Richard C. Veith

Depression, the autonomic nervous system, and coronary heart disease.

Depression is a risk factor for medical morbidity and mortality in patients with coronary heart disease (CHD). Dysregulation of the autonomic nervous system (ANS) may explain why depressed patients are at increased risk. Studies of medically well, depressed psychiatric patients have found elevated levels of plasma catecholamines and other markers of altered ANS function compared with controls. Studies of depressed patients with CHD have also uncovered evidence of ANS dysfunction, including elevated heart rate, low heart rate variability, exaggerated heart rate responses to physical stressors, high variability in ventricular repolarization, and low baroreceptor sensitivity. All of these indicators of ANS dysfunction have been associated with increased risks of mortality and cardiac morbidity in patients with CHD. Further research is needed to determine whether ANS dysfunction mediates the effects of depression on the course and outcome of CHD, and to develop clinical interventions that improve cardiovascular autonomic regulation while relieving depression in patients with CHD. ANS = autonomic nervous system; CHD = coronary heart disease; HRV = heart rate variability; MI = myocardial infarction; NE = norepinephrine; SNS = sympathetic nervous system.

Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study

Objective: The Enhancing Recovery in Coronary Heart Disease study was a multicenter clinical trial in which patients with depression and/or low perceived social support after an acute myocardial infarction were randomly assigned to an intervention consisting of cognitive behavior therapy and, in some cases, sertraline, or to usual care. There was no difference in survival between the groups. A possible reason why the intervention failed to affect survival is that too many patients with mild, transient depression were enrolled. Another is that some patients died too soon to complete the intervention. This analysis evaluates whether there was a difference in late (ie, ≥6 months after the myocardial infarction) mortality among initially depressed patients who had a Beck Depression Inventory score ≥10 and a past history of major depression, and who completed the 6-month post-treatment assessment. It also examines the relationship between change in depression and late mortality. Methods: Out of the 1,165 (47%) of the Enhancing Recovery in Coronary Heart Disease study participants who met our criteria, 57 died in the first 6 months, and 858 (409 usual care, 449 intervention) completed the 6-month assessment. Cox regression was used to analyze survival. Results: The intervention did not affect late mortality. However, intervention patients whose depression did not improve were at higher risk for late mortality than were patients who responded to treatment. Conclusions: Patients whose depression is refractory to cognitive behavior therapy and sertraline, two standard treatments for depression, are at high risk for late mortality after myocardial infarction.

High-dose estradiol improves cognition for women with AD Results of a randomized study

Objective: To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. Methods: Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17β-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. Results: Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. Conclusions: Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: Results of a placebo-controlled, double-blind, pilot study.

