Family history of depression and therapeutic outcome: findings from STAR*D.

OBJECTIVE: It is unclear whether a positive family history of depression affects the clinical presentation or effectiveness of treatment for major depressive disorder (MDD). We aimed to determine whether depressed patients with a positive family history of depression differed from those without in terms of baseline sociodemographic and clinical characteristics, including concurrent comorbid conditions and treatment outcome with citalopram in a large, multicenter effectiveness trial. METHOD: Clinical outcome and sociodemographic information were collected on 2876 participants with DSM-IV MDD enrolled from July 2001 through April 2004 in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Participants with and without a family history of depression, as determined by self-report at initial assessment, were compared. RESULTS: Over half (55.6%) (1585/2853) of the evaluable sample reported a positive family history of depression. A positive family history of depression was associated with an earlier age at onset of MDD, a longer length of illness, and more comorbid generalized anxiety disorder and prior suicide attempts. These participants had a slightly faster onset of remission, and slightly greater side effect burden, but they did not differ overall in response or remission rates. CONCLUSIONS: A family history of depression was associated with several clinical characteristics, although its usefulness as a predictor of treatment outcome is questionable. The slightly faster remission with an SSRI despite the slightly greater side effect burden indicates the effectiveness of using an SSRI in treating depressed patients both with and without a family history of depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528.

Acute cardiac allograft rejection in nitric oxide synthase-2(-/-) and nitric oxide synthase-2(+/+) mice: effects of cellular chimeras on myocardial inflammation and cardiomyocyte damage and apoptosis.

BACKGROUND: The contribution of nitric oxide synthase (NOS)-2 to myocardial inflammation and cardiomyocyte necrosis and apoptosis during allograft rejection was investigated through heterotopic cardiac transplantation in mice. METHODS AND RESULTS: In the first experiments, hearts from C3H donor mice were transplanted into NOS-2(-/-) and NOS-2(+/+) C57BL/6J.129J recipients. A second series of experiments included NOS-2(-/-) donor hearts transplanted into NOS-2(-/-) recipients and wild-type NOS-2(+/+) donor hearts transplanted into wild-type NOS-2(+/+) recipients. (All donors were C57BL/6J and recipients were C57BL/6J.129J.) In the first series of experiments, no significant differences were observed in allograft survival, rejection score, total number of apoptotic nuclei (TUNEL), total number of apoptotic cardiomyocytes, or graft NOS-2 mRNA and protein. Positive NOS-2 immunostaining occurred in endothelial cells and cardiomyocytes in the allografts; the inflammatory infiltrate was NOS-2 positive only when recipients were NOS-2(+/+). In the second series of experiments, cardiac allograft survival was significantly increased in the NOS-2(-/-) mice (26+/-13 versus 17+/-8 days, P<0.05), along with significant reductions in inflammatory infiltrate, rejection score, and total number of apoptotic nuclei (23.5+/-9.5 versus 56.4+/-15.3, P<0.01) and of apoptotic cardiomyocytes (2.9+/-1.6 versus 6.9+/-2.7, P<0.05). No NOS-2 or nitrotyrosine, a marker of peroxynitrite exposure, was detected in NOS-2(-/-) allografts transplanted into NOS-2(-/-) recipients. CONCLUSIONS: The data suggest that NO derived from NOS-2 contributes to the inflammatory response and to cardiomyocyte damage and apoptosis during acute cardiac allograft rejection.

Inducible nitric oxide synthase expression in smooth muscle cells and macrophages of human transplant coronary artery disease.

BACKGROUND: The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation. METHODS AND RESULTS: We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells. CONCLUSIONS: iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.

Increased immunoreactive endothelin-1 in human transplant coronary artery disease.

