Antidepressants, autonomic function and mortality in patients with coronary heart disease: data from the Heart and Soul Study.

BACKGROUND: Antidepressants reduce depressive symptoms in patients with coronary heart disease, but they may be associated with increased mortality. This study aimed to examine whether the use of tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitors (SSRI) is associated with mortality in patients with coronary heart disease, and to determine whether this association is mediated by autonomic function. METHOD: A total of 956 patients with coronary heart disease were followed for a mean duration of 7.2 years. Autonomic function was assessed as heart rate variability, and plasma and 24-h urinary norepinephrine. RESULTS: Of 956 patients, 44 (4.6%) used TCA, 89 (9.3%) used SSRI, and 823 (86.1%) did not use antidepressants. At baseline, TCA users exhibited lower heart rate variability and higher norepinephrine levels compared with SSRI users and antidepressant non-users. At the end of the observational period, 52.3% of the TCA users had died compared with 38.2% in the SSRI group and 37.3% in the control group. The adjusted hazard ratio (HR) for TCA use compared with non-use was 1.74 [95% confidence interval (CI) 1.12-2.69, p = 0.01]. Further adjustment for measures of autonomic function reduced the association between TCA use and mortality (HR = 1.27, 95% CI 0.67-2.43, p = 0.47). SSRI use was not associated with mortality (HR = 1.15, 95% CI 0.81-1.64, p = 0.44). CONCLUSIONS: The use of TCA was associated with increased mortality. This association was at least partially mediated by differences in autonomic function. Our findings suggest that TCA should be avoided in patients with coronary heart disease.

The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.

PURPOSE: Lamotrigine (LTG), vigabatrin (VGB) and gabapentin (GBP) are three anti-epileptic drugs (AEDs) used in the treatment of children with epilepsy for which long-term retention rates are not currently well known. This study examines the efficacy, long-term survival and adverse event profile of these three agents used as add-on therapy in children with refractory epilepsy over a 10-year period. METHODS: Three separate audits were conducted between February 1996 and September 2000. All children studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure free or achieved >50% reduction in seizure frequency for 6 months or more after starting therapy. Adverse events and patient survival for each drug were recorded at the end of the study period. RESULTS: Between September 1990 and February 1996, 132 children received LTG, 80 VGB and 39 GBP. At the 10-year follow-up audit, 33% of the children on LTG had a sustained beneficial effect on their seizure frequency in contrast to 19% for VGB and 15% for GBP. No significant difference in efficacy was found in children with partial seizures. Children with epileptic encephalopathy (EE) including myoclonic-astatic epilepsy and Lennox-Gastaut Syndrome (LGS) achieved a more favorable response to LTG. The main reasons for drug withdrawal were lack of efficacy for VGB, apparent worsening of seizures for GBP and the development of a rash for LTG. CONCLUSIONS: Lamotrigine is a useful add-on therapy in treating children with epilepsy. It has a low adverse event profile and a sustained beneficial effect in children with intractable epilepsy.

Postmenopausal estrogen therapy and depressive symptoms in older women.

BACKGROUND: Evidence regarding the effect of postmenopausal estrogen therapy on mood is limited. METHODS: To determine whether postmenopausal estrogen therapy is associated with fewer depressive symptoms in elderly women, we conducted a cross-sectional study of 6, 602 white women ages 71 years or older who were recruited from population-based listings in Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley, Pa. Use of estrogen and progestin was determined by interview. Participants completed the Geriatric Depression Scale short form (GDS) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. RESULTS: A total of 6.3% (72/1,150) of current estrogen users, 7.2% (142/1,964) of past estrogen users, and 9.0% (313/3,488) of never users reported 6 or more symptoms of depression (P =.004). Current estrogen users had a decreased risk of reporting 6 or more depressive symptoms, compared with not current (past or never) users of estrogen (odds ratio [OR], 0.7; 95% CI, 0.5 to 0.9; P =.01], adjusted for living alone, bilateral oophorectomy, current smoking, physical activity, social network, self-perceived health, cognitive function, functional status, and antidepressant use. However, excluding women who use estrogen or progestin alone, we were unable to find an association between current use of combined estrogen plus progestin therapy and depressive symptoms (adjusted OR, 0.8; 95% CI, 0.5 to 1.4; P =.5). CONCLUSIONS: This cross-sectional study found that current use of unopposed estrogen was associated with a decreased risk of depressive symptoms in older women. Additional studies are needed to understand the effect of combined estrogen and progestin therapy on the prevalence of depressive symptoms in older women.

Randomized trial of case-finding for depression in elderly primary care patients.

