Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects.

Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolam-treated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolam-treated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where high doses are employed.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment.

Following promising preliminary evidence, the benzodiazepine-derivative alprazolam was studied in a large, placebo-controlled, eight-week, flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder. Of 526 patients, 481 completed three weeks of treatment; however, significantly more placebo (102/234) than alprazolam (21/247) recipients subsequently dropped out of the trial, primarily citing ineffectiveness (of placebo) as the reason. Alprazolam was found to be effective and well tolerated. There were significant alprazolam-placebo differences in improvement for (1) spontaneous and situational panic attacks, (2) phobic fears, (3) avoidance behavior, (4) anxiety, and (5) secondary disability, all significant by the end of week 1. At the primary comparison point (week 4), 82% of the patients receiving alprazolam were rated moderately improved or better vs 43% of the placebo group. At that point, 50% of the alprazolam recipients vs 28% of placebo recipients were free of panic attacks.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.

Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety.

In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.

Citation patterns in anxiety disorders research in 14 journals: 1990-1991.

The authors reviewed the distribution of citations in 278 anxiety disorder studies published in 14 journals in 1990 and 1991. Although both psychiatrists and psychologists frequently authored studies, few journals showed evidence of a substantial interdisciplinary perspective. The 278 anxiety disorder studies contained 3,199 references to articles in the 14 journals. There was a high percentage of "self-citation" in some of the journals and only limited evidence of citations across journal and author disciplines. These findings suggest that anxiety disorder research findings are often not widely disseminated across disciplines.

Personality features of obsessive-compulsive disorder.

The authors evaluated personality dysfunction in 23 patients with primary obsessive-compulsive disorder and an age- and sex-matched group of patients with major depressive disorder. There were no significant differences between the two patient groups with respect to mean personality trait scores or the frequency or type of personality disorder diagnosis. A mixed personality disorder with avoidant, dependent, and passive-aggressive features was most commonly observed in the obsessive-compulsive group. There was a very low frequency of schizoid or compulsive personality disorder.

Brief treatment of emergency room patients with panic attacks.

OBJECTIVE: Most research on treatment for panic disorder has involved chronic forms of the illness. To determine the efficacy of early intervention, the authors examined the effects of treatment for patients with panic attacks who were seen in the emergency room, which is the first point of contact with the health delivery system for many persons with panic attacks. METHOD: The subjects were 33 patients with panic attacks seen in two emergency rooms. The presence of panic attacks was confirmed with a modified version of the Structured Clinical Interview for DSM-III-R; approximately 40% of the patients met the DSM-III-R criteria for panic disorder with agoraphobia. The patients were randomly assigned to groups receiving reassurance (N = 16) or exposure instruction (N = 17). Scores on the Fear Questionnaire agoraphobia subscale, Mobility Inventory, and Beck Depression Inventory and the frequency of panic attacks were determined at baseline, 3 months, and 6 months. RESULTS: The subjects who received exposure instruction significantly improved over the 6-month period on depression, avoidance, and panic frequency. The reassurance subjects did not improve on any measure and eventually reported more agoraphobic avoidance. CONCLUSIONS: These results suggest that early intervention with exposure instruction may reduce the long-term consequences of panic attacks. The exposure instruction was of value even though the subjects had relatively low levels of avoidance at the outset of the study.

Suicidal ideation and suicide attempts in panic disorder and social phobia.

OBJECTIVE: Using the original National Institute of Mental Health Epidemiologic Catchment Area (ECA) suicide questions in a clinical setting and including a comparison group of patients with social phobia, the authors attempted to replicate the finding of Weissman and associates of a greater risk of suicidal ideation and suicide attempts associated with panic disorder. METHOD: One hundred six patients with panic disorder and 41 patients with social phobia answered the five ECA suicide questions and completed a psychometric assessment package at an anxiety disorders clinic. RESULTS: Thirty-three (31%) of the patients with panic disorder and 14 (34%) of the patients with social phobia reported suicidal ideation in the past year, but only one of the patients with panic disorder and two of the patients with social phobia actually made suicide attempts in the past year. Nineteen (18%) of the patients with panic disorder and five (12%) of the patients with social phobia reported making suicide attempts at other times in their lives. Patients who had made past suicide attempts were significantly more likely to report previous psychiatric hospitalizations and past treatment for depression than were patients who had never attempted suicide. CONCLUSIONS: These results are consistent with the findings of Weissman and associates that a large proportion of individuals with panic disorder report suicidal ideation. However, many patients with social phobia also reported suicidal ideation, and few individuals in either diagnostic group had actually made recent suicide attempts. Although 12%-18% of the patients reported lifetime suicide attempts, there is evidence to suggest that these were in the context of depressive symptoms.