BACKGROUND: The pathogenesis of transplant coronary artery disease (TCAD) is unknown, but it is thought to derive from an interaction between immune and nonimmune factors, leading to smooth muscle cell proliferation and accumulation in the expanded neointima. Endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties for vascular smooth muscle cells, has recently been demonstrated in native vessel atherosclerosis. The present study used immunohistochemistry to investigate the role of ET-1 in TCAD. METHODS AND RESULTS: ET-1 immunoreactivity and cellular localization were assessed in human coronary arteries with TCAD (n = 13) and in normal coronary arteries (n = 10) with single- and double-label immunohistochemistry. The intensity of immunostaining was determined by a semiquantitative method. Diffuse and intense ET-1 immunoreactivity was found in 11 of 13 patients with TCAD (85%), mainly in myointimal cells and, in lesser amounts, in macrophages and endothelial cells. In contrast, normal coronary arteries had only faint immunostaining localized to the endothelial layer. Mean semiquantitative grade was significantly higher in TCAD than in normal arteries (1.8 versus 0.7; P < .05). ET-1 was more frequently present in lipid-rich, atheromatous lesions than in lipid-poor, proliferative ones. Intimal neovessels consistently immunostained for ET-1. CONCLUSIONS: Immunoreactivity for ET-1 is significantly increased in TCAD, possibly as a result of stimulatory cytokines and growth factors that are upregulated in the posttransplant state. The results suggest a role for this mitogenic peptide in the pathogenesis of graft arteriosclerosis.

Nonadrenergic noncholinergic innervation. Anatomic distribution of calcitonin gene-related peptide-immunoreactive tissue in the dog heart.

Calcitonin gene-related peptide (CGRP) has inotropic and chronotropic effects in rat and guinea pig hearts. It also may mediate nonadrenergic noncholinergic regulation of canine cardiac electrophysiology. In this study, immunohistochemistry was used to determine the anatomic distribution of CGRP in mature dog heart and autonomic ganglia controlling cardiac function. The stellate ganglia had scattered CGRP-immunoreactive cells and nerve processes; intracardiac ganglia contained stained nerve processes but no CGRP-immunoreactive cells. Although the extramural coronary arteries were modestly innervated by varicose individual nerve processes, the great majority of CGRP-immunoreactive neural tissue in the heart existed adjacent to the sinoatrial node where varicose nerve processes coursed in numerous large nerve bundles. Each bundle contained only a few stained processes, however, indicating that CGRP-immunoreactive nerve processes were accompanying another type of autonomic tissue. Double staining and immunoultrastructure confirmed that the nerve bundles were heterogeneous. Similar nerve bundles were fewer in the left atrium, the region of the atrioventricular node, atrioventricular bundle, and the ventricles. In contrast to the distribution of sympathetic neural tissue, CGRP-immunoreactive nerve processes virtually were nonexistent among muscle fibers. We conclude that 1) CGRP-immunoreactive neural tissue likely affects sympathetic and parasympathetic ganglia that control cardiac function, 2) the preponderance of this nonadrenergic noncholinergic tissue near regions of specialized muscle (especially the sinoatrial node) suggests an efferent function in the canine heart, and 3) the presence of varicosities along CGRP-immunoreactive nerve processes within heterogeneous nerve bundles may indicate that direct axo-axonal contact is the mechanism by which these nonadrenergic noncholinergic nerve processes modulated other autonomic neural tissue.

Electrophysiology and ultrastructure of canine subendocardial Purkinje cells isolated from control and 24-hour infarcted hearts.

Ventricular arrhythmias that accompany myocardial infarction in dogs may be secondary to the altered electrophysiological properties of the subendocardial Purkinje fibers that survive 24 hours after the coronary occlusion. To better understand the ionic mechanisms that underlie the altered electrical activity of these fibers, we have dispersed, using an enzymatic technique, Purkinje cells from the subendocardium of the infarcted ventricle (IZPCs) and compared their electrical and structural properties to Purkinje cells dispersed from fiber strands (SPCs) and from the subendocardium of the noninfarcted ventricle (NZPCs). Ultrastructural analysis of these cells shows that IZPCs contain an increased number of lipid droplets when compared with the SPCs and NZPCs. In addition, transmembrane action potentials of IZPCs have reduced resting potentials, action potential amplitudes, and upstroke velocity and are increased in duration when compared with either SPCs or NZPCs. Input resistance of IZPCs is increased over that measured in control cells (SPCs and NZPCs). Furthermore, the time course of the process of electrical restitution of action potential duration is altered in IZPCs with long action potentials. Finally, using K+-sensitive microelectrode techniques, we have determined that intracellular free K+ activity (aKi) in IZPCs (93.7 +/- 15 mM) is not significantly different from control aKi measurements (SPC, 106 +/- 13 mM; NZPC, 103 +/- 12 mM). Thus a reduction in aKi does not provide a basis for the reduced resting potentials observed in IZPCs. By studying the relation between the resting potential and log [K+]o we determined that in IZPCs with reduced resting potentials, there is a significant increase in the PNa/PK ratio when compared with control. In summary, to better understand the cellular basis of ventricular arrhythmias postinfarction, we have developed a single cell model that will allow for more rigorous electrophysiological studies of the specific ionic currents that underlie the abnormal electrophysiology.