OBJECTIVE: To determine the effect of case-finding for depression on frequency of depression diagnoses, prescriptions for antidepressant medications, prevalence of depression, and health care utilization during 2 years of follow-up in elderly primary care patients. DESIGN: Randomized controlled trial. SETTING: Thirteen primary care medical clinics at the Kaiser Permanente Medical Center, an HMO in Oakland, Calif, were randomly assigned to intervention conditions (7 clinics) or control conditions (6 clinics). PARTICIPANTS: A total of 2,346 patients aged 65 years or older who were attending appointments at these clinics and completed the 15-item Geriatric Depression Scale (GDS). GDS scores of 6 or more were considered suggestive of depression. INTERVENTIONS: Primary care physicians in the intervention clinics were notified of their patients' GDS scores. We suggested that participants with severe depressive symptoms (GDS score >/= 11) be referred to the Psychiatry Department and participants with mild to moderate depressive symptoms (GDS score of 6 -10) be evaluated and treated by the primary care physician. Intervention group participants with GDS scores suggestive of depression were also offered a series of organized educational group sessions on coping with depression led by a psychiatric nurse. Primary care physicians in the control clinics were not notified of their patients' GDS scores or advised of the availability of the patient education program (usual care). Participants were followed for 2 years. MEASUREMENTS AND MAIN RESULTS: Physician diagnosis of depression, prescriptions for antidepressant medications, prevalence of depression as measured by the GDS at 2-year follow-up, and health care utilization were determined. A total of 331 participants (14%) had GDS scores suggestive of depression (GDS >/= 6) at baseline, including 162 in the intervention group and 169 in the control group. During the 2-year follow-up period, 56 (35%) of the intervention participants and 58 (34%) of the control participants received a physician diagnosis of depression (odds ratio [OR], 1.0; 95% confidence interval [CI], 0.6 to 1.6; P =.96). Prescriptions for antidepressants were received by 59 (36%) of the intervention participants and 72 (43%) of the control participants (OR, 0.8; 95% CI, 0.5 to 1.2; P =.3). Two-year follow-up GDS scores were available for 206 participants (69% of survivors): at that time, 41 (42%) of the 97 intervention participants and 54 (50%) of the 109 control participants had GDS scores suggestive of depression (OR, 0.7; 95% CI, 0.4 to 1.3; P =.3). Comparing participants in the intervention and control groups, there were no significant differences in mean GDS change scores (-2.4 +/- SD 3.7 vs -2.1 SD +/- 3.6; P =.5) at the 2-year follow-up, nor were there significant differences in mean number of clinic visits (1.8 +/- SD 3.1 vs 1.6 +/- SD 2.8; P =.5) or mean number of hospitalizations (1.1 +/- SD 1.6 vs 1.0 +/- SD 1.4; P =.8) during the 2-year period. In participants with initial GDS scores > 11, there was a mean change in GDS score of -5.6 +/- SD 3.9 for intervention participants (n = 13) and -3.4 +/- SD 4.5 for control participants (n = 21). Adjusting for differences in baseline characteristics between groups did not affect results. CONCLUSIONS: We were unable to demonstrate any benefit from case-finding for depression during 2 years of follow-up in elderly primary care patients. Studies are needed to determine whether case-finding combined with more intensive patient education and follow-up will improve outcomes of primary care patients with depression.

Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Previous studies have suggested that depression is associated with falls and with low bone density, but it is not known whether depression leads to an increased risk of fracture. SUBJECTS AND METHODS: We conducted a prospective cohort study in elderly white women who were recruited from population-based listings in the United States. At a second visit (1988-1990), 7414 participants completed the 15-item Geriatric Depression Scale and were considered depressed if they reported 6 or more symptoms of depression. We measured bone mineral density (BMD) in the spine and hip using dual energy x-ray absorptiometry at the second visit, and asked participants about incident falls (yes/no) at 4 follow-up visits. Nonvertebral fractures were ascertained for an average of 6 years following the depression measure, and verified radiologically. We determined incident vertebral fractures by comparing lateral spine films obtained at the first visit (1986-1988) with repeat films obtained an average of 3.7 years later (1991-1992). RESULTS: The prevalence of depression (Geriatric Depression Scale score > or = 6) was 6.3% (467/7414). We found no difference in mean BMD of the hip and lumbar spine in women with depression compared with those without depression. Women with depression were more likely to experience subsequent falls than women without depression (70% vs 59%; age-adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9; P<.001), an association that persisted after adjusting for potential confounding variables (OR, 1.4; 95% CI, 1.1-1.8; P=.004). Women with depression had a 40% (age-adjusted hazard ratio [HR], 1.4; 95% CI, 1.2-1.7; P<.001) increased rate of nonvertebral fracture (124 fractures in 3805 woman-years of follow-up) compared with women without depression (1367 fractures in 59 503 woman-years of follow-up). This association remained strong after adjusting for potential confounding variables, including medication use and neuromuscular function (HR, 1.3; 95% CI, 1.1-1.6; P=.008). Further adjustment for subsequent falls appeared to explain part of this association (HR, 1.2; 95% CI, 1.0-1.5; P = .06). Women with depression were also more likely to suffer vertebral fractures than women without depression, adjusting for history of vertebral fracture, history of falling, arthritis, diabetes, steroid use, estrogen use, supplemental calcium use, cognitive function, and hip BMD (OR, 2.1; 95% CI, 1.4-3.2; P<.001). CONCLUSIONS: Depression is a significant risk factor for fracture in older women. The greater frequency of falls among individuals with depression partially explains this finding. Other mechanisms responsible for the association between depression and fracture remain to be determined.

