Improved statistical analysis of moclobemide dose effects on panic disorder treatment.

Clinical trials with several measurement occasions are frequently analyzed using only the last available observation as the dependent variable [last observation carried forward (LOCF)]. This ignores intermediate observations. We reanalyze, with complete data methods, a clinical trial previously reported using LOCF, comparing placebo and five dosage levels of moclobemide in the treatment of outpatients with panic disorder to illustrate the superiority of methods using repeated observations. We initially analyzed unprovoked and situational, major and minor attacks as the four dependent variables, by repeated measures maximum likelihood methods. The model included parameters for linear and curvilinear time trends and regression of measures during treatment on baseline measures. Significance tests using this method take into account the structure of the error covariance matrix. This makes the sphericity assumption irrelevant. Missingness is assumed to be unrelated to eventual outcome and the residuals are assumed to have a multivariate normal distribution. No differential treatment effects for limited attacks were found. Since similar results were obtained for both types of major attack, data for the two types of major attack were combined. Overall downward linear and negatively accelerated downward curvilinear time trends were found. There were highly significant treatment differences in the regression slopes of scores during treatment on baseline observations. For major attacks, all treatment groups improved over time. The flatter regression slopes, obtained with higher doses, indicated that higher doses result in uniformly lower attack rates regardless of initial severity. Lower doses do not lower the attack rate of severely ill patients to those achieved in the less severely ill. The clinical implication is that more severe patients require higher doses to attain best benefit. Further, the significance levels obtained by LOCF analyses were only in the 0.05-0.01 range, while significance levels of <0.00001 were obtained by these repeated measures analyses indicating increased power. The greater sensitivity to treatment effect of this complete data method is illustrated. To increase power, it is often recommended to increase sample size. However, this is often impractical since a major proportion of the cost per subject is due to the initial evaluation. Increasing the number of repeated observations increases power economically and also allows detailed longitudinal trajectory analyses.

Escitalopram: an open-label study of bereavement-related depression and grief.

BACKGROUND: Approximately 8 million Americans suffer the loss of an immediate family member each year. Chronic depression may develop following bereavement-about 15% of the bereaved are depressed at 1 year. Several studies of psychotropic medications have demonstrated improvement in depression ratings, but little data exists for selective serotonin reuptake inhibitor treatment in bereavement-related depression. METHODS: Thirty adults were treated with escitalopram for 12 weeks in open fashion for a major depressive episode following loss of a close family member (parent, sibling, child, or spouse/significant other). Main outcome measures were the Hamilton Depression Rating Scale, the Montgomery-Asberg Rating Scale, the Texas Revised Inventory of Grief, and the Inventory of Complicated Grief. RESULTS: Twenty-nine of thirty participants returned for at least one set of efficacy measures after starting medication. Nineteen subjects (66%) experienced a 50% or greater improvement on the Hamilton Depression Scale. Fifteen subjects (52%) achieved remission, defined as a final score of 7 or less on the Hamilton Depression Scale. Escitalopram significantly reduced depressive symptoms (P<0.001) over time. Subjects with uncomplicated grief and those with complicated grief improved similarly over time. Subjects with and without PTSD improved to a similar degree. Escitalopram was well tolerated. LIMITATIONS: Open-label design, psychotherapy was not controlled, relatively short treatment period, variation in grief scales make comparisons to other studies difficult, all subjects with complicated grief also were clinically depressed, and gender discrepancy of sample. CONCLUSIONS: Escitalopram improved depressive, anxiety, and grief symptoms in individuals experiencing a major depressive episode related to the loss of a loved one.

Cognitive style, alprazolam plasma levels, and treatment response in panic disorder.