Shifts in diagnostic frequencies of schizophrenia and major affective disorders at six North American psychiatric hospitals, 1972-1988.

OBJECTIVE: This study tested the impression that there have been significant shifts in the relative diagnostic frequencies of schizophrenia and major affective disorders. METHOD: Data on discharge diagnoses from 1972 to 1988 were gathered from six North American psychiatric teaching hospitals (data from one extended through 1991), and rates for schizophrenia and major mood disorders were evaluated. RESULTS: Total annual discharges increased by 6.6% during the study period. Large reciprocal shifts in the frequencies of diagnoses of schizophrenia and major affective disorders were found; schizoaffective disorder was a minor diagnosis. Beginning in the early 1970s, a gradual increase in the frequency of diagnoses of major affective disorders at all sites was accompanied by a corresponding decrease in diagnoses of schizophrenia at five of the six centers. Schizophrenia diagnoses decreased from a peak of 27% in 1976 to 9% in 1989 (a threefold decrease), and diagnoses of major affective disorders rose from a low of 10% in 1972 to 44% in 1990 (a fourfold increase). CONCLUSIONS: Several forces may have influenced these changes. 1) DSM-III narrowed the definition of schizophrenia and broadened the category of major affective disorders. 2) Treatment-oriented diagnostic bias associated with the availability of lithium and other mood-altering agents may have encouraged consideration of affective disorders. 3) Economic and social forces, including better third-party reimbursement rates, may have favored affective diagnoses. 4) True increases in the incidence of affective disorders may have occurred. 5) Although a real decrease in new cases of schizophrenia may have occurred, this effect was probably minor and dominated by a larger shift of such diagnoses to affective categories.

Delayed gastric emptying and improvement with domperidone in a patient with anorexia nervosa.

A woman with anorexia nervosa who displayed severe bloating after eating was treated with domperidone, a novel compound with prokinetic properties. Both subjective ratings of satiety and assessment of gastric emptying documented improvement.

Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale. RESULTS: In intent-to-treat endpoint analyses of 203 of the patients, significantly more of the 134 patients given sertraline (N=71 [53%]) than of the 69 patients receiving placebo (N=20 [29%]) were considered responders according to their CGI improvement scores at the end of treatment. The mean reductions in the social phobia subscale of the Marks Fear Questionnaire and in the total score on the Brief Social Phobia Scale were 32.6% and 34.3% in the sertraline group and 10.8% and 18.6% in the placebo group, respectively. Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures. Sertraline was well tolerated: 103 (76%) of the 135 sertraline-treated patients and 54 (78%) of the 69 placebo-treated patients completed the study. CONCLUSIONS: Sertraline is an effective treatment for patients with generalized social phobia.

Adinazolam-SR in panic disorder with agoraphobia: relationship of daily dose to efficacy.

BACKGROUND: We report the results from a multicenter, double-blind, randomized, fixed-dose study designed to evaluate the relationship between daily dose and efficacy of adinazolam-SR in patients with panic disorder with agoraphobia. METHOD: Patients (N = 315) were randomized to one of four treatment groups (placebo, N = 83; 30-mg group, N = 79; 60-mg group, N = 81; and 90-mg group, N = 72) and then treated twice daily for 4 weeks. All treatment groups were comparable demographically. Primary efficacy measures included total number of panic attacks, global improvement score using the Clinical Global Impressions (CGI) scale, phobic anxiety dimension of the Symptom Checklist-90 phobic cluster, overall phobia state using the Phobia Scale, and severity of illness on the CGI. RESULTS: The 60- and 90-mg/day adinazolam-SR treatment groups showed superior results when compared with the placebo group at Week 4 while the 30-mg group did not. Treatment with adinazolam-SR was well tolerated, with sedation the only treatment-emergent symptom that occurred more frequently in patients treated with adinazolam-SR than placebo. CONCLUSION: These results suggest that adinazolam-SR at doses of 60-mg/day or greater administered twice daily is a safe and effective treatment in selected patients with panic disorder with agoraphobia.

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the TaqIA polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

Sequence of improvement in agoraphobia with panic attacks.

In a multi-center comparison of alprazolam to placebo in the treatment of agoraphobia with panic attacks, the sequence of sustained remission in both treatment groups, was panic attacks before phobias. This may suggest that phobias are secondary to panic attacks in the pathogenesis of the disorder, although other explanations may account for these data and are discussed.

Attachment in mothers with anxiety disorders and their children.

