging from 10 to 60 mg administered once weekly appears to be effective maintenance treatment for patients with panic disorder who were initially treated successfully with daily fluoxetine. A once-weekly regimen may allow for considerable cost savings and may serve as a convenient alternative method for treating panic disorder.

Anxious depression.

Depression and anxiety often coexist. When they co-occur, both anxiety and depression appear to be more severe. Increased morbidity, poorer acute and long-term outcome, increased suicide risk, and increased treatment resistance are associated with comorbid anxiety and depression. The term anxious depression has taken on newer meaning with the changes in the diagnostic system that allow for concurrent diagnosis of anxiety disorders and major depression. Attention to the subtype of both anxiety and depression could have significant effects on treatment choice by the clinician. The authors review some historical aspects of anxious depression and also highlight some of the advances in differential diagnosis and treatment of coexisting depression and anxiety.

Fenfluramine challenge test as a marker of serotonin activity in patients with Alzheimer's dementia and agitation.

BACKGROUND: Changes in serotonin (5-HT) have been described in both Alzheimer's disease (AD) and aggressive/agitated behaviors. This paper explores a possible association between 5-HT deficits and agitation in AD, using prolactin response to d,1-fenfluramine administration as a probe for 5-HT activity. METHODS: Five AD patients with agitation and 5 without agitation received a 60-mg oral dose of d,1-fenfluramine. Prolactin levels were obtained at baseline, and 2 and 3 hours following administration. RESULTS: Change in prolactin levels from baseline to 3 hours was significantly larger among the agitated than the nonagitated Alzheimer's patients. Further, there was a positive and significant correlation between change in prolactin levels from baseline and level of agitation. CONCLUSIONS: These findings suggest an association between 5-HT responsiveness and agitation in AD.

Sleep Deprivation in social phobia and generalized anxiety disorder.

BACKGROUND: Sleep deprivation has been shown to improve depressive symptoms in some patients with major depressive disorder, but it has not been tested in patients with generalized anxiety disorder (GAD) or social phobia (SP). METHODS: To determine if sleep deprivation altered anxiety or depressive symptoms in patients with GAD (n = 7) or SP (n = 8), we sleep deprived patients and normal controls (n = 18) for one night. RESULTS: On one measure of anxiety, GAD patients improved compared with controls, but there were otherwise no significant change differences between controls and SP or GAD patients. CONCLUSIONS: The lack of benefit is consistent with previous findings that sleep deprivation provides no benefit to patients with other anxiety disorders. Sleep deprivation may be a biological intervention that distinguishes anxiety from affective disorders.

Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia.

BACKGROUND: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). METHODS: The density (Bmax) and dissociation constant (Kd) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). RESULTS: The GSP group was found to have a significantly lower PBR Bmax than the NC group (GSP = 2764 +/- 1242 vs. NC = 4327 +/- 1850 fmol/mg protein, df = 1,100, F = 22.7, p = .00001). CONCLUSIONS: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.

Effects of the cholecystokinin agonist pentagastrin in patients with generalized anxiety disorder.

OBJECTIVE: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects. METHODS: Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin. RESULTS: Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects. CONCLUSIONS: Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects.

Panic disorder across the life span: a differential diagnostic approach to treatment resistance.

There has been significant progress over the past 30 years in our understanding of the treatment of panic disorder. There are now several different classes of pharmacological treatments, as well as cognitive-behavioral treatments that have been shown to have efficacy in treating panic disorder. Despite the increase in the knowledge base, many patients are only partially responsive or unresponsive to initial treatment efforts. A differential diagnostic approach to reviewing possible causes for treatment failure is presented. These causes include coexisting psychiatric disorders, unrecognized medical factors, environmental stressors, and others. Additionally, a review of factors specifically related to elderly and to very young treatment-resistant panic disorder patients is presented, along with some suggestions for evaluation and treatment. Based on the limited literature and clinical experience, practical clinical suggestions for approaching identified factors are presented.

Biological basis of generalized anxiety disorder.

Despite the considerable revisions to diagnostic criteria, recent data indicate that generalized anxiety disorder (GAD) is one of the most common anxiety disorders. Growing evidence also indicates that GAD is a serious illness, which frequently causes moderate impairment and often requires prolonged treatment. Thus, investigation of the biological correlates of GAD may be helpful in the development of effective treatments for this disorder. Recent data suggest possible abnormalities in the regulatory mechanisms of several important biological components in GAD patients. Maladaptive responses to stressful stimuli have been observed in the locus-ceruleus-norepinephrine-sympathetic nervous system, the hypothalamic-pituitary-adrenocortical axis, and the cholecystotin system. Abnormalities in other important CNS modulators, such as 5-HT and gamma-aminobutyric acid, may also be involved in the biology of GAD. In the following article, the authors will review the existing information regarding these potential biological abnormalities in GAD.