This study investigated an anxiety-prone cognitive style (measured by the Anxious Thoughts and Tendencies Questionnaire, AT&T) as a predictor of the acute response to increasing alprazolam plasma levels in panic disorder. Panic disorder patients (n=26) were treated with escalating doses of alprazolam for 4 weeks, then a fixed dose of 1 mg four times a day for 4 weeks. At 0, 1, 2, 3, 4, 6, and 8 weeks, trough alprazolam plasma levels; clinical, self-report, and performance measures; and vital signs were assessed. Panic attack data were from daily diaries. The repeated response measures were analyzed in relation to alprazolam plasma levels using SAS GENMOD, with patients classified as high or low on the baseline AT&T. Panic attacks, anticipatory anxiety, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, and clinicians' global ratings improved with increasing alprazolam plasma levels. Hopkins Symptom Checklist-90 Anger-Hostility; Profile of Mood States Vigor, Confusion, and Friendliness; and speed and accuracy of performance worsened. Patients with high AT&T scores were worse throughout the study on situational panics, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, the Hamilton Rating Scale for Depression, and Clinical Global Improvement; most Hopkins Symptom Checklist-90 clusters; Profile of Mood States Anxiety, Depression, and Confusion; and Continuous Performance Task omissions. We conclude that in panic disorder: (1) alprazolam has a broad spectrum of clinical activity related to plasma levels in individual patients; (2) sedation, disinhibition, and performance deficits may persist for at least a month after dose escalation ends; (3) marked anxiety-prone cognitions predict more symptoms throughout treatment, but do not modify the response to alprazolam and therefore should not influence the choice of alprazolam as treatment.

Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs.

The objective of this study was to ascertain the relationship of alprazolam plasma levels and an anxiety-prone cognitive style to the characteristics and severity of early withdrawal after abrupt discontinuation of alprazolam in 26 patients with panic disorder. After 8 and 9 weeks of fixed-dose treatment, patients were hospitalized for 24 hours. On 1 admission, ordered at random, treatment was maintained; on the other, placebo was substituted double blind. The Anxious Thoughts and Tendencies questionnaire was administered before treatment. Alprazolam plasma levels were measured 7 times on the day after each admission. Before each blood sampling, the Profile of Mood States and performance tasks were administered, and vital signs were recorded. On the day after abrupt discontinuation of alprazolam, Profile of Mood States anxiety, depression, fatigue, and confusion increased; vigor and elation decreased; speed on the digit symbol substitution task improved; and systolic blood pressure increased substantially over time. High Anxious Thoughts and Tendencies scores were related specifically to more anxiety. Our findings (1) confirm that dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure are part of the early syndrome of withdrawal from alprazolam in patients with panic disorder, notably as the drop in plasma levels approaches 50%; (2) indicate a psychomotor deficit persisting beyond dose stabilization; (3) suggest that an anxiety-prone cognitive style measurable before undertaking treatment may be a risk factor for more severe anxiety upon discontinuation; and (4) provide a rationale for applying cognitive behavior therapy during benzodiazepine taper.

Psychopathology of panic attacks in panic disorder.

PURPOSE: This study examined the relationships among certain subtypes of panic attacks (full vs. limited symptom; spontaneous vs. situational) and between these subtypes, panic disorder subtypes, and other characteristics of panic disorder, especially agoraphobia. METHOD: Data were drawn from a large (n = 1,168) treatment study of panic disorder in which panic attacks were carefully subtyped and counted using a diary. Relationships between variables at baseline were examined primarily using non-parametric methods, and the course of improvement for panic subtypes among completers was plotted. RESULTS: The median number of spontaneous panic attacks per week at baseline was similar among patients with panic disorder without agoraphobia (PD), limited phobic avoidance (PDL), and agoraphobia (PDA). The median number of situational attacks and the median agoraphobia ratings rose progressively across diagnostic subtypes. Anticipatory anxiety, HAM-A, HAM-D, and disability scores were higher in PDA than in PD. Full and limited symptom panic attacks were positively correlated. The proportion of total attacks that were limited rose during the first two weeks of treatment, suggesting conversion of full to limited symptom attacks before complete disappearance. Spontaneous and situational attacks were correlated minimally or not at all. Agoraphobia ratings were more positively correlated with situational than with spontaneous panic attacks. Few of the correlations among measures at baseline were high. CONCLUSIONS: Full and limited symptom panic attacks differ primarily in severity. Spontaneous and situational attacks are relatively independent, and situational attacks are more closely related to agoraphobia. These findings are consistent with previous work suggesting that spontaneous attacks reflect a biological component, whereas situational attacks reflect a cognitive component in the psychopathology-- and possibly the pathogenesis-- of panic disorder. This provides a rationale for the use of combined pharmacotherapy and psychotherapy in the treatment of panic disorder. Future investigations of panic disorder should carefully separate panic attack subtypes.

