Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors

Treatment of depression and anxiety disorders with selective serotonin reuptake inhibitors (SSRIs) has been shown by numerous studies to be generally effective. Less well understood is how clinically to address the residual anxiety symptoms a significant minority of such patients treated with SSRIs continue to experience. We assessed quetiapine as adjunctive therapy to SSRIs for patients with anxiety symptoms complicating a depressive or anxiety disorder. Patients receiving a stable dosage of an SSRI for at least 6 weeks who also had persistent anxiety symptoms (Hamilton Anxiety scale [HAM-A] > or =16), were enrolled in a 9-week, open-label, variable dose study. Changes in clinical status were assessed with the Hamilton Depression Rating Scale (HAM-D), HAM-A, and State Anxiety Inventory (SAI). Statistically and clinically significant reductions of > or =50% in the HAM-D and HAM-A occurred by the second week of treatment in 10 of the 11 patients. These improvements continued throughout the study along with a significant improvement on the SAI scale. The most frequent side effects reported were mild dry mouth, constipation, and transient drowsiness with dose escalation. The results provide evidence that quetiapine may be an effective adjunctive treatment for recalcitrant anxiety symptoms in individuals treated with SSRIs for either anxiety or depressive disorders. Given the open-label design of the trial, more rigorous studies are clearly indicated.     

An open pilot study of interpersonal psychotherapy for panic disorder (IPT-PD)

Interpersonal psychotherapy (IPT) is a time-limited psychotherapy initially developed to treat depression. It has yet to be studied systematically for treatment of panic disorder. We modified IPT for the treatment of panic disorder and tested this treatment in an open clinical trial with 12 patients seeking treatment of DSM-IV panic disorder. Patients were assessed before during and after treatment. At completion of treatment, nine patients (75%) were independently categorized as responders (i.e., rated as much improved or very much improved on the Clinical Global Impression-Change Scale). Substantial improvement was found for panic symptoms, associated anxiety and depressive symptoms, and physical and emotional well-being. Degree of change in this sample approximated that obtained in studies using established treatments such as cognitive behavioral therapy. Results, though preliminary, suggest that IPT may have efficacy as a primary treatment of panic disorder. Further study is warranted.     

Fluoxetine for the treatment of childhood anxiety disorders

OBJECTIVE: To assess the efficacy and tolerability of fluoxetine for the acute treatment of children and adolescents with generalized anxiety disorder, separation anxiety disorder, and/or social phobia. METHOD: Anxious youths (7-17 years old) who had significant functional impairment were randomized to fluoxetine (20 mg/day) (n = 37) or placebo (n = 37) for 12 weeks. RESULTS: Fluoxetine was effective in reducing the anxiety symptoms and improving functioning in all measures. Using intent-to-treat analysis, 61% of patients taking fluoxetine and 35% taking placebo showed much to very much improvement. Despite this improvement, a substantial group of patients remained symptomatic. Fluoxetine was well tolerated except for mild and transient headaches and gastrointestinal side effects. Youths with social phobia and generalized anxiety disorder responded better to fluoxetine than placebo, but only social phobia moderated the clinical and functional response. Severity of the anxiety at intake and positive family history for anxiety predicted poorer functioning at the end of the study. CONCLUSIONS: Fluoxetine is useful and well tolerated for the acute treatment of anxious youths. Investigations regarding the optimization of treatment to obtain full anxiety remission and the length of treatment necessary to prevent recurrences are warranted.     