Preliminary evidence from clinical studies indicates that treatment with estrogen augments cognitive function for women with Alzheimers disease (AD). The neurobiology of estrogen, particularly its neuromodulatory and neuroprotective actions, provide a viable basis to support such cognition-enhancing effects. We conducted a placebo-controlled, double-blind, parallel-group design pilot clinical study to evaluate the cognitive and neuroendocrine response to estrogen administration for postmenopausal women with AD. Twelve women with probably AD of mild-moderate severity completed the study. During an eight week treatment period, six women received 0.05 mg/day dosage of 17 beta-estradiol via a skin patch and the remaining six wore a placebo skin patch. Subjects were randomized to equal distribution, and evaluated at baseline, at weeks 1, 3, 5, and 8 on treatment, and at weeks 9, 10, 11, and 13 off treatment. On each day of evaluation, cognition was assessed using a battery of neuropsychological tests, and blood samples were collected to measure plasma concentrations of estradiol and estrone. In addition, several neuroendocrine markers were measured in plasma to evaluate the relationship between estrogen-induced cognitive effects and fluctuations in the catecholaminergic and insulin-like growth factor systems. Significant effects of estrogen treatment were observed on attention (i.e. Stroop: number of self-corrections in the Interference condition, F[1,8] = 8.22, P < 0.03) and verbal memory (i.e., Buschke: delayed cued recall, F[3,30] = 4.31, P < 0.02). The salutary effects of estrogen on cognition were observed after the first week of treatment, and started to diminish when treatment was terminated. For women treated with estrogen, enhancement in verbal memory was positively correlated with plasma levels of estradiol (r = 0.96, P < 0.02) and negatively correlated with concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) in plasma (r = -0.92, P < 0.03). Furthermore, a trend in the data was evident to suggest a negative relationship between plasma levels of insulin-like growth factor-1 (IGF-1) and verbal memory (r = -0.86, P = 0.06). Estrogen administration suppressed peripheral markers of the IGF system, as evidenced by a negative correlation between plasma concentration of estradiol and IGF-1 (r = -0.93, P < 0.03), and a trend for a similar relationship between plasma levels of estradiol and IGFBP-3 (r = -0.86, P = 0.06). With respect to the catecholamines assayed, norepinephrine was positively correlated with verbal memory (r = 0.95, P < 0.02) for women who were treated with estrogen. Furthermore, there was a trend to suggest a negative relationship between plasma epinephrine levels and the number of errors committed on a test of attention (r = -0.84, P = 0.07). In the placebo group, no significant effects of estrogen replacement were evident either on measures of cognition or on any of the neuroendocrine markers. The results of this study suggest that estrogen replacement may enhance cognition for postmenopausal women with AD. Furthermore, several markers of neuroendocrine activity may serve to index the magnitude of estrogen-induced facilitation on cognition. In addition, research findings from the present study will provide important information for the design of larger prospective clinical studies that are essential to definitively establish the therapeutic role of estrogen replacement for postmenopausal women with AD.

Symptomatic depression in elderly medical outpatients. I. Prevalence, demography, and health service utilization

The authors assessed the prevalence and demography of depressive symptoms, their association with specific chronic diseases, and their influence on health service use in a large sample of elderly men seen in a primary care setting. Twenty‐four percent of respondents reported clinically significant depressive symptoms; the prevalence of major depressive disorders was estimated at 10%, but only 1 % reported receiving mental health treatment by a specialist. Self‐reported marital separation or divorce and physical disability affecting employment were strongly associated with high depression scores, whereas the normative stresses of aging (widowhood, retirement, social isolation) were not. Only chronic lung disease was differentially associated with high depression scores, and this effect was weak. The authors discuss the implications of these findings for the design of comprehensive health services for the elderly with chronic disease.

The Depression Interview and Structured Hamilton (DISH): Rationale, development, characteristics, and clinical validity

Objective The Depression Interview and Structured Hamilton (DISH) is a semistructured interview developed for the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study, a multicenter clinical trial of treatment for depression and low perceived social support after acute myocardial infarction. The DISH is designed to diagnose depression in medically ill patients and to assess its severity on an embedded version of Williams’ Structured Interview Guide for the Hamilton Depression scale (SIGH-D). This article describes the development and characteristics of the DISH and presents a validity study and data on its use in ENRICHD. Methods In the validity study, the DISH and the Structured Clinical Interview for DSM-IV (SCID) were administered in randomized order to 57 patients. Trained interviewers administered the DISH, and clinicians administered the SCID. In ENRICHD, trained research nurses administered the DISH and recorded a diagnosis. Clinicians reviewed 42% of the interviews and recorded their own diagnosis. The Beck Depression Inventory (BDI) was administered in both studies. Results In the validity study, the SCID diagnosis agreed with the DISH on 88% of the interviews (weighted &kgr; = 0.86). In ENRICHD, the clinicians agreed with 93% of the research nurses’ diagnoses. The BDI and the Hamilton depression scores derived from the DISH in the two studies correlated 0.76 (p < .0001) in the validity study and 0.64 (p < .0001) in ENRICHD. Conclusions These findings support the validity of the DISH as a semistructured interview to assess depression in medically ill patients. The DISH is efficient in yielding both a DSM-IV depression diagnosis and a 17-item Hamilton depression score.

