Jay B. Cohn

Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms. A meta-analysis of eight randomized, controlled studies.

This report presents the results of a retrospective analysis of pooled efficacy data from eight studies in which buspirone was compared to placebo in 520 patients with generalized anxiety disorder (GAD). In addition to evaluating overall efficacy in the composite patient data base, four criteria were used to identify subsets of patients with GAD who had coexisting depressive symptoms of at least moderate intensity: (1) a score of > or = 2 on the Hamilton Anxiety (HAM-A) Rating Scale item 6 (depressed mood), (2) a score of > or = 2 on the Hamilton Depression (HAM-D) Rating Scale item 1 (depressed mood), (3) a HAM-D total score of > or = 18, or (4) a HAM-D Retardation Factor value (items 1, 7, 8, and 14) greater than the median for the group. Overall, patients treated with buspirone demonstrated significant (p < or = 0.001) improvement over baseline in total HAM-A scores compared to patients who received placebo. Buspirone also produced significant (p < or = 0.001) global improvement compared to placebo as assessed by the attending physician. Of the GAD patients stratified according to the four criteria for coexisting depressive symptoms, a substantial percentage (44-64%) of the total patient sample exhibited significant depressive symptoms as part of their anxiety disorder. Patients with GAD and coexisting depressive symptoms of at least moderate intensity exhibited significantly greater improvement with buspirone compared to placebo treatment regardless of the stratification criterion used. They also responded at least as well or better to buspirone therapy as did those with GAD who had less intense depressive symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of buspirone and clorazepate in anxious outpatients

Buspirone, a new nonbenzodiazepine anxiolytic agent, was compared with clorazepate in a double-blind, multicenter trial conducted with 336 outpatients who had moderate to severe anxiety. The two treatments were equally effective for relief of symptoms, including anxiety with associated depression. Although both agents were generally well tolerated, the profile of side effects was dissimilar. Drowsiness and depression occurred significantly (p less than 0.055) more frequently with clorazepate, whereas nausea and headache occurred significantly (p less than 0.055) more frequently with buspirone. Clorazepate-treated patients were significantly (p less than 0.055) more likely to have had an adverse experience that was considered drug related or that interfered with the therapeutic effect. In this study, buspirone was shown to be an effective antianxiety agent, causing significantly less sedation than clorazepate.

The Oral Dose-Effect Relationship for Fluvoxamine: a Fixed-Dose Comparison Against Placebo in Depressed Outpatients

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

Analysis of Individual Symptoms in Generalized Anxiety – A Pooled, Multistudy, Double-Blind Evaluation of Buspirone

Pooled data for 427 patients with generalized anxiety disorders were analyzed retrospectively from six double-blind trials evaluating buspirone, a nonbenzodiazepine anxiolytic, in the treatment of generalized anxiety disorder. After a 4- to 7-day washout period, patients were allocated at random to receive treatment over a 4-week period. Buspirone dose ranged from 10 to 60 mg. Patients were assessed on entry and at weekly intervals using the 14 symptom groups (items) of the Hamilton Anxiety Rating Scale (HAM-A). Buspirone improved all symptom groups significantly; onset of anxiolytic activity was observed at week 1 in 3 groups of psychic symptoms of anxiety. Within 2 weeks, 8 of the 14 symptom groups were improved significantly by buspirone versus placebo, and symptoms of anxiety improved further up to the 4-week end point. Psychic symptoms of anxiety improved earlier in general than the somatic symptoms of anxiety. At the end of treatment, analyses of the HAM-A scores indicated that all of the 14 symptom groups (individual items), the total HAM-A score, and the 2 composite Psychic and Somatic Anxiety Factors were significantly improved with buspirone as compared to placebo. The beneficial effects of buspirone were not compromised by any significant side effects.

Long-Term Comparison of Alprazolam, Lorazepam and Placebo in Patients with an Anxiety Disorder

In a double‐blind, placebo‐controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam. Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam. The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg. Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale, with a trend toward more improvement in the alprazolam group in the later weeks of the study. Target Symptoms, Physicians and Patients Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo. The major side effects were sedation and drowsiness; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo. An overall rating of side effect severity was not significantly different among the three groups.