Pharmacologic treatment of anxiety disorders in children and adolescents

This article reviews the pharmacologic treatment of anxiety disorders in children and adolescents. These disorders are quite common and can be considered a "silent epidemic" because they are more often reported by the children and adolescents than by their parents. Tricyclic antidepressants (TCAs), benzodiazepines, buspirone, and selective serotonin reuptake inhibitors (SSRIs) have been used to treat anxiety disorders in children and adolescents with varying degrees of success. Considering safety and efficacy, the SSRIs appear to be the first-line treatment for anxiety disorders in youth, but more studies are needed to confirm preliminary results. Tricyclic antidepressants and benzodiazepines may be considered when the child has not responded to SSRIs or when adverse effects have exceeded benefits. Although nonpharmacologic approaches for the treatment of anxiety in children and adolescents are beyond the scope of this article, their importance is to be underscored and they should be considered as part of the treatment plan. Over the next decade, research data will be generated regarding the treatment of anxiety disorders in youth. Ongoing research studies include the use of fluoxetine (B. Birmaher, personal communication, 1999) and fluvoxamine (J. Walkup, personal communication, 1999) for the treatment of generalized anxiety disorder, separation anxiety disorder, or social phobia; and buspirone for generalized anxiety disorder in children. Despite these efforts, there is a need for more studies to examine the safety and efficacy of different pharmacologic treatments, as well as longitudinal studies to monitor for long-term tolerability and side effects. Pharmacokinetic studies for children and adolescents will provide information on the metabolism and absorption of these medications and delineate the developmental differences between children and adolescents when compared to adults. Finally, and perhaps most importantly, studies that compare medication, psychosocial treatments, and their combination are needed.     

Changes in anxiety sensitivity with pharmacotherapy for panic disorder

Fear of anxiety symptoms (anxiety sensitivity) has been implicated in the etiology and maintenance of panic disorder, and has been shown to improve with cognitive-behavioral treatment. The impact of pharmacotherapy on anxiety sensitivity is less clear. We administered the Anxiety Sensitivity Index (ASI) during a 12-week randomized controlled trial investigating the relative efficacy of paroxetine, paroxetine plus sustained clonazepam, and paroxetine plus brief clonazepam for patients with panic disorder. We found a mean reduction in ASI scores of 9.6 points, which correlated with symptomatic improvement, and did not differ significantly between groups. Our data provides further evidence that pharmacotherapy leads to significant acute reductions in fears of anxiety symptoms in patients with panic disorder, albeit at levels that may be somewhat less than the changes associated with CBT. Implications of these findings are discussed relative to optimizing pharmacologic treatment of panic disorder.     

The use of the Panic and Agoraphobia Scale (P & A) in a controlled clinical trial

BACKGROUND: A new 13-item scale has been developed for measuring severity of illness in patients with panic disorder and agoraphobia, the Panic and Agoraphobia Scale (P & A). The scale has five subscales covering the main factors that reduce quality of life in panic disorder patients (panic attacks, avoidance, anticipatory anxiety, disability and worries about health). The application of this scale in a double-blind placebo-controlled panic disorder trial is described. At the same time, the aim of the study was to compare the therapeutic effects of aerobic exercise with a treatment of well-documented efficacy. METHODS: Patients with Panic disorder (DSM-IV) were randomly assigned to three treatment modalities: running (n=45), clomipramine (n=15) or placebo (n=15). Treatment efficacy was measured with the Panic and Agoraphobia Scale (P & A) and other rating scales. RESULTS: According to the P & A and other scales, both exercise and clomipramine led to a significant decrease of symptoms in comparison to placebo treatment. Clomipramine was significantly more effective and improved anxiety symptoms significantly earlier than exercise. The evaluation of the P & A subscales revealed that exercise exerted its effect mainly reducing anticipatory anxiew and panic-related disability. CONCLUSIONS: The new Panic and Agoraphobia Scale was shown to be sensitive to differences between different panic treatments. Analysis of the scales five subscores may help to understand mechanisms of action of panic disorder treatments.     

SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis

OBJECTIVE: To compare the short-term efficacy of selective serotonin reuptake inhibitors (SSRIs) vs. tricyclic antidepressants (TCAs) in the treatment of panic disorder (PD) a meta-analysis was conducted. METHOD: Included were 43 studies (34 randomized, nine open), pertaining to 53 treatment conditions, 2367 patients at pretest and 1804 at post-test. Outcome was measured with the proportion of patients becoming panic-free, and with pre/post Cohen's d effect sizes, calculated for four clinical variables: panic, agoraphobia, depression, and general anxiety. RESULTS: There were no differences between SSRIs and TCAs on any of the effect sizes, indicating that both groups of antidepressants are equally effective in reducing panic symptoms, agoraphobic avoidance, depressive symptomatology and general anxiety. Also the percentage of patients free of panic attacks at post-test did not differ. The number of drop-outs, however, was significantly lower in the group of patients treated with SSRIs (18%) vs. TCAs (31%). CONCLUSION: SSRIs and TCAs are equal in efficacy in the treatment of panic disorder, but SSRIs are tolerated better.     