Cardiovascular Effects of Tricyclic Antidepressants in Depressed Patients with Chronic Heart Disease

Twenty-four depressed patients with heart disease were treated for four weeks in a double-blind trial of imipramine, doxepin, or placebo to assess the effects of tricyclic antidepressants on ventricular function and rhythm. The tricyclic antidepressants had no effect on left ventricular ejection fraction at rest or during maximal exercise, as measured by radionuclide ventriculograms obtained before and after treatment. Premature ventricular contractions were reduced by imipramine but were not consistently changed by doxepin or placebo. Treatment with imipramine and doxepin, but not placebo, was associated with significant improvement (P less than 0.001) in standard ratings of depression. Our findings underscore the need for a reappraisal of the cardiovascular risks of tricyclic antidepressants and suggest that in the absence of severe impairment of myocardial performance, depressed patients with preexisting heart disease can be effectively treated with these agents without an adverse effect on ventricular rhythm or hemodynamic function.

Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease

BACKGROUND Although it is now well established that psychiatric depression is associated with adverse outcomes in patients with coronary heart disease (CHD), the mechanism underlying this association is unclear. Elevated heart rate (HR) and plasma norepinephrine (NE), possibly reflecting altered autonomic nervous system activity, have been documented in medically well depressed psychiatric patients, and this pattern is associated with increased risk for cardiac events in patients with CHD. The purpose of this study was to determine whether autonomic nervous system activity is altered in depressed CHD patients. METHODS HR, plasma NE, and blood pressure (BP) were measured in 50 depressed and 39 medically comparable nondepressed CHD patients at rest and during orthostatic challenge. RESULTS Resting HR (p = .005), and the change from resting HR at 2, 5, and 10 min after standing (p = .02, .004, and .02, respectively), were significantly higher in the depressed than in the nondepressed patients. There were no differences between the groups in NE or in BP at rest, or in standing minus resting change scores at any time during orthostatic challenge (p < .05). CONCLUSIONS Depression is associated with altered autonomic activity in patients with CHD, as reflected by elevated resting HR and an exaggerated HR response to orthostatic challenge. Previously reported differences in NE levels between depressed and nondepressed patients were not replicated.

Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra.

The hormone insulin can down-regulate the function and synthesis of the re-uptake transporter for norepinephrine (NET) in vivo and in vitro. In the present study we tested whether this action of insulin is generalized to another member of the catecholamine transporter family. We determined the level of dopamine transporter (DAT) mRNA expression in the ventral tegmental area (VTA)/substantia nigra compacta (SNc) of rats which were chronically treated with vehicle or insulin via the third cerebral ventricle (i.c.v.). DAT mRNA was significantly elevated in the VTA/SNc of rats treated with insulin, as compared with levels in vehicle-treated rats. This is in contrast to our previous observation that i.c.v. insulin decreases NET mRNA in the rat locus coeruleus, and suggests that insulin may have differential and specific modulatory effects on CNS catecholaminergic pathways.

Screening for Depression in Hospitalized Geriatric Medical Patients

As part of an effort to improve the detection of depression in geriatric hospitalized medical patients, the validity of two self‐rating depression scales, the Zung Self‐rating Depression Scale (SDS) and the Popoff Index of Depression (ID), was evaluated. These two scales were completed by 42 medical inpatients whose mean age was 68 years. A psychiatrist who was “blind” to scale results interviewed each patient and diagnosed the presence or absence of depression according to the Diagnostic and Statistical Manual‐III (DSM‐III) criteria for Major Depressive Episode. On both the SDS and the ID, there was significant agreement between the scale results and the interview diagnosis. Compared with the interview diagnosis, the SDS had a sensitivity of 58 per cent and a specificity of 87 per cent, and it correctly identified 74 per cent of the patients as being either depressed or nondepressed. The ID had a sensitivity of 88 per cent and a specificity of 52 per cent, and it correctly identified 66 per cent of the patients. Although performance on both scales is reduced compared with that of younger depressed patients, these self‐rating scales appear to be useful aids for the detection of depression in geriatric medical patients.