Edward Schweizer

Moclobemide in social phobia: A controlled dose-response trial

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management

The treatment of anxiety has evolved through various phases. Currently, there is a growing recognition that anxiety disorders are frequently chronic and/or recurrent. There is also less optimism than a decade ago that benzodiazepines will be replaced by alternative agents that are not active at the benzodiazepine receptor. Consequently. the understanding and management of benzodiazepine dependence and withdrawal continue to be of some clinical importance. This article briefly reviews the withdrawal syndrome and the pharmacological and patient variables that contribute to it. It then summarizes the various approaches to managing benzodiazepine dependence and withdrawal.

Placebo-controlled trial of venlafaxine for the treatment of major depression.

Results are presented of the first double-blind, placebo-controlled trial of a novel antidepressant venlafaxine, which preclinically has demonstrated serotonin, norepinephrine, and dopamine reuptake inhibiting effects. Sixty outpatients meeting DSM-III-R criteria for major depression were randomized to receive 6 weeks of treatment with one of three fixed doses of venlafaxine—25 mg three times a day, 75 mg three times a day, or 125 mg three times a day—or placebo. Significant improvement was observed in depression scores at all doses, with the high dose resulting in earlier improvement, by week 2. For the combined venlafaxine treatment groups, 68% achieved a moderate or marked improvement on the Clinical Global Impression scale, compared with only 31% for the placebo group. Venlafaxine was well tolerated, and nervousness, sweating, and nausea were the only adverse effects observed more frequently with drug compared with placebo.

Abnormal salivary cortisol levels in social phobic patients in response to acute psychological but not physical stress.

BACKGROUND Little is known about the hypothalamic-pituitary-adrenal axis response to acute stressful behavioral challenges in patients with social phobia. METHODS Eighteen patients with social phobia and 17 normal volunteers participated in two behavioral stressors: a speech task and physical exercise. RESULTS Normal volunteers (n = 14) demonstrated a significant 50% increase in salivary cortisol levels to the speech task. Three nonresponding normal volunteers demonstrated a 17% decrease. In contrast, patients with social phobia demonstrated dichotomous changes. Seven social phobia patients demonstrated a significantly higher 90% increase in salivary cortisol to the speech task, whereas the remaining patients (n = 11) were nonresponders demonstrating a 32% decrease in cortisol. Both patient groups were significantly more anxious than the normal volunteers. In contrast to the response to a speech task, social phobics showed a cortisol response to physical exercise of similar magnitude as normal volunteers. CONCLUSIONS The results indicated dichotomies in magnitude and in distribution of the cortisol response to a speech task between social phobia patients and normal volunteers. Social phobia patients responded differently than normal volunteers to a stressor associated with social evaluation but not to physical exercise. These results suggest adaptation of distinct biological processes specific to different stressful conditions in social phobia.

Gepirone in anxiety: a pilot study.

Ten patients suffering from generalized anxiety disorder were treated, after a single-blind placebo washout week, with the nonbenzodiazepine anxiolytic gepirone in a 6-week open label trial. Mean Hamilton Anxiety scores improved from 24.8 to 7.1 (p < 0.01). Other physician- and patient-rated scales showed comparable improvement on a mean maximal dose of 41 mg of gepirone. The medication appeared to be nonsedating and well tolerated. The anxiolytic effect of the medication was very marked in several cases, and gepirone appears to have promise as an anxiolytic agent.

A Double-Blind, Placebo-Controlled Study of a CCK-B Receptor Antagonist, CI-988, in Patients With Generalized Anxiety Disorder

