Measuring disability in subjects with anxiety disorders.

Subjects with anxiety disorders display substantial disabilities in health-related quality of life. The Sheehan Disability Scale (SDS) and SF-36 Questionnaire (SF-36) have been administered to subjects with anxiety disorders participating in psychopharmacology clinical trials and observational studies to evaluate their impaired functioning. The SDS does not address and does not include all the disabilities important to subjects with anxiety disorders and susceptible to being affected by drugs with anxiolytic effects, all of which are associated with significant problems. As a single-state-in-time rating, the SDS is often inadequate to discern subtle, but important,changes which may occur between measurements. The SF-36 as a measure of health status can, on the other hand, assess only the patient's behavior most directly affected by the disorder and treatment. As a result, the SF-36 enables the differentiation of functioning and well-being of subjects with anxiety disorders from diverse populations. There is little documentary evidence that demonstrates the value and actual performance of the SDS and SF-36 for the intended purpose. In the absence of a general consensus concerning operational definition, the measurement of disability in this patient population with these scales may be obsolete. There is the need for more specific and simple instruments capable to assess the distinct pattern of impairment associated with subjects with anxiety disorders.

Key considerations for long-term studies with anxiolytics.

Long-term (minimum six months) safety and efficacy studies with an anti-anxiety agent are aimed at identifying the emergence of any clinical effects not observed during shorter periods of treatment including the identification of late occurring adverse events, loss of therapeutic benefit, or post-treatment withdrawal effects. There is the need to establish diagnostic criteria for persistent anxiety for patients who truly benefit from long-term therapy. Risk factors predisposing to drug dependence should be assessed prior to continuous use. Ideally, long-term continuous studies should be blinded, comparative and placebo-controlled, with an adequate duration of the withdrawal phase. The treatment response of the elderly in comparison to the overall patient sample should be emphasised.

Buspirone therapy in anxious elderly patients: a controlled clinical trial.

Forty patients over 65 years of age with anxiety symptoms due to an anxiety state (N = 20) or secondary to neurotic depression (N = 20) took part in a double-blind, placebo-controlled trial conducted in a primary care practice. All patients were receiving concomitant drug therapy for chronic medical conditions; 70% were receiving two or more nonpsychotropic drugs in addition to the study medication. Patients were randomly assigned to treatment with buspirone 5-30 mg/day or placebo for 4 weeks, with clinical evaluations made weekly. One buspirone-treated and two placebo-treated patients discontinued treatment after 2 weeks because of lack of efficacy. Buspirone treatment resulted in significantly greater (p less than or equal to 0.05) improvement on the Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinical Global Impression assessment than did placebo. Mild adverse experiences were reported by five buspirone-treated and nine placebo-treated patients. Buspirone (mean dose, 18 mg/day) proved equally effective for elderly patients suffering anxiety states or neurotic depression at doses similar to those used in younger patients, and was well tolerated by elderly patients receiving treatment for other chronic medical conditions.

A double-blind comparison of buspirone, clobazam, and placebo in patients with anxiety treated in a general practice setting.

Sixty patients being treated for anxiety in a primary care facility received (double-blind) buspirone, the benzodiazepine drug clobazam, or placebo for 3 weeks. The mean daily dose at the end of treatment was 23 mg for buspirone and 21 mg for clobazam. Patients were assessed weekly using the Hamilton Rating Scale for Anxiety and Clinical Global Impression scale. Both active treatments produced significant improvement in anxiety symptoms compared with placebo as early as the first week of treatment, and there was progressive improvement over the subsequent 2 weeks. Response to buspirone was equally favorable in anxious patients who experienced depressive symptomatology.

Clinical pharmacokinetics of oral buspirone in patients with impaired renal function.

12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p less than 0.05) greater pharmacokinetic median values: half-life (t 1/2) = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L.h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.

Buspirone pharmacokinetics in patients with cirrhosis.

The pharmacokinetics of a single oral dose of buspirone (20 mg) were determined in 12 patients with cirrhosis and 12 normal subjects. The mean AUC of buspirone was 55 +/- 38 s.d. ng ml-1 h in cirrhotics and 3.5 +/- 2.4 s.d. ng ml-1 h in normals. The time until maximum concentration (tmax) attained was similar in the two groups (0.6 vs 0.7 h), but mean maximum concentration Cmax was higher in patients (18.8 +/- 16.3 s.d. ng ml-1) than in normals (1.2 +/- 0.8 s.d. ng ml-1). Mean elimination half-life of buspirone was greater in cirrhotics, but this difference was marginally significant statistically (cirrhotics, 6.1 +/- 3.5 s.d. h, normals 3.2 +/- 1.5 s.d. h, P = 0.05). Eight of 12 patients and seven of 12 normal subjects had a second peak in the plasma concentrations of buspirone. In patients this occurred at 10.8 +/- 7.4 s.d. h after the dose, and its mean concentration was 3.1 +/- 6.6 ng ml-1. In normal subjects the second peak occurred at 4.3 +/- 2.1 h after the dose and its mean concentration was 0.5 +/- 0.3 ng ml-1. On the kinetic evidence buspirone should be used with caution in liver disease.

Comparative efficacy of etodolac and placebo in rheumatoid arthritic patients.

Twenty-four patients with active rheumatoid arthritis were studied in a 4-week double-blind, placebo-controlled, parallel group trial. They were treated with a low dose (25, 50, and 100 mg twice daily) or high dose (100, 200, or 300 mg twice daily) of etodolac or with placebo. In both groups four patients received placebo and eight the active drug in a fixed-titration regimen. Doses were increased weekly and kept at the highest level during the last 2 weeks. Clinical and laboratory assessments were completed before drug and on days 8, 15, and 29. Seventeen patients completed 29 days and seven discontinued the study earlier: six on placebo and one on low dose. Etodolac-low dose was significantly more effective than placebo in nine of ten clinical assessments and in all ten at high dose. Etodolac was well tolerated. All patients had negative tests for occult blood at all times. Etodolac was an effective anti-inflammatory agent and appeared to be safe in doses of 50-600 mg per day.