Potential effectiveness and safety of olanzapine in refractory panic disorder.

Panic disorder is a common and disabling psychiatric disorder. Despite treatment advances, refractory panic disorder requires novel interventions. One such pharmacologic intervention with theoretical and case study support includes olanzapine, a thienobenzodiazepine medication currently approved for schizophrenia in the United States. Ten people with refractory DSM-IV diagnosed panic disorder completed an 8-week, open-label, flexible-dose clinical trial. Baseline, in-treatment, and end-of-treatment data for panic attacks, anticipatory anxiety, phobic avoidance, and impairment were collected. Data were analyzed using SPSS software. Refractory panic disorder patients required a wide dose range averaging 12.3 mg/day of olanzapine to significantly improve or ablate panic attacks. On the average, number of attacks decreased from 6.1/week at baseline to 1.1/week at the end of treatment, and anticipatory anxiety from 32% of the day to 8% of the day. At treatment end, 5 of 10 participants (50%) were panic free, 4 (40%) had one attack in the previous week, 1 (10%) had seven attacks in the previous week, and 6 of 10 participants (60%) were anticipatory anxiety free. There were also statistically and clinically significant improvements in impairment over the course of the trial. There were no significant changes in vital signs, emergent side effects, or average weight, although 6 of 10 people did gain weight. Olanzapine is potentially effective and safe in panic disorder. Due to study limitations, further clinical trials are needed to demonstrate effectiveness.

Long-term effectiveness of cognitive therapy in major depressive disorder.

Cognitive therapy of depression, based on the cognitive theory of depression, is an established treatment for major depressive disorder. Although few clinicians expect acute treatment of depression with antidepressant medication to prevent long-term relapse of the illness, some practitioners of cognitive therapy report long-term effectiveness in preventing relapse after short-term treatment. We set out to reanalyze follow-up studies in the literature, using intent-to-treat principles to assess the long-term effects of acute treatment with cognitive therapy. From an initial reference list of 97 citations that met our search criteria (controlled clinical trials of cognitive therapy in depression with follow-up), we found five trials that met our inclusion criteria. This report reviews and reanalyzes these five trials, published between 1981 and 1992, which compare cognitive therapy and tricyclic antidepressant therapy. Overall, the evidence favors a longer-term effect for cognitive therapy over tricyclic antidepressants alone.

Treatment of panic disorder with agoraphobia in an anxiety disorders clinic: factors influencing psychiatrists' treatment choices.

The main objective of this report was to identify patient characteristics that led psychiatrists in an academic anxiety disorders clinic to make a decision about intensive treatment of patients with panic disorder with agoraphobia (PDA) with cognitive-behavioral therapy (CBT) alone, CBT plus a high-potency benzodiazepine (CBT+BZ) or CBT combined with BZ and an antidepressant, fluoxetine (CBT+BZ+AD). On the basis of their clinical judgment and collaborative negotiation with the patient, psychiatrists chose one of the three treatment modalities for 102 PDA outpatients. Two stepwise logistic regressions were performed to explore pre-treatment patient characteristics the psychiatrists may have considered in choosing among these treatments. One regression examined the decision to add BZ to CBT, while the other examined the decision to add AD to CBT+BZ. Psychiatrists generally used combination treatments in patients with more severe PDA. CBT alone was a more likely choice for dominant anxiety-related cognitive phenomena. Patients with prominent panic attacks and somatic symptoms were more likely to be treated with CBT+BZ, while those who also had significant depressive symptoms and higher disability levels were more likely to receive CBT+BZ+AD. Patients in all three treatment groups showed significant reduction in symptoms during intensive treatment and reached similar end states. In a clinic setting where CBT is accepted as the basic treatment for PDA, psychiatrists added BZ to control prominent panic symptoms and added AD to elevate depressed mood and help cope with marked disability. These choices appear rational and resulted in substantial clinical improvement at the end of intensive treatment in the clinic.

Review of the long-term effectiveness of cognitive behavioral therapy compared to medications in panic disorder.