Recent developments in the psychopharmacology of anxiety disorders.

Anxiety disorders are the most prevalent mental disorders in the United States. In the past 3 decades, substantial advances have been made in the ability to identify and treat anxiety disorders including panic disorder (PD), social phobia (SP), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). It is now known that these common, usually chronic disorders confer significant disability to untreated sufferers. This overview highlights some of the important advances in pharmacological treatment of anxiety disorders. Evidence for efficacy of the various pharmacological agents (including relevant oral dosing and plasma-level data) and of acute and long-term treatment, and the disadvantages of medication treatment are discussed. Finally, some important clinical questions remaining to be addressed by psychopharmacological research are reviewed.

Generalized anxiety disorder: issues in epidemiology.

Despite the considerable attention that has been focused on the anxiety disorders by the medical and research communities over the last decade, relatively little attention has been devoted to the investigation of generalized anxiety disorder (GAD). However, the available population-based studies have provided clinically relevant information about this disorder. The emerging picture is that GAD is a common and chronic disorder, affecting primarily women, and one that leads to significant distress and impairment. Subjects with GAD frequently utilize health care services and require medication treatment. Since a major portion of health care services is consumed by a small fraction of patients, early detection and effective intervention may reduce unnecessary and costly health care.

Agitation as a possible expression of generalized anxiety disorder in demented elderly patients: toward a treatment approach.

Symptoms of generalized anxiety disorder are commonly observed in elderly persons and especially in those suffering from dementia. In the demented elderly, these symptoms are often defined as agitation. Approximately 60% of demented persons will present with symptoms of agitation at some point during the course of their illness. The presence of agitation has devastating consequences for the patient and the caregiver. This paper reviews some of the existing literature with regard to the etiology and treatment of agitation in the demented elderly. Agitated behaviors are generally divided in three categories (verbal agitation physically nonaggressive agitation, and aggressive agitation). It is suggested that each category may have a different etiology and treatment; verbal agitation is often related to underlying medical conditions, physically nonaggressive behavior responds to behavioral treatment, and aggressive agitation is more likely to respond to a combination of behavioral and pharmacologic treatment.

Body dysmorphic disorder in patients with anxiety disorders and major depression: a comorbidity study.

OBJECTIVE: The authors evaluated the frequency of body dysmorphic disorder in patients with a primary diagnosis of anxiety disorders and major depression. METHOD: Patients with social phobia (N = 54), obsessive-compulsive disorder (N = 53), generalized anxiety disorder (N = 32), panic disorder (N = 47), and major depression (N = 42) and normal comparison subjects (N = 33) were studied. RESULTS: Body dysmorphic disorder was most common in patients with social phobia (11%) and obsessive-compulsive disorder (8%); it was less prevalent among patients with panic disorder (2%), generalized anxiety disorder (0%), and major depression (0%) and among normal subjects (0%). CONCLUSIONS: These findings suggest that body dysmorphic disorder may share etiologic elements with social phobia and obsessive-compulsive disorder.

Somatic symptoms in generalized anxiety disorder with and without comorbid psychiatric disorders.

The authors compared the distribution of somatic symptoms associated with generalized anxiety disorder in 28 patients with "pure" generalized anxiety disorder and 77 patients with generalized anxiety disorder plus comorbid current or lifetime psychiatric diagnoses. They found no significant differences in individual symptom endorsement between the two groups, indicating that the basic symptoms of generalized anxiety disorder are specific to the disorder itself.

Psychiatric comorbidity in patients with generalized anxiety disorder.

OBJECTIVE: The goal of this study was to test the validity of generalized anxiety disorder as an independent diagnostic entity and to evaluate the prevalence and type of other psychiatric disorders coexisting with generalized anxiety disorder. Although a few published studies have addressed the subject, this study presents data from a larger group of subjects and excludes concurrent major depression as a potential confound. METHOD: The authors studied patients with a primary diagnosis of generalized anxiety disorder assigned after evaluation with the Structured Clinical Interview for DSM-III-R. Patients with a concurrent major depressive episode were excluded. All diagnoses for which the patient met criteria were determined, including lifetime occurrence of major depressive episode and substance use. RESULTS: One hundred nine patients with generalized anxiety disorder were included in the analysis. Twenty-eight (26%) of these patients were not given any other lifetime psychiatric diagnosis. The most prevalent comorbid diagnoses were social phobia (25 [23%] of the patients) and simple phobia (23 [21%] of the patients). Forty-six (42%) of the patients with generalized anxiety disorder had experienced at least one major depressive episode during their lifetime. CONCLUSIONS: These results support previous findings of high rates of psychiatric comorbidity in generalized anxiety disorder and validate the usefulness of generalized anxiety disorder as a separate diagnostic entity.