This multicenter, double-blind, placebo-controlled, parallel-group, randomized study assessed the efficacy, safety, and tolerability of a novel CCK-B antagonist CI-988 in the treatment of generalized anxiety disorder (GAD). Patients received placebo or CI-988 (300 mg/day, thrice daily) for 4 weeks. Patients with a primary diagnosis of GAD according to DSM-III-R criteria were randomized. The study design included a 1- to 2-week single-blind placebo baseline phase, followed by a 4-week double-blind treatment phase. Efficacy was measured weekly by Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impressions of Severity and Change, UCLA-Multi Dimensional Anxiety Scale, and Hamilton Rating Scale for Depression. Patients were also evaluated to determine whether they met criteria for irritable bowel syndrome (IBS) at screening and were evaluated with a gastrointestinal visual analog scale at each visit. Eighty-eight patients were randomized to CI-988 (N = 45) and placebo (N = 43) at three centers. CI-988 did not demonstrate an anxiolytic effect superior to placebo in this clinical trial. There was no significant difference in mean change in HAM-A total between placebo (-7.73) and CI-988 (-8.64). However, a significant treatment-by-center interaction and a highly variable placebo response rate among the three centers limit the interpretation of the results. CI-988 did not have an effect on symptoms of IBS other than diarrhea, which worsened in patients with IBS. Other than a higher incidence of some gastrointestinal symptoms (diarrhea, dyspepsia, flatulence, and nausea), CI-988 was well tolerated. Results suggest that testing higher oral doses of CI-988 may be warranted.

Panic disorder: long-term pharmacotherapy and discontinuation.

This article compares panic disorder (PD) medications and discusses long-term therapy. In a review of the literature, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and benzodiazepines prove effective in treating PD. MAOIs treat comorbid depression; frequent side effects are dizziness and orthostatic hypotension. SSRIs are better tolerated than MAOIs, producing mild anticholinergic effects, but also producing gastrointestinal side effects and sexual dysfunction. Benzodiazepines are generally well tolerated when titrated gradually; moderate sedation is the most common short-term side effect. Long-term risks are physical dependence and withdrawal reactions. One hundred six PD patients were enrolled in a double-blind, 8-month, placebo-controlled trial of alprazolam and imipramine. In the 8-week short-term phase, daily dosages were titrated up to 10 mg/day of alprazolam and 250 mg/day of imipramine. The greatest number of dropouts occurred during this phase (lack of improvement and/or side effects). Alprazolam patients had a significantly more rapid onset of improvement and lower adverse events and attrition rates. In the 6-month maintenance period, patients continued short-term treatment. Patients receiving either alprazolam or imipramine developed tolerance to some side effects. At maintenance-phase completion, 62% of the alprazolam-group patients and 26% of both the imipramine- and placebo-group patients were panic free (p<0.01). Dosages were tapered to zero over 3 weeks; one third of the alprazolam patients could not discontinue. During the unblinded, 15-month follow-up, patients received open treatment selected by personal physicians on an as-needed basis. At the end of follow-up, all patients were reassessed. Patients who had completed both short-term and maintenance phases were far more likely to be panic-free (85% vs. 55%; p<0.01). PD is chronic and recurrent, and 8 months is an effective treatment period. Maintenance treatment does not lead to tolerance, even with benzodiazepines. Dose tapering must be very gradual. Completion of a long-term maintenance program strongly predicts remission.

The clinical course and long-term management of generalized anxiety disorder

&NA; Evidence suggests that generalized anxiety disorder (GAD) has a fairly chronic course marked by significant long‐term distress and comorbidity. Research has focused on short‐term treatment of GAD, and long‐term outcome studies after either short‐ or long‐term treatment have been relatively neglected. The authors discuss the benefits and risks of various drug and nondrug therapies used in the long‐term management of generalized anxiety disorder and suggest avenues for future research.

Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy : effects on withdrawal symptoms and taper outcome

Abstract Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19 ± 17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1–2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (χ2 = 7.34; df 2; P < 0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches.

Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

This randomized, double-blind clinical trial involving 198 generalized anxiety disorder (GAD) patients was conducted to more clearly define gepirones role for the treatment of anxiety in daily dosages of 10 to 45 mg compared with diazepam and placebo. A secondary goal was to test for possible discontinuation symptoms after abrupt discontinuation of therapy. After a 1-week washout period, patients were treated for 8 weeks and then abruptly shifted under single-blind conditions for 2 weeks on placebo. The highest attrition rate occurred with patients on gepirone (58%) and the lowest on diazepam (34%). Medication intake for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5 mg/day gepirone and was similar at week 8. The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam. Clinical improvement data showed gepirones anxiolytic response to be delayed, being significant from placebo beginning at week 6, whereas diazepam caused significantly more relief than placebo from week 1 onward. Taper results showed that only diazepam, but not gepirone, caused a temporary worsening of anxiety symptoms or rebound.