Fluvoxamine in the treatment of anxiety disorders

Fluvoxamine is a selective-serotonin reuptake inhibitor (SSRI) that has proved effective in large double-blind, randomized, controlled trials involving patients with social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder. Improvements have also been demonstrated in patients with post-traumatic stress disorder, as well as those with a range of obsessive-compulsive spectrum disorders including binge eating disorder, bulimia nervosa, pathological gambling, and body dysmorphic disorder. Several well controlled studies have confirmed the efficacy of fluvoxamine in children and adolescents with OCD, SAD, and other anxiety disorders, and it was the first SSRI to be registered for the treatment of OCD in children. Fluvoxamine is well tolerated. In common with other SSRIs, the most frequently reported adverse event is nausea. Fluvoxamine does not cause sedation or cognitive impairment and is associated with a low risk of sexual dysfunction, suicidality, and withdrawal reactions. It is safe in overdose and has no significant effect on body weight or cardiovascular parameters.     

Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.     

ADHD Rating Scale IV: psychometric properties from a multinational study as a clinician-administered instrument

The development of rating scales for attention-deficit/hyperactivity disorder (ADHD) has traditionally focused on parent-or teacher-rated scales. However, clinician-based instruments are valuable tools for assessing ADHD symptom severity. The ADHD Rating Scale IV (ADHD RS), clinician administered and scored, has been validated as a useful instrument to assess ADHD symptoms among American children and adolescents. In this study, we assessed the psychometric properties of the scale in a recent clinical trial conducted mainly in Europe with over 600 children and adolescents diagnosed with ADHD. The trial was conducted in 11 European countries plus Australia, Israel, and South Africa. Results based on data in the study indicate that this version of the scale has acceptable psychometric properties including inter-rater reliability, test-retest reliability, internal consistency, factor structure, convergent and divergent validity, discriminant validity, and responsiveness. There were low-to-moderate ceiling and floor effects. The psychometric properties were comparable with other validated scales for assessing ADHD symptom severity. These results were consistent across the 14 countries participating in this trial. Overall, the data from this study support the use of the ADHD RS as a clinician-rated instrument for assessing the severity of ADHD symptoms in children and adolescents in Europe.     

Treating children and adolescents with selective serotonin reuptake inhibitors: how long is appropriate?

This article addresses a key question on the use of selective serotonin reuptake inhibitors (SSRIs) among children and adolescents. As briefly reviewed, recent randomized controlled trials have established the safety and efficacy of SSRIs in the acute treatment of major depression and anxiety disorders among children and adolescents. Major questions emerge in light of these data concerning the potential risks and benefits of long-term SSRI use among children and adolescents who receive significant short-term benefits from SSRI treatment. The current review summarizes research on longitudinal outcomes, neuroscience, and psychopharmacology to formulate a set of preliminary recommendations on long-term SSRI use. A review of data in these areas supports three conclusions. First, for children who achieve marked reduction in anxiety or depressive symptoms on an SSRI, clinicians should consider recommending a medication-free trial. Second, when indicated, this medication-free trial should coincide with the first low-stress period occurring after 1 year of continual SSRI treatment. Third, SSRI treatment should be reinitiated in children who exhibit signs of relapse during this medication-free trial.     

Panic disorder in children and adolescents: a review.

OBJECTIVE: Panic disorder has been considered an adulthood disorder that does not occur in children or adolescents. The authors' goals were to critically review the available evidence for panic attacks and/or panic disorder in children and adolescents, to review the limited data on the biological basis of panic disorder as it has been studied in children and adolescents, to discuss the possible treatment approaches for panic disorder in children, and to suggest potential opportunities for further research on panic disorder in children. DATA COLLECTION: Sixty-three articles pertaining to panic disorder in children and adolescents were critically reviewed. These articles included retrospective histories of adults with panic disorder, clinical case reports of children and adolescents with panic disorder, studies of psychiatrically referred children and adolescents, reports from epidemiologic community and school samples of children and adolescents, studies of children and adolescents at risk for psychiatric disorder, reports of panic-like symptoms in pediatric patients, family studies of panic, studies of the biological basis of panic in adults, and studies of treatment for panic. FINDINGS: There is strong evidence that panic disorder occurs in children and adolescents and that its clinical presentation in this population is similar to that found in adults. CONCLUSIONS: Extending the many adult studies of panic disorder to children and adolescents would be extremely fruitful. Like adults with panic disorder, many children and adolescents are brought to emergency and medical clinics for the physical symptoms of unrecognized panic disorder.     

Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety disorder.

OBJECTIVE: The study compared the safety and efficacy of sertraline, a selective serotonin reuptake inhibitor, and placebo in the treatment of generalized anxiety disorder in children and adolescents. METHOD: The study subjects were 22 children and adolescents age 5-17 years who met the DSM-IV criteria for generalized anxiety disorder according to the Anxiety Disorders Interview Schedule for Children-Revised and who had a Hamilton Anxiety Rating Scale score > or = 16. The patients underwent a 2-3-week prestudy evaluation period, followed by a 9-week double-blind treatment phase in which they were randomly assigned in blocks of four to receive either sertraline or pill placebo. The maximum dose of sertraline was 50 mg/day. Primary outcome measures were the Hamilton anxiety scale and the Clinical Global Impression scale. RESULTS: The Hamilton anxiety scale total score, psychic factor, and somatic factor and the Clinical Global Impression severity and improvement scales showed significant differences with treatment in favor of sertraline over placebo beginning at week 4. Self-report measures reflected these results at the end of treatment. CONCLUSIONS: The results of this double-blind, placebo-controlled trial suggest that sertraline at the daily dose of 50 mg is safe and efficacious for the treatment of generalized anxiety disorder in children and adolescents.     

A comparison of citalopram and paroxetine in the treatment of panic disorder: a randomized, single-blind study.

BACKGROUND: Serotonin Selective Re-uptake Inhibitors (SSRIs) are the drugs of choice for treating panic disorder (PD). In vitro studies have shown different pharmacodynamic profiles for SSRIs, but their clinical relevance is still unknown. Paroxetine, the SSRI with the strongest serotonergic effect, also shows significant cholinergic and noradrenergic activities. In this class of drugs, citalopram is the most selective for serotonin. We compared these two drugs and their effectiveness and tolerability in a sample of patients with PD in a two-month treatment course. METHOD: Fifty-eight patients with PD were randomly assigned to either the paroxetine or the citalopram treatment group in a single-blind, randomized design. Each patient was assessed at days 0, 7 and 60 by the Panic Associated Symptoms Scale (PASS), the Sheehan Disability Scale (SDS) and the Fear Questionnaire (FQ). Primary outcome measures were the percentage of patients free of panic attacks, anticipatory anxiety and phobic avoidance in the last week of the trial and the percentage of good responders, as defined by a reduction of at least 50% from baseline of both PASS and SDS global scores at day 60. RESULTS: At day 60, 86% of patients receiving citalopram and 84% of those receiving paroxetine responded well to treatment. No significant differences between the two drugs were found. Both were well tolerated, although sexual side effects and weight gain were frequent. Anticipatory anxiety decreased significantly after the first week of treatment, and no initial worsening in the panic attacks was observed. CONCLUSION: Paroxetine and citalopram show similar anti-panic properties and a good tolerability profile. Our results support evidence that the serotonergic system plays a significant role in the anti-panic properties of these two SSRIs.     

The effects of aggression on symptom severity and treatment response in a trial of cognitive behavioral therapy for panic disorder

BackgroundPrevious research suggests that patients with panic disorder exhibit higher levels of aggression than patients with other anxiety disorders. This aggression is associated with more severe symptomatology and interpersonal problems. However, few studies have examined whether higher levels of aggression are associated with a worse treatment response in this population.MethodsThe present study sought to examine the association of aggression with panic disorder symptom severity in a sample of 379 patients who participated in a trial examining long-term strategies for the treatment of panic disorder.ResultsWe found that aggression was significantly associated with higher baseline levels of panic disorder symptoms, anxiety, depression, and functional impairment. Further, we found that patients higher in aggression did not achieve the same level of improvement in general anxiety symptoms during treatment compared to patients lower in aggression, even when controlling for baseline anxiety symptom severity.ConclusionThese results suggest that more research is needed concerning patients with anxiety disorders with higher aggression, as they may be a group in need of additional treatment considerations.     