Panic disorder is a recurrent and disabling illness. It is believed that Cognitive Behavioral Therapy (CBT) has a long-term protective effect for this disorder. This would offer CBT considerable advantage over medication management of panic disorder, as patients often relapse when they are tapered off their medications. This is a review of the literature about the long-term effectiveness of CBT. We searched for follow-up studies of panic disorder using CBT. Of the 78 citations produced in the initial search, most had major methodological flaws, including ignoring losses to follow-up, not accounting for interval treatment, and unclear reporting. Three papers met strict methodological criteria, and two of these demonstrated a modest protective effect of CBT in panic disorder patients. We make recommendations for well-designed studies involving comparisons of medications and cognitive behavior therapy.

A general anxiety-prone cognitive style in anxiety disorders.

OBJECTIVE: This study compared scores on the Anxious Thoughts & Tendencies (AT&T) questionnaire, a putative measure of a general anxiety-prone cognitive style, among patients with panic disorder without agoraphobia (PD, n=62), panic disorder with agoraphobia (PDA, n=29), generalized anxiety disorder (GAD, n=43), limited social phobia (LSP, n=34), generalized social phobia (GSP, n=33), and community residents (n=319). METHOD: Candidates for treatment studies completed a diagnostic interview and the AT&T. AT&T scores were compared among anxious groups using analysis of variance. Then depressed and non-depressed patients were compared. The final analysis compared anxious groups without comorbid depressive or anxiety disorders. RESULTS: AT&T scores were highest in PDA patients, followed by patients with GAD or GSP, then patients with PD or LSP, with community residents lowest. Depressed patients were higher than non-depressed patients. Patients with current or past comorbid depressive disorders did not differ. The ranking of anxious groups on AT&T scores remained unchanged after exclusion of patients with comorbid disorders. Patients with PD or LSP without comorbidity had the same AT&T levels as the community sample. CONCLUSIONS: The AT&T discriminates PDA and GAD from PD per our hypothesis. The low AT&T levels among patients with PD and LSP suggest no association with a general anxiety-prone cognitive style. LSP and GSP may be distinct disorders. The cognitive style assessed by the AT&T is also associated with depression and may be a marker for vulnerability to depression. Definitive conclusions about a pathogenic role for cognitions require their measurement before the onset of the disorder.

Interactive model of therapeutic response in panic disorder: moclobemide, a case in point.

It was proposed that pre-post regression slopes be used to index treatment response when the effect of baseline scores differed among treatments (interaction between treatment and baseline score). Reanalyses of two studies using imipramine and fluoxetine in panic disorder showed doserelated decreases in pre-post slopes for the frequency of unexpected panic attacks, but not for the frequency of situational panic attacks or measures of agoraphobia. This report presents similar analyses of data from a study using moclobemide. Patients (N = 452) with panic disorder were randomized to placebo or a fixed dose of moclobemide (75, 150, 300, 600, or 900 mg/day). They were treated double-blindly and evaluated at baseline and 1, 2, 3, 4, 6, and 8 weeks later. The authors analyzed the frequency of unexpected and situational panic attacks compiled from a daily diary, and fear and avoidance ratings based on the patient's main phobia using baseline (pre) and end-point (post) values for all randomized patients. Adjoining dose groups were combined. Both unexpected and situational panic attacks showed systematic doserelated suppression of pre-post treatment slopes. Neither pre-post slopes nor adjusted posttreatment means for fear and avoidance differed reliably between treatment arms. This study replicates the authors' earlier findings, except for situational panic attacks, which probably were not reliably identified. Antidepressants selectively suppress panic attacks, especially unexpected attacks, but not agoraphobia. The findings are consistent with the hypothesis that panic disorder with agoraphobia has clinically separable biologic and cognitive components that respond differentially to treatment. Antidepressants benefit primarily patients with many unexpected panic attacks. Investigators should evaluate pre-post treatment slopes before comparing adjusted posttreatment means (analysis of covariance).

Do antidepressants selectively suppress spontaneous (unexpected) panic attacks? A replication.