Comparison of early and delayed inpatient dexamethasone suppression tests.

Ninety-five inpatients completed a dexamethasone suppression test (DST) within 72 hours after admission and again after at least 1 week of medication-free hospital care. The frequency of cortisol nonsuppression in patients with endogenous depression (ED) was high and not significantly different at both tests. In patients with diagnoses other than ED, the higher rate of cortisol nonsuppression at the first DST was associated with a significant decrease in test specificity. Change in postdexamethasone cortisol levels at repeat testing was associated with a decrease in depressive symptomatology, but was not related to weight change during hospitalization.

Serial dexamethasone suppression tests in depressed patients treated only with electroconvulsive therapy.

Several systematic studies have evaluated serial dexamethasone suppression tests (DST) in patients with major depression who were treated with antidepressant medications. DST changes were noted to parallel clinical improvement in most recovering patients. If serial DSTs are a valid state-related correlate of depressive pathophysiology, all types of effective antidepressant treatment should result in DST 'normalization'. However, no treatment modalities other than antidepressant medications have been studied serially with systematic assessments. To test whether serial DSTs reflect clinical progress in depressives treated solely with electroconvulsive therapy (ECT), we studied weekly DSTs and Hamilton Rating Scales for Depression (HRSD) in 22 drug-free depressed patients. We observed progressive DST 'normalization' in most patients and moderately high correlations between weekly DST and HRSD values throughout treatment. Most patients receiving ECT became DST suppressors. In most patients the DST appeared to reflect the severity of depressive pathophysiology, perhaps providing serial feedback to clinicians monitoring the progress of treatment with ECT.

Prolactin response to TRH in depression.

We studied the prolactin response to TRH in 53 unmedicated psychiatric inpatients. The prolactin response of females was significantly greater than the response of male subjects. There was no significant difference in the prolactin response to TRH between depressed patients and those with other psychiatric diagnoses. There was no significant relationship between the prolactin response to TRH and the severity of depression, the TSH response to TRH or the resistance to suppression of cortisol secretion by dexamethasone.

Hormone response to repeated electroconvulsive therapy: effects of naloxone.

Plasma prolactin (PRL), cortisol, and growth hormone (GH) were measured before, and at 15-min intervals for 1 hr after, electroconvulsive therapy (ECT). This was repeated over a series of 6 consecutive treatments for each of 12 depressed drug-free inpatients. Patients received naloxone, 2 mg or 20 mg, by intravenous infusion before the third and fifth treatment. ECT was consistently followed by a release of PRL and cortisol, although two patterns of PRL response could be distinguished. In eight patients, the PRL response did not change significantly with repeated ECT, whereas in four patients, the plasma PRL increased tenfold after the first treatment and decreased after each successive treatment. The GH level varied widely, with no evidence of a reliable response to ECT. Opiate receptor blockade with low- or high-dose naloxone did not alter the release of PRL or cortisol after ECT. These findings demonstrate a reliable PRL and cortisol response to ECT, but do not support a role for endogenous opiates in these hormonal changes.

Cortisol escape from morphine suppression.

Twenty-one unmedicated, sequentially admitted psychiatric patients of either sex and four male healthy volunteers were given an intravenous injection of 2.5 mg morphine. Blood samples were drawn immediately before and at 30-minute intervals for 3 hours after the injection and assayed for cortisol. Morphine suppressed cortisol secretion. Early resumption of cortisol secretion (escape) was more frequent in patients with a diagnosis of major depressive disorder and with abnormal dexamethasone suppression test results. The sensitivity of this infusion paradigm for the diagnosis of major depressive disorder was 40%, and the specificity was 82%. The implications of these findings for the pathophysiology of depression are discussed.

Opioid regulation of hypothalamic-pituitary-adrenal function in depression.

A morphine infusion paradigm was used to investigate opioid mechanisms in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression. The subjects were unmedicated psychiatric inpatients and healthy volunteers. Morphine suppressed cortisol secretion. Early resumption of cortisol secretion was associated with a diagnosis of major depression and abnormal dexamethasone suppression test results. Our data suggest that the hyperactivity of the HPA axis observed in depression is abnormally resistant to opioid inhibition as well as glucocorticoid feedback.

