Hypocholesterolemia and affective disorders.

The authors' specific aim was to assess hypocholesterolemia in 203 patients hospitalized because of affective disorders (depression, bipolar disorder, and schizoaffective disorder) compared with 1,595 self-referred subjects in an urban supermarket screening and with 11,864 subjects in the National Health and Nutrition Examination Survey II, a national probability sample. Low plasma cholesterol concentrations (< 160 mg/dL) were much more common in patients with affective disorders (20%) than in urban supermarket screenees (4%, P < or = 0.001) or in the National Health and Nutrition Examination Survey II subjects (10%, P < or = 0.001). When paired with supermarket screenees by age and sex, patients with affective disorders had much lower plasma total cholesterol (P < or = 0.0002), low-density lipoprotein cholesterol (P < or = 0.001), and high-density lipoprotein cholesterol (P < or = 0.0001), and higher triglyceride concentrations (P < or = 0.03). Neither the severity of the affective disorders nor severity-age interactions were associated with plasma cholesterol concentrations (P > 0.1); age and plasma cholesterol were positively associated (P = 0.01). None of the psychoactive drugs had a significant independent association with the patients' low-density lipoprotein cholesterol. Plasma cholesterol in patients hospitalized with affective disorders is shifted markedly downward toward hypocholesterolemic concentrations (< 160 mg/dL). There is no evidence that low plasma cholesterol could cause or worsen affective disorders.

Postmenopausal cyclic estrogen-progestin therapy lowers lipoprotein[a].

In 21 postmenopausal women, ages 45 to 55 years, we assessed the effects of 3 months of cyclic estrogen-progestin therapy on lipoprotein[a] (Lp[a]), lipids, lipoproteins, apolipoproteins, blood pressure, and insulin/glucose relationships. After a pretherapy baseline study, conjugated estrogens (0.625 mg for 21 days) and medroxyprogesterone acetate (5 mg last 10 days) were given to the women cyclically for 3 months, and then the study was repeated. During hormone replacement therapy, mean plasma Lp[a] fell 25% (from 20 to 15 mg/dl) (p = 0.0001), apolipoprotein B fell 14% (p = 0.01), and triglyceride fell 15% (p = 0.01), while high-density lipoprotein cholesterol (HDLC) rose 26% (p = 0.0001) and apolipoprotein A1 rose 25% (p = 0.003). The area under the insulin curve after oral glucose tolerance fell 33% (p = 0.0001), while the ratio of insulin area to glucose area fell 22% (p = 0.006). Mean systolic and diastolic blood pressure fell, respectively, 6% and 10% (p = 0.0001 for both). We speculate that the potential cardioprotective effect of estrogen-progestin therapy in postmenopausal women may be mediated through lowering Lp(a) as well as raising HDLC and apolipoprotein A1, lowering apolipoprotein B and blood pressure, and decreasing insulin resistance.

Hypocholesterolemia, hypertriglyceridemia, suicide, and suicide ideation in children hospitalized for psychiatric diseases.

To assess relationships of total plasma cholesterol (TC) and triglyceride (TG) values to suicide, suicide ideation, and hospitalization for psychiatric disease, we studied 220 children, ages 5 to 18 y, hospitalized with affective, adjustment, disruptive, anxiety, schizophrenic, other, and organic psychiatric disorders. The 135 male and 85 female patients had higher TG values (p = 0.0001 and 0.0003, respectively) and higher Quetelet Indices (p = 0.0001 and 0.003, respectively) than the 732 male and 316 female schoolchild controls; male patients had higher TC values than male controls (p = 0.014). Substance abuse in patients was an independent inverse determinant of TC value (p = 0.05); TG value correlated positively with alcohol use (p < or = 0.1) and substance abuse (p < 0.05). After covariance adjustment for age, race, sex, and Quetelet, children having adjustment disorders with depression had much lower covariance-adjusted TC value than control schoolchildren (3.91 versus 4.29 mmol/L, p = 0.003), whereas those with disruptive behavior with oppositional defiant disorder had much higher adjusted TC value (5.09 mmol/L, p = 0.0001). After covariance adjusting for age, race, sex, Quetelet, cigarette smoking, alcohol use, and substance abuse, children having adjustment disorders with concomitant depression had the highest group suicide tendencies (attempts and ideation) and the lowest covariance-adjusted TC value (4.03 mmol/L). Conversely, children having disruptive behavior with attention deficit hyperactivity disorder or disruptive behavior with oppoistional defiant disorder had 50% lower suicide index than those with adjustment disorders with concomitant depression and higher adjusted TC levels (4.45 and 5.12 mmol/L, p = 0.0003).(ABSTRACT TRUNCATED AT 250 WORDS)

Beta blockers, Lp(a), hypertension, and reduced basal fibrinolytic activity.