The purpose of this study was to test the following interrelated hypotheses in a larger sample by attempting to replicate supportive results from a small therapeutic study: (1) the pathogenesis of panic disorder includes at least two identifiable components: a biological component represented by spontaneous (unexpected) panic attacks, and a cognitive component represented by situational attacks and especially by phobias; (2) these components respond differently to treatment; (3) many biological processes respond to an effective intervention in proportion to their deviance from "normal" prior to treatment ("Law of Initial Value"); and (4) the response of spontaneous panic attacks to an effective treatment conforms to that model. Previously, the authors reanalyzed an 8-week therapeutic study of panic disorder that included groups treated with placebo and with imipramine (225 mg daily). The criteria of response were spontaneous panic attacks (biological component), situational panic attacks (both components), and agoraphobia ratings (cognitive component). The analyses compared the regression lines for posttreatment status on pretreatment status in the imipramine and placebo groups. The effect of imipramine on spontaneous panic attacks fitted the hypothesized model: the pre-post slope in the placebo group was approximately 1 (45 degrees), whereas the slope in the imipramine group was approximately 0. There was no significant difference in pre-post slopes between the imipramine and placebo groups for situational panic attacks or agoraphobia ratings. For this report, the authors applied the same approach to another larger data set from a study using a similar design, but a different antidepressant. In this multicenter, double-blind study, patients with panic disorder were randomly assigned to receive 10 weeks of treatment with placebo (N = 78) or fluoxetine 10 mg (N = 84) or 20 mg (N = 81) daily. Spontaneous and situational panic attacks were registered in a daily diary, and agoraphobia was rated at each visit. Using baseline and endpoint data, fluoxetine had a statistically significant, dose-dependent, suppressive effect on spontaneous panic attacks, as measured by the pre-post slopes in the three treatment groups. The placebo group showed some response (slope = 0.69). There were no significant drug effects on situational panic attacks. On ratings of agoraphobia, the slopes in the placebo and the fluoxetine 20 mg groups did not differ, but the slope in the fluoxetine 10 mg group was significantly less than that in the placebo group, suggesting a therapeutic drug effect on agoraphobia only at the lower dose. These results are consistent with the stated hypotheses. They suggest that the therapeutic effects of antidepressants on panic disorder may be due primarily to the specific suppression of spontaneous panic attacks among patients with high baseline pathologic findings. Implications of these results for concepts of pathogenesis, clinical practice, and therapeutic research regarding panic disorder are discussed.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.

Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half-lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.

The revised Anxious Thoughts and Tendencies (AT&T) scale: a general measure of anxiety-prone cognitive style.

BACKGROUND: The AT&T was developed from a perspective which proposes that panic disorder with agoraphobia arises from interaction between a specific biological predisposition, expressed in spontaneous panic attacks, and a general anxiety-prone cognitive style. Many items of the original AT&T, a putative measure of the cognitive component, were complex and ambiguous; and normative data were not available. METHOD: In this research, the items were simplified and clarified. A community sample of northern New Mexico Hispanics and geographically matched non-Hispanic whites was identified from an earlier epidemiological study. The sample included 151 Anglos and 168 Hispanics; 98 respondents aged 18-34, 75 aged 35-49, 69 aged 50-64, and 77 aged 65 or more; and 111 men and 208 women. RESULTS: Factor analysis produced one major factor with high loadings from the 15 negatively worded items, that accounted for about 41% of the total variation in the 15 items. The mean major factor score for Anglos was 1.65 with a standard deviation of 0.48, and for Hispanics was 1.76+/-0.52. F = 4.17, df = 1/311, P < 0.05, and effect size d = 0.22. There were no significant age or gender effects. Item analysis of the major factor produced item/total correlations from 0.49 to 0.68 and a Cronbach's alpha of 0.91. In a separate clinical sample of 30 patients with panic disorder, the test-retest correlation of the major factor at baseline and after 8 weeks of treatment was 0.75. In the community sample, the correlations of the major factor with anxiety-related clusters of the SCL-90 were: Somatization, 0.36; Anxiety, 0.53: and Phobia, 0.44. CONCLUSIONS AND RECOMMENDATIONS: We recommend that the AT&T be reduced to the 15 items of its major factor, and we supply quantiles and moments based on the full community sample of 319 as a standard of comparison. Further research with the AT&T in clinical samples of patients with anxiety disorders is ongoing.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997.