Prolactin response to morphine in depression.

Twenty-two unmedicated inpatients with major depression and 18 healthy volunteers of either sex were given an intravenous injection of 5 mg morphine. Blood samples were drawn immediately before and at intervals for 3 hrs after the injection and assayed for prolactin. Morphine stimulated prolactin secretion. The prolactin response of females was significantly greater than the response of male subjects. There were no significant differences in the prolactin response to morphine between depressed and healthy subjects. The implications of these findings for the hypothesized role of the opioid system in the pathophysiology of depression are discussed.

Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing.

Structural and electrophysiological properties of the epicardial muscle which survives on the surface of transmural infarcts of the canine heart (epicardial border zone) were studied at different times after occlusion of the left anterior coronary artery (LAD). Isolated preparations were superfused in vitro, transmembrane potentials recorded, and impulse propagation mapped. In preparations from subacute infarcts (1 and 5 days), resting potential, action potential amplitude, upstroke velocity, and duration were all significantly reduced. Well-defined directional differences in propagation occurred. Propagation was more rapid in the direction perpendicular to the left anterior coronary artery than in the direction perpendicular to the base of the heart, because of the uniform anisotropic structure of the surviving muscle fibers which were arranged in tightly packed bundles oriented perpendicular to the left anterior coronary artery. The only ultrastructural abnormalities found in these muscle fibers was an accumulation of large amounts of lipid droplets. As the infarcts healed, resting potential, action potential amplitude, and upstroke velocity returned to normal by 2 weeks, although action potential duration decreased further. Lipid droplets had disappeared, and connective tissue had invaded the epicardial border zone, separating the muscle bundles. By 2 months, action potentials were normal, but the muscle fibers were widely separated and disoriented by the connective tissue (parallel bundles no longer were found). In these regions with a nonuniform anisotropic structure, the well-defined directional differences in impulse propagation were lost. However, activation was very slow, perhaps because of diminished connections between cells. The persistence of slow conduction in healed infarcts may contribute to the occurrence of chronic arrhythmias.

Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease.

The cellular electrophysiologic and structural characteristics of arrhythmic and non-arrhythmic atria isolated from feline hearts with spontaneously occurring cardiomyopathy were studied. The animals were divided into three groups according to the degree of left atrial enlargement: mild (group I), moderate (group II), and severe (group III). The right atria were of relatively normal size. Microelectrode recordings showed that inexcitable cells were present in both left and right atria of all groups but were most numerous in the left atria of group III animals. Most inexcitable cells had low resting membrane potentials. There was also a significant reduction in resting membrane potentials, maximum rate of phase 0 depolarization, and action potential amplitude of excitable cells in left atria of animals in groups II and III, whereas action potentials of excitable cells in the right atria were normal. Acetylcholine or norepinephrine often restored excitability to cells that originally did not generate action potentials. Norepinephrine also caused slow-response action potentials as well as abnormal automaticity and triggered activity due to delayed afterpotentials. The diseased atria showed marked structural abnormalities, which were most pronounced in group III cats, including large amounts of interstitial fibrosis, cellular hypertrophy and degeneration, and thickened basement membranes. Therefore electrophysiologic abnormalities and concurrent changes in cell structure may be involved in the genesis of atrial tachyarrhythmias caused by cardiomyopathy.

Morphine inhibits cortisol and stimulates prolactin secretion in man.

The role of opioids in endocrine regulation has been the subject of numerous studies. Surprisingly, however, the acute endocrine effects of morphine on basal hormonal levels in man have not been adequately documented. We report here the effects of intravenous morphine (5 mg) on plasma cortisol and prolactin. Fourteen healthy volunteers (nine male, five female) received morphine at 0930 hr. Blood samples were collected immediately before and 30, 60, 90, 120 and 180 min after the injection. In six of the male subjects the procedure was repeated with a placebo (normal saline) injection. Morphine stimulated prolactin release. There was a trend for a greater response in females compared to male subjects. Cortisol secretion was markedly suppressed by morphine. In sharp contrast to the results obtained with placebo, cortisol levels following morphine declined progressively at a rate consistent with the half-life of cortisol. This downward trend of cortisol values continued uninterrupted for the duration of the experiment in all 14 subjects. These results are consistent with the presence of an inhibitory opioid mechanism in the human hypothalamo-pituitary-adrenal axis.