OBJECTIVE: This study examined adult attachment in mothers diagnosed with anxiety disorders and child-mother attachment in their children. METHOD: Eighteen mothers with Axis I anxiety disorders completed the Adult Attachment Interview and standardized questionnaires. These mothers and their preschool children (n = 20) then participated in the Strange Situation Procedure. RESULTS: All mothers were classified as nonautonomous with respect to attachment, with 78% judged unresolved. When those judged unresolved were reassigned to their alternate categories, the proportion of nonautonomous mothers was 61%. Eighty percent of the children were classified as insecurely attached, with 65% judged disorganized. When those judged disorganized were reassigned to their alternate categories, the proportion of insecurely attached children was 55%. Sixty-five percent of the children matched their mother's attachment classification. Mothers of securely attached children reported fewer recent life events, fewer depressive symptoms, and a greater sense of parenting competence than mothers of insecurely attached children. CONCLUSIONS: These results suggest that attachment measures can be applied to anxious populations. The high rate of insecurity among offspring of anxious mothers indicates a need for longitudinal studies of these children.

Biological challenges in obsessive compulsive disorder.

1. Obsessive compulsive disorder and affective disorder have been investigated by means of various biological challenges. 2. Total sleep deprivation and methylphenidate challenge were used to determine the effects on a group of subjects with obsessive compulsive disorder. 3. The findings of a lack of response to total sleep deprivation and methylphenidate in obsessive compulsive patients contrasts with the findings in affective disorder patients. 4. The findings are more consistent with those in studies of panic disorder. 5. The relationship of obsessive compulsive disorder to affective and anxiety disorder may be elucidated by further studies.

Psychopharmacological treatment of panic disorder and related states: a placebo controlled study of alprazolam.

The paper consists of two parts. A review of the relationship of panic disorder to the phobic states and the treatment of these disorders by means of tricyclic antidepressants, MAOIs, beta blocking drugs and benzodiazepines. A double blind study of alprazolam and placebo in 118 patients with agoraphobia and panic is presented. In an eight week study alprazolam was found to be significantly superior to placebo in the treatment of panic attacks, phobic avoidance, anticipatory anxiety and general anxiety.

Negative priming for obsessive-compulsive checkers and noncheckers.

Negative priming--the slowing of a response to an item that was recently ignored--was investigated in three groups: obsessive-compulsive disorder (OCD) checkers, OCD noncheckers, and nonclinical control participants. All groups performed both a standard negative priming task, selecting targets based on a perceptual feature (i.e., color), and a modified negative priming task, selecting targets based on a semantic feature (i.e., referent size). All three groups demonstrated significant negative priming in both tasks, although the negative priming was much larger in the novel, semantic task than in the common, perceptual one. The findings suggest that patients with OCD do not demonstrate impairments in negative priming, contrary to earlier claims (Enright & Beech, 1990, 1993a, 1993b; Enright, Beech, & Claridge, 1995).

Benzodiazepine dependence.

Benzodiazepines (BDPs) are widely used drugs that are effective in controlling the symptoms of anxiety. Tolerance develops rapidly to some of the effects but not to anxiolytic effect in most patients. Dependence occurs at usual therapeutic doses and in a small proportion of patients is accompanied by an enormous increase in the dose taken. The majority of subjects using very high doses are dependent on other substances concurrently. On discontinuing BDPs patients may suffer from relapse of the original condition, rebound in the severity of the symptoms of the original condition or the onset of new symptoms in an abstinence syndrome. If BDPs are discontinued abruptly there may be severe consequences such as seizures. With tapering of the dose, even if this is rapid and from high dose, high potency BDP, the subject will probably experience considerable discomfort but rarely life-threatening effects. Whilst there is concern that BDPs are used too freely, the conditions treated are accompanied by significant morbidity and mortality. The prevalence of pure BDP dependence is low and it is still a matter of debate as to how often BDPs should be prescribed, for which conditions and for what length of time.

Pre-treatment predictors of treatment outcome in panic disorder and agoraphobia treated with alprazolam and exposure.

Pre-treatment predictors of treatment outcome were examined in a group of 144 patients with panic disorder and agoraphobia randomly allocated to alprazolam+exposure (AE), placebo+exposure (PE), alprazolam+relaxation (AR), and placebo+relaxation (PR). First-time psychotropic medication use, severity of agoraphobic disability, and longer duration of illness predicted less global improvement at post-treatment. Pre-treatment severity of agoraphobia predicted less improvement both in the short- and the long-term. Predictors of poorer outcome at 6-month follow-up were older age, past history of depression, severity of phobia targets, and longer duration of illness. Sex, source of referral, pre-treatment depression-anxiety-panic, and expectancy from treatment did not relate to outcome.