OBJECTIVE: To assemble expert clinical experience and judgment regarding the treatment of anxiety disorders in a systematic, quantitative manner, particularly with respect to changes during the preceding five years. METHOD: A panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options relevant to seven vignettes describing typical cases of different anxiety disorders. RESULTS: The preferred initial treatment strategy in 1992 was a combination of medication with a psychological therapy for all vignettes except simple phobia, where a psychological procedure alone was favored. There was little change in 1997, primarily some decrease in the choice of psychological therapy and some increase in the choice of medication for social phobia. Experts recommending a medication in 1992 most often chose as first-line treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA) for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's most frequent recommendation for agoraphobia, PD, and OCD changed to a specific serotonin reuptake inhibitor (SSRI); and they also recommended these compounds more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or TCAs. However, in 1997 many again chose a combination of medications, often a BZ plus a SSRI, so that, overall, there was only a small decline in recommendations for BZs. As second-line medications (1997 only), the experts recommended SSRIs most often for most vignettes, but a TCA for PD and GAD. Recommendations for a combination of medications rose substantially for most vignettes, usually a BZ plus an antidepressant. CONCLUSIONS: Combined cognitive-behavioral therapy plus medication was highly favored by the experts as the initial treatment strategy for anxiety disorders. During the preceding five years, SSRIs displaced older antidepressants as the experts' first-line choices for the pharmacotherapy of anxiety disorders. In case of an unsatisfactory response, the experts' second-line choices more often were an older antidepressant or a combination of an antidepressant plus a BZ. According to the experts' judgements, the BZs, especially combined with an antidepressant, remain mainstays of pharmacotherapy for anxiety disorders.

Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997.

A follow-up survey in 1997 to a 1992 study of the recommendations of an international expert panel on the use of benzodiazepines (BZDs) and other psychotherapeutic medications in the treatment of anxiety disorders suggests that the BZDs remain a mainstay of pharmacotherapy for most of these conditions. BZDs were mentioned more often than any other class of drugs as preferred first-line therapy for anxiety disorders, except obsessive compulsive disorder. The introduction of the selective serotonin reuptake inhibitors (SSRIs) did not significantly affect the experts' recommendations for the use of BZDs as first-line pharmacotherapy. Rather, the SSRIs displaced the tricyclic antidepressants. Some implications of the continuing recommendations for the use of BZDs in anxiety disorders are discussed.

Panic disorder and agoraphobia: a sufferer's perspective.

This is a story by a woman about her life with panic, agoraphobia, and depression. She tells us about the clinical features, the heritable components, the environmental contributions, the developmental penalties, the social consequences, and the therapies for these conditions far more vividly than even the most dramatic of our systematic studies. But this is more than a clinical vignette. It is a human story of courage to proceed undaunted in the face of terror and despair to ultimately prevail over the most formidable internal obstacles. Nowadays I rarely see Mrs. Edwards. She is too busy living. I know she is productively and gratifyingly employed and engaged with her family. Usually I learn of her adventures here and abroad through letters written in the same captivating style as the autobiography below. I have witnessed Mrs. Edwards reading her story to others with similar problems, to medical students, and to psychiatric residents. The impact invariably was stunning. Making her acquaintance even in the dry print medium is an unforgettable learning experience.

Medication side effects in anxious patients: negative placebo responses?

The purpose of the present study was to detect any problems among anxious patients in switching from alprazolam to extended release alprazolam. Fifty-four patients with an anxiety disorder, stabilized on alprazolam, entered the study. During the first 2 weeks, all patients took alprazolam as usual. During the second 2 weeks, they all took the same dosage of the extended release formulation. They were evaluated weekly with standard clinical measures and were asked to report any adverse medical events. The clinical measures showed modest, steady improvement over the course of the study. Patients reporting adverse medical events increased from 26% of the sample to 60% after the switch of dosage forms. Most of these events were anxiety-like (48%) or sedative (37%). Patients who developed sedative events took slightly higher mean doses of alprazolam. Patients who developed anxiety-like events had higher baseline scores on the Somatization, Anxiety and Phobia clusters of the SCL-90. The results suggest that more anxious patients confronted with a change of regimen commonly generate anxiety symptoms that they attribute to the medication, i.e., negative placebo responses, perhaps especially if they have a tendency toward somatization. A study designed to sort out pharmacological and psychological effects and further explore the mechanisms at work is indicated.