Association between depressive symptoms and mortality in older women. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Major depression is associated with increased mortality, but it is not known whether patients who report depressive symptoms have greater mortality. SUBJECTS AND METHODS: We performed a prospective cohort study of 7518 white women 67 years of age or older who were recruited from population-based listings in Baltimore, Md, Minneapolis, Minn, Portland, Ore, and the Monongahela Valley, Pa. Participants completed the Geriatric Depression Scale (short form) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. Women were followed up for an average of 6 years. If a participant died, we obtained a copy of the official death certificate and hospital records, if available, and used International Classification of Diseases, Ninth Revision, codes to classify death attributable to cardiovascular, cancer, or noncancer, noncardiovascular cause. RESULTS: Mortality during 7-year follow-up varied from 7% in women with no depressive symptoms to 17% in those with 3 to 5 symptoms to 24% in those with 6 or more symptoms of depression (P<.001). Of 473 women (6.3%) with 6 or more depressive symptoms at baseline, 24% died (111 deaths in 2610 woman-years of follow-up) compared with 11% of women who reported 5 or fewer symptoms of depression (760 deaths in 41 460 woman-years of follow-up) (P<.001). Women with 6 or more depressive symptoms had a 2-fold increased risk of death (age-adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.75-2.61; P<.001) compared with those who had 5 or fewer depressive symptoms. This association remained strong after adjusting for potential confounding variables, including history of myocardial infarction, stroke, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, smoking, perceived health, and cognitive function (HR, 1.47; 95% CI, 1.14-1.88; P=.003). Depressive symptoms were associated with an increased adjusted risk of death from cardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.5; P= .003), and non-cancer, noncardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.7; P = .01), but were not associated with deaths from cancer (HR, 1.0; 95% CI, 0.6-1.7; P=.93). CONCLUSIONS: Depressive symptoms are a significant risk factor for cardiovascular and noncancer, noncardiovascular mortality but not cancer mortality in older women. Whether depressive symptoms are a marker for, or a cause of, life-threatening conditions remains to be determined.

Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study.

BACKGROUND: Though among the most abundant human steroid hormones, the physiologic role of dehydroepiandrosterone and its sulfate (DHEAS) is not known. Our goal was to determine if DHEAS is associated with cognition and mood in older women, and if baseline DHEAS levels are predictive of cognitive decline. METHODS: In a prospective cohort, we studied 394 randomly selected community-dwelling women, aged 65 years or older, currently enrolled in the Study of Osteoporotic Fractures. Subjects were administered a modified Mini-Mental State Exam, Trials B, Digit Symbol, and the Geriatric Depression Scale-Shortened (GDSS), at study onset and 4-6 years later. Serum was obtained at study initiation for DHEAS analysis. RESULTS: DHEAS levels declined with age, as expected. There was no consistent association of DHEAS quartile or log DHEAS with any of the four outcomes, even after multivariate adjustment. Change in cognitive performance overtime was not associated with DHEAS levels. Analysis of the 32 women without any detectable DHEAS compared to those with detectable levels revealed higher measures on the GDSS (mean score 3.4 +/- 3.6 compared with 1.6 +/- 2.3, p = .028) and a higher percentage with depression (21.7% compared with 4.6%, p = .001). CONCLUSIONS: Serum DHEAS is not a sensitive predictor of cognitive performance or decline on a selected neuropsychological battery in elderly community women; however, nondetectable levels may be associated with depression.

Case-finding instruments for depression. Two questions are as good as many.

