This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Asberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, -12.3 to -4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.
Objectives-Cigarette smoking may influence rheumatoid arthritis (RA) disease incidence and may have direct biological eVects on the lungs and systemically. This study sought to determine if cigarette smoking is associated with RA disease severity. Methods-Clinical evaluations of patients seen in the University of Iowa rheumatology and orthopaedic ambulatory clinics were conducted. A letter of interest was mailed to 1701 patients who were first assigned an ICD-9-CM diagnostic code for RA in one of these clinics. A total of 857 patients expressed interest and were oVered a clinical examination and 395 were evaluated over an 18 month period. Of these, 336 satisfied examiner criteria for prevalent RA and were included in the analysis. The disease characteristics and arthritis care utilisation of these patients seemed representative of prevalent cases in the general community. RA disease severity was assessed by radiographic bone erosions (graded as either present/ absent and using the Larsen system), rheumatoid factor seropositivity, and presence of subcutaneous rheumatoid nodules. Results-Pack years of cigarette smoking was significantly associated with rheumatoid factor seropositivity (p = 0.0001), radiographic erosions (p = 0.024), and nodules (p = 0.051). After adjustment for potential confounders, smokers with ≥25 pack years were 3.1 times more likely to be rheumatoid factor positive (95% CI 1.7, 5.6) and 2.4 times more likely to show radiographic erosions (95% CI 1.2, 4.5) than never smokers. Less severe radiographic disease seemed to be more strongly associated with cigarette smoking than more severe disease. Conclusion-Cigarette smoking may adversely influence the severity of RA in a potentially dose dependent fashion.
Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.
Objective. To determine the prevalence and important clinical predictors of radiographic and physiologic abnormalities indicative of rheumatoid arthritis interstitial lung disease (RA-ILD).Methods. An unselected cohort of patients with a confirmed diagnosis of RA and known lung disease were identified (n = 336) and evaluated for RA disease activity and seventy. Outcomes included abnormalities determined by the pulmonary function tests of forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLco), and/or chest radiographic findings of interstitial infiltrates. We used multivariable statistical modeling to determine the independent significance of cigarette smoking and other RA-specific factors on the pulmonary abnormalities of interest.Results. At least 1 of the 3 abnormal findings was identified by pulmonary tests in 32.4% of all patients. These abnormal findings included an FVC <80% of predicted in 42 patients, a DLco <80% of predicted in 64 patients, and evidence of radiographic interstitial infiltrates in 40 patients. After statistical adjustment for confounding factors, pack-years of cigarette smoking remained a significant predictor of low DLco (p = Submitted for publication January 22, 1996; accepted in revised form May 2, 1996. interstitial abnormalities on chest radiograph (odds ratio for 2 2 5 pack-years = 3.76,95% CI 1.59,8.88). The Health Assessment Questionnaire (HAQ) Disability Index (DI) was also an important risk factor for the decline in both the DLco ( p = -1.15, 95% CI -2.00, -0.30) and FVC ( p = -0.23, 95% CI -032, -0.13).-
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