To assess the hypothesis that beta blocker use and hypertension are associated with high lipoprotein(a) [Lp(a)] or with reduced basal fibrinolytic activity, the authors studied relationships of hypertension and beta blockers to Lp(a), lipids, lipoproteins, apolipoproteins, and basal fibrinolytic activity in 385 patients consecutively referred for diagnosis and therapy of hyperlipidemia. A second aim was to determine possible gender differences in fibrinolytic activity among patients with hypertension. Ninety-nine patients (58 women [88% post-menopausal] and 41 men) had drug-treated hypertension. In women, hypertension was a positive, independent predictor of the major inhibitors of fibrinolysis, plasminogen activator inhibitor antigen (p = 0.017), and plasminogen activator inhibitor activity (p = 0.004). In men and women, major risk factors for atherosclerosis were significant, independent predictors of reduced basal fibrinolysis. Median Lp(a) in the 99 patients with hypertension (16 mg/dL) did not differ from Lp(a) (18 mg/dL) in normotensive patients (p > 0.1). Of the 385 patients, the 39 beta blocker users had higher plasminogen activator inhibitor activity (p = 0.01), higher triglyceride (p = 0.02) levels, and higher Quetelet Indices (p = 0.01) than non-users (n = 346). After covariance adjusting for age, Quetelet Indices, sex, and triglycerides, plasminogen activator inhibitor activity was not higher in beta blocker users than in non-users (p > 0.1). Median Lp(a) did not differ in beta blocker users (16 mg/dL) and in non-users (17 mg/dL), p greater than 0.1. Hypertensive, predominantly post-menopausal women are likely to have high plasminogen activator inhibitor activity and plasminogen activator inhibitor antigen with concurrent reduced fibrinolytic activity, as well as high fibrinogen levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.

Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Protein C and S deficiency, thrombophilia, and hypofibrinolysis: pathophysiologic causes of Legg-Perthes disease.

In eight patients with Legg-Perthes disease, we assessed the etiologic roles of thrombophilia caused by protein C and protein S deficiency and hypofibrinolysis mediated by low levels of tissue plasminogen activator activity. We speculated that thrombosis or hypofibrinolysis were common causes of Legg-Perthes disease. Three of the eight patients had protein C deficiency; they came from kindreds with previously undiagnosed protein C deficiency. In one of these three kindreds there were six protein C-deficient family members (beyond the proband child), four of whom had thrombotic events as adults. One of the eight patients had protein S deficiency, as did his brother who had sustained mesenteric vein thrombosis at age 43. One of the eight patients who had normal proteins C, S, and antithrombin III had hypofibrinolysis, failing to elevate tissue plasminogen activator activity after 10 min of venous occlusion at 100 mm Hg. Plasminogen activator inhibitor, alpha 2-antiplasmin, and fibrinogen values were normal in all eight patients. Beyond their Legg-Perthes disease, none of the eight patients had evidence for venous thrombosis. Of the eight patients, four had thrombophilia and one had hypofibrinolysis, disorders that we believe contributed to thrombotic venous occlusion of the femur with subsequent venous hypertension and bone death that characterize Legg-Perthes disease.

Hypofibrinolysis: a common, major cause of osteonecrosis.

In 30 patients with osteonecrosis of the hip (12 idiopathic, 18 secondary), we assessed the role of hypofibrinolysis mediated by high levels of plasminogen activator inhibitor (PAI). We evaluated hypofibrinolysis as a common, potentially reversible, pathophysiologic cause of idiopathic osteonecrosis. In all 18 patients with secondary osteonecrosis, PAI was normal, as was the ability to activate fibrinolysis. Nine of the 12 patients with idiopathic osteonecrosis had exceptionally high PAI levels and could not normally elevate tissue plasminogen activator (tPA-Fx), the major stimulator of fibrinolysis, after 10 min of venous occlusion at 100 mm Hg. The group of 12 patients with idiopathic osteonecrosis, compared to the 18 with secondary osteonecrosis, had low mean stimulated tPA-Fx (1.92 vs. 7.6 IU/ml, P < or = .001) and very high stimulated PAI-Fx (70 vs. 7.6 U/ml, P < or = .01). Three of the 12 patients with idiopathic osteonecrosis had both normal PAI and normal stimulated tPA-Fx. These three patients and 14 of the 18 with secondary osteonecrosis had high lipoprotein (a) [Lp(a)] (> 20 mg/dl). Mean Lp(a) was much higher (60 mg/dl) in the patients with secondary osteonecrosis than Lp(a) (16 mg/dl, P < or = .001) in the 12 patients with idiopathic osteonecrosis. These findings suggest that hypofibrinolysis mediated by high PAI is a common cause of idiopathic osteonecrosis, whereas high Lp(a) may play an etiologic role in secondary osteonecrosis. Prospective studies of patients with high PAI and/or high Lp(a) should be carried out to assess further their apparently causal roles in osteonecrosis.

Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor.

Familial hypofibrinolysis with 3 generation, autosomal dominant, very high levels of plasminogen activator inhibitor activity (PAI-Fx) and antigen (PAI-Ag) was etiologically associated with bilateral idiopathic osteonecrosis in 2 brothers. They, their mother, 2 brothers, sister, and all 4 of her children (none of whom had yet developed osteonecrosis), all had very high PAI and could not elevate tissue plasminogen activator after 10 minutes of venous occlusion at 100 mmHg. Familial high PAI levels with concurrent hypofibrinolysis co-segregated with familial combined hyperlipidemia, both being independent risk factors for premature coronary heart disease. If thrombi block venous drainage in the femur, familial hypofibrinolysis mediated by familial high PAI with inability to lyse thrombi would contribute to venous hypertension of bone, bone anoxia, and bone death characteristic of osteonecrosis.

Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women.

Our specific aim was to assess severe hypertriglyceridemia and pancreatitis that occurred when postmenopausal estrogen replacement therapy (ERT) or tamoxifen had been given by their physicians to women with preexisting, usually covert, primary familial hypertriglyceridemia. We retrospectively studied 31 women referred for diagnosis and therapy of hypertriglyceridemia over 2.75 years whose initial visit fasting plasma triglyceride levels were > 750 mg/dl. Of the 31 women with hypertriglyceridemia, 12 (39%) had been given exogenous estrogen by their physicians (11 ERT, one tamoxifen). Ten of the 12 women, while undergoing ERT, had triglyceride levels > 1200 mg/dl. In triglyceride referral categories 750 to 1000, 1000-1500, and > 1500 mg/dl, 17% (2 of 12), 33% (3 of 9), and 70% (7 of 10), respectively, of the 31 women with hypertriglyceridemia were receiving ERT. The higher the triglycerides were at referral, the greater was the likelihood that women were taking ERT (x2 = 6.6, p = 0.035). Four of the seven women with triglyceride levels > 1500 mg/dl while undergoing ERT were hospitalized with severe acute pancreatitis; another two had severe abdominal pain thought to be pancreatic in origin. To quickly lower dangerously high triglyceride levels, ERT was stopped in all 12 women. Lopid (1.2 to 1.5 gm/day) was given to the seven women not already taking it, and four were also given omega-3 fatty acids (4 to 15 gm/day). Median plasma triglyceride level at the initial visit in the 12 women undergoing ERT was 1665 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

High lipoprotein(a) in children from kindreds with parental premature myocardial infarction.

In 98 children from 98 kindreds, 49 with and 49 without parental premature myocardial infarction (age < or = 45 y), our specific aim was to determine whether, and to what degree, lipoprotein(a) [Lp(a)] and other atherogenic lipids and lipoproteins might be overexpressed in children from premature infarction kindreds. Median Lp(a) (270 mg/L) in case boys was nearly twice that in control boys (140 mg/L) (p < or = 0.001). In a logistic regression model including age, Quetelet index (relative ponderosity), Lp(a), apo A1, apo B, triglyceride, and pubertal status, the 24 case boys had higher Lp(a) (p = 0.03), higher triglyceride (p = 0.036), and marginally lower apo A1 (p = 0.06) than the 26 control boys. Median Lp(a) in case girls (200 mg/L) was much higher than in control girls (150 mg/L) (p < or = 0.01). In a logistic regression model including age, Quetelet index, Lp(a), apo A1, apo B, triglyceride, and menarchal status, Lp(a) was higher (p = 0.02), apo B was marginally higher (p = 0.07), and apo A1 was lower (p = 0.008) in 25 case girls than in 23 control girls. Reflecting familial clustering of major lipid-lipoprotein risk factors for coronary heart disease, children from kindreds with premature parental myocardial infarction were distinguished from children from control kindreds by high Lp(a) and also had higher apo B and triglyceride and lower apo A1 levels.

Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men.

To assess relationships of endogenous testosterone with fibrinolysis and coronary heart disease risk factors in 55 newly referred hyperlipidemic men, we studied the relationships of testosterone to basal fibrinolytic activity, lipids, lipoproteins, and apolipoproteins. Testosterone correlated positively with the major stimulator of fibrinolysis, tissue plasminogen activator activity (r = 0.30; p = 0.02) and correlated inversely with two independent coronary heart disease risk factors, plasminogen activator inhibitor activity, the major fibrinolysis inhibitor (r = -0.33; p = 0.01), and fibrinogen (r = -0.39; p = 0.004). Testosterone correlated inversely with plasma triglycerides (r = -0.33; p = 0.01). Stepwise multiple regression was done with fibrinolytic activities as the dependent variables, and age, Quetelet Index (relative ponderosity), apolipoprotein A-I, apolipoprotein B, triglyceride, testosterone, time of blood sampling, and lipoprotein (a) as explanatory variables. Testosterone was an inverse, independent predictor of fibrinogen (p = 0.002); 53% of the variance of fibrinogen could be accounted for by age and triglyceride level (positive; p = 0.001, p = 0.01), and by apolipoprotein A-I and testosterone (negative; p = 0.02, p = 0.002). Testosterone was an independent inverse predictor of tissue plasminogen activator antigen (p = 0.0008), with tissue plasminogen activator antigen correlating inversely with tissue plasminogen activator activity. Quetelet index and apolipoprotein B were independent negative predictors of tissue plasminogen activator activity (p = 0.02, p = 0.03); Quetelet index and triglycerides were independent positive predictors of plasminogen activator inhibitor activity (p = .0001, p = .0001) and alpha 2-antiplasmin (p = 0.0003, p = 0.009).(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance treatment and psychobiologic correlates of endogenous subtypes.

Although the endogenous subtype in depression has long been thought to have prognostic significance, to date no long-term maintenance treatment trial has examined the relative risk of recurrence in patients meeting criteria for this subtype. Following our analysis of the primary hypotheses regarding the relationship between treatment assignment and outcome [Frank et al. (1990) Arch. Gen. Psychiatry 47, 1093-1099], we now examine psychobiologic and maintenance treatment correlates for these recurrent unipolar patients grouped according to melancholic, endogenous but not melancholic, and non-endogenous subtype at index presentation. No differences were observed among the three groups in overall survival time; however, in the 52 patients who received psychotherapy without active medication during the maintenance phase, length of survival was inversely related to endogeneity. Interestingly, no differences were found among the three groups in EEG sleep parameters when studied either at baseline or following recovery.

Treatment of imipramine-resistant recurrent depression, III: Efficacy of monoamine oxidase inhibitors.

BACKGROUND: The effectiveness of monoamine oxidase inhibitors (MAOIs) in tricyclic resistant depression has received surprisingly little systematic study. METHOD: Patients who failed to respond to sustained, adequate treatment with the tricyclic imipramine (mean maximum dosage = 260 mg/day) and interpersonal psychotherapy were withdrawn from imipramine and treated in a standardized, but open-label 6-week trial with either phenelzine (N = 4; 60 mg/day) or tranylcypromine (N = 36; mean = 38.5 mg/day) and continued interpersonal psychotherapy. RESULTS: Forty of 42 patients (95%) completed the trial, of whom 23 (58%) responded to treatment. Highly significant improvement was documented on measures of depression, reversed neurovegetative symptoms, and somatic symptoms. Response was significantly correlated with severity of depression (pre-MAOI score on the Hamilton Rating Scale for Depression), severity of a composite score of anergic and reversed neurovegetative features, and low levels of improvement during initial imipramine/interpersonal psychotherapy. Of patients who met criteria for proposed subforms of anergic or atypical depression, 67% (18/27) responded (p less than .05); 77% (17/22) of patients who scored above the mean on the composite measure of anergic and reversed neurovegetative features responded (p less than .01). CONCLUSION: These findings provide strong evidence of the utility of MAOIs in tricyclic-resistant depression, especially in patients with features such as fatigue, volitional inhibition, motoric retardation, hypersomnia, and/or weight gain.