Alprazolam in the treatment of panic attack patients with and without major depression

Sixteen patients with panic attacks were treated with alprazolam at an anxiety clinic between March 1982 and April 1983. For all patients charts were reviewed for baseline data and treatment results at 1 and 6 months. Quantitated self-rating scales and the Clinical Global Impressions scale were used to assess progress. Alprazolam appeared effective for panic, agoraphobia, and depressive symptoms in 7 of 11 patients with either panic disorder or agoraphobia with panic attacks (DSM-III-defined diagnoses); side effects occurred in 4 of the 11 patients, were limited to oversedation, and resulted in no discontinuations of drug. However, alprazolam was ineffective in controlling panic, agoraphobia, and depression in 5 patients with panic attacks and secondary major depressive episode; for this group of patients, side effects were apparently paradoxical and required drug discontinuation in 3 of these 5 patients.     

Anxiety as a correlate of response to the acute treatment of bipolar I disorder

OBJECTIVE: Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the role of anxiety in bipolar disorder, the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder. METHOD: The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder. Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms. RESULTS: History of panic attacks proved to be a significant correlate of nonremission. Anxiety, as assessed with the composite variable, was associated with longer time to remission, as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms. Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects. They also required a greater number of medications, either sequentially or in combination, in order to achieve remission. CONCLUSIONS: The findings suggest that anxiety is a clinically meaningful correlate of poor outcome in the acute treatment of bipolar I disorder.     

Hoarding among patients seeking treatment for anxiety disorders

The aim of the present study was to examine the prevalence of hoarding symptoms among individuals presenting for treatment of anxiety symptoms. Participants included 130 adults who were seeking treatment at an outpatient anxiety disorders clinic between January 2004 and February 2006. During their initial assessment, participants (31 with panic disorder, 15 specific phobia, 27 social phobia, 36 obsessive-compulsive disorder, 21 generalized anxiety disorder, mean age 37 years, 57% female, 88% White) completed the Saving Inventory-Revised, a self-report measure of hoarding symptoms, and several measures of anxiety symptoms, depressive symptoms, and functional impairment. Approximately 12-25% of anxious patients reported significant hoarding symptoms. Patients diagnosed with generalized anxiety disorder and obsessive-compulsive disorder were more likely to report significant hoarding symptoms than were those with panic disorder or specific phobia. Hoarding symptoms were positively correlated with trait anxiety, depressive symptoms, and functional impairment. These findings suggest that hoarding symptoms may be associated with anxiety disorders other than obsessive-compulsive disorder. The findings further suggest that hoarding symptoms may be underreported by anxious populations since typical intake assessments do not include specific questions about hoarding and individuals with hoarding symptoms may be unlikely to spontaneously report them.     

A randomized, controlled trial of the effectiveness of cognitive-behavioral therapy and sertraline versus a waitlist control group for anxiety disorders in older adults.

OBJECTIVE: This study is the first to investigate the relative effectiveness of cognitive-behavioral therapy (CBT) compared with a selective serotonin reuptake inhibitor (SSRI; sertraline) in a randomized, controlled trial on the treatment of anxiety disorders in older adults. METHOD: Eighty-four patients 60 years of age and over with a principal diagnosis of generalized anxiety disorder, panic disorder, agoraphobia, or social phobia were randomly assigned to one of three conditions: 15 sessions of CBT, pharmacologic treatment with an SSRI (sertraline; maximum dosage 150 mg), or a waitlist control group. Participants completed measures of primary outcome (anxiety) and coexistent worry and depressive symptoms at baseline, posttreatment, and at three-month follow up. RESULTS: Attrition rates were high in both treatment groups. Consequently, findings are based on a relatively small sample of completers (N = 52). Although both CBT and sertraline led to significant improvement in anxiety, worry, and depressive symptoms both at posttreatment and at three-month follow up, sertraline showed superior results on worry symptoms. Effect size estimates for CBT were in the small to medium range both at posttreatment (mean d = 0.42) and at three-month follow up (mean d = 0.35), whereas effect sizes for sertraline fell into the large range (posttreatment mean d = 0.94 and three-month follow up mean d = 1.02). The waitlist condition showed virtually no effects (posttreatment mean d = .03). CONCLUSIONS: Our findings strongly suggest that the pharmacologic treatment of late-life anxiety with SSRIs has not been given the proper attention in research to date.