OBJECTIVE: To determine the validity of a two-question case-finding instrument for depression as compared with six previously validated instruments. DESIGN: The test characteristics of a two-question case-finding instrument that asks about depressed mood and anhedonia were compared with six common case-finding instruments, using the Quick Diagnostic Interview Schedule as a criterion standard for the diagnosis of major depression. SETTING: Urgent care clinic at the San Francisco Department of Veterans Affairs Medical Center. PARTICIPANTS: Five hundred thirty-six consecutive adult patients without mania or schizophrenia. MEASUREMENTS AND MAIN RESULTS: Measurements were two questions from the Primary Care Evaluation of Mental Disorders patient questionnaire, both the long and short forms of the Center for Epidemiologic Studies Depression Scale, both the long and short forms of the Book Depression Inventory, the Symptom-Driven Diagnostic System for Primary Care, the Medical Outcomes Study depression measure, and the Quick Diagnostic Interview Schedule. The prevalence of depression, as determined by the standardized interview, was 18% (97 of 536). Overall, the case-finding instruments had sensitivities of 89% to 96% and specificities of 51% to 72% for diagnosing major depression. A positive response to the two-item instrument had a sensitivity of 96% (95% confidence interval [CI], 90-99%) and a specificity of 57% (95% CI 53-62%). Areas under the receiver operating characteristic curves were similar for all of the instruments, with a range of 0.82 to 0.89. CONCLUSIONS: The two-question case-finding instrument is a useful measure for detecting depression in primary care. It has similar test characteristics to other case-finding instruments and is less time-consuming.

Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis.

OBJECTIVE: To estimate the risk of myocardial infarction (MI) and death in patients with unstable angina who are treated with aspirin plus heparin compared with patients treated with aspirin alone. DATA SOURCES: Studies were retrieved using MEDLINE, bibliographies, and consultation with experts. STUDY SELECTION: Only published trials that enrolled patients with unstable angina, randomized participants to aspirin plus heparin vs aspirin alone, and reported incidence of myocardial infarction or death were included in the meta-analysis. DATA EXTRACTION: Patient outcomes including MI or death, recurrent ischemic pain, and major bleeding during randomized treatment; revascularization procedures after randomization; and MI or death during the 2 to 12 weeks following randomization were extracted by 2 authors, 1 of whom was blinded to the journal, institution, and author of each study. DATA SYNTHESIS: Six randomized trials were included. The overall summary relative risk (RR) of MI or death during randomized treatment was 0.67 (95% confidence interval [CI], 0.44-1.02) in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The summary RRs for secondary endpoints in patients treated with aspirin plus heparin compared with those treated with aspirin alone were 0.68 (95% CI, 0.40-1.17) for recurrent ischemic pain; 0.82 (95% CI, 0.56-1.20) for MI or death 2 to 12 weeks following randomization; 1.03 (95% CI, 0.74-1.43) for revascularization; and 1.99 (95% CI, 0.52-7.65) for major bleeding. We found no statistically significant heterogeneity among individual study findings. CONCLUSIONS: Our findings are consistent with a 33% reduction in risk of MI or death in patients with unstable angina treated with aspirin plus heparin compared with those treated with aspirin alone. The bulk of evidence suggests that most patients with unstable angina should be treated with both heparin and aspirin.

Effect of substrate on the regulation of exoprotease production by Pseudomonas aeruginosa ATCC 10145.

Exoprotease production by Pseudomonas aeruginosa ATCC 10145 was growth-associated when cultures were grown on complex substrates such as proteins but it occurred during the decelerating growth phase when the organism was grown on amino acids, mixtures of amino acids or simple carbon sources. NH4Cl and simple carbon sources caused repression. Exoprotease was produced in chemostat cultures in response to growth under any of the nutrient limitations studied (carbon, nitrogen or phosphate). Furthermore, by growing at rates less than approximately 0.1 h-1, the repression of enzyme production could be overcome to a large degree. At low growth rates there was an inverse relationship between growth rate and exoprotease production. Thus, exoprotease production was depressed by available energy sources and was increased in response to any nutrient limitation.

The protonmotive force in Pseudomonas aeruginosa and its relationship to exoprotease production.

In Pseudomonas aeruginosa ATCC 10145 a negative correlation was observed between the protonmotive force (delta P) and the amount of exoprotease produced, with a decrease in delta P resulting in an increase in exoprotease. The two components of delta P, the transmembrane pH gradient (delta pH) and the membrane potential (delta psi) were examined independently and it was observed that delta psi varied very little under the conditions which influenced the activities of exoprotease. However, a positive correlation existed between pH and exoprotease production although the intracellular pH varied very little with either changes in growth rate or changes in extracellular pH. It was observed that with a decrease in growth rate, delta pH became more alkaline and increased exoprotease activities were recorded. Furthermore, an increase in extracellular pH to give an artificial alteration in delta pH, and, consequently, a decrease in delta P, increased exoprotease production, thus confirming the importance of delta pH in exoprotease production.