Hypnotic Efficacy of Estazolam Compared with Flurazepam in Outpatients with Insomnia

Eslazolam is a new benzodiazepine hypnotic agent with an intermediate half‐life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double‐blind, placebo‐controlled, multicenter, 7‐night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Neuroendocrine effects of buspirone in patients with generalized anxiety disorder

This study investigated a therapeutic regimen of buspirone, a new anxioselective drug, in patients with generalized anxiety disorder. The single-blind study, conducted in 23 outpatients, consisted of 28 days of buspirone treatment followed by four days of placebo treatment. Patients received a single 10-mg dose of buspirone on study day one, which was titrated to 10 mg three times daily by study day seven and which remained at 10 mg three times daily through study day 28. Blood samples were drawn on days one, 14, 28, and 32 for determination of plasma levels of prolactin, growth hormone, and cortisol. The therapeutic effect of buspirone was assessed by standard psychometric rating scales. When titrated to a total daily dose of 30 mg per day (10 mg three times daily), buspirone provided effective antianxiety therapy and had no significant effect on plasma levels of prolactin, growth hormone, or cortisol.

Development of an early detection battery for dementia of the Alzheimer type

1. To develop a diagnostic battery sensitive to and specific for the early detection of Alzheimer disease (AD) dementia, the authors reviewed over 400 journal articles dealing with the diagnosis of A.D. or senile dementia and cognitive assessment in organic brain dysfunction and closed head injury. 2. We culled those studies that met our criteria for solid, reliable and statistically significant results and recommend the testing paradigms that most often produced good discrimination of mild AD dementia from normal senescence. 3. These include tests of language, verbal and non-verbal memory, perception, praxis, attention and reasoning. 4. The battery we assembled takes less than 1 hour to administer, requires no special equipment, and was designed as an early screen for use by psychologists, psychiatrists and other trained health care professionals; it is not intended for repeated administration, as in pharmacological or longitudinal studies.

Effect of bromocriptine mesylate on induced hyperprolactinemia in stabilized psychiatric outpatients undergoing neuroleptic treatment

Therapeutic doses of phenothiazines increased serum levels of prolactin, resulting in a number of side effects. Bromocriptine, a potent dopamine agonist, appears to effectively reduce the serum prolactin level. In this open pilot study, bromocriptine mesylate (Parlodel, Sandoz) was administered in an escalating dose schedule to 11 stabilized psychiatric outpatients with hyperprolactinemia resulting from thioridazine HCl (Mellaril, Sandoz) treatment. 6 of 9 patients showed decreases. Overall global psychiatric evaluations were unchanged over the course of combined therapy for all but 1 patient, who showed improvement. The trend of decreased prolactin serum levels indicates that bromocriptine mesylate may prove a useful adjunct to reduce the side effects of hyperprolactinemia.

Efficacy and safety of pentoxifylline in geriatric patients with intermittent claudication

The effects of pentoxifylline on intermittent claudication were evaluated at a dose of 1200 mg/day in an open-label twelve-week study on geriatric patients with chronic occlusive arterial disease (COAD). Standardized treadmill testing and clinical signs and symptoms of COAD were followed up before and during drug administration. Twenty-four subjects with a mean age of 73.5 years, capa ble of walking between 20 and 200 meters on the treadmill, were entered into the trial; 22 participated for eight weeks and 19 completed the study in terms of treadmill walking distance measurements at 12 weeks. The mean walking dis tance for all patients was increased 111% over baseline at week 12. Thirteen subjects were considered drug responders ( ≥ 50% increase in treadmill walking distance) and 9 were considered nonresponders (<50% increase). Improve ments in clinical signs and symptoms of COAD were noted. Decreases in ele vated systemic systolic pressures (but not diastolic) were unexpectedly observed in many drug responders. Seven of 19 males reported sexual function improve ments while receiving pentoxifylline. Fourteen (58%) of the 24 subjects reported mild side effects of dyspepsia, nausea, vomiting, dizziness, headache, or insom nia; no subjects were withdrawn from the study because of side effects. In sum mary, pentoxifylline improved function and symptoms in 13 of 22 geriatric patients with intermittent claudication; the drug was safe and well tolerated at the usual dosage in this geriatric patient population.