Body weight gain after administration of antipsychotic drugs: correlation with leptin, insulin and reproductive hormones

Excessive body weight gain, hyperprolactinemia and low gonadal steroid serum levels are often observed during chronic administration of antipsychotic drugs (AP). Clinical and experimental findings suggest that leptin, the peptidic hormone involved in long-term body weight regulation, and reproductive hormones are interrelated. Therefore, we assessed circulating leptin levels in healthy, lean women (n = 12) and men (n = 7) before and after short-term administration of the AP sulpiride (SUL, 200 mg/day). In addition, we studied psychotic obese (n = 9) and lean women (n = 13) under chronic treatment with diverse AP. No significant weight changes were observed after SUL administration in healthy women--initial weight: 54.9+/-2.6 Kg; final weight: 55.04+/-2.6, NS. Leptin levels did not change either: 11.9+/-1.5 ng/ml. vs. 10.6+/-1.3, NS. By contrast, a small, but significant weight gain was found in SUL-treated men--60.6+/-1.9 Kg. vs. 61.3+/-2.1, p = 0.004. Leptin and insulin levels were significantly higher after SUL administration--leptin: 2.77+/-0.22 ng/ml. vs. 13.9+/-2.5, p=0.035; insulin: 3.59+/-0.17 mIU/ml vs. 8.81+/-0.81, p = 0.0001. In these subjects, leptin levels positively correlated with body weight change (p = 0.006), and serum prolactin change (p = 0.001). Obese psychotic women (Body Mass Index, BMI, Kg/m2 = 31.5+/-1.03) displayed higher leptin levels than non-obese psychotic women (BMI = 25.5+/-0.52): 26.8+/-4.8, vs. 12.8+/-3.4 ng/ml, p = 0.006. In these women, a significant positive correlation was found between leptin levels and BMI (p = 0.0001), and between leptin and basal insulin levels (p = 0.001). These results show that the expected circulating leptin elevation which is observed when body weight raises, is preserved in people treated with AP drugs.     

Does long-term use of valproate cause weight gain in prepubertal epileptic children?

In this experiment, we studied the effect of valproate (VPA) on weight gain, and serum leptin levels in prepubertal epileptic children receiving VPA. Our purpose was to determine whether or not long-term use of VPA causes weight gain in childhood, and to evaluate serum leptin levels in a group of prepubertal children receiving VPA. Our study included 15 patients (9 males, 6 females) with new diagnosed epilepsy and 16 healthy age-matched controls (9 males, 7 females). The subjects' ages ranged from 9 months to 12 years. Weight gain was noted in 9 (60%) of 15 patients in the study group, and 8 (50%) of 16 subjects in the control group (p > .05). There was no difference between the groups for body mass index (BMI) and serum leptin levels. Although higher serum leptin levels were found in the patients treated with VPA weight gaining (5.65 +/- 3.06 ng/ml vs. 3.28 +/- 1.69 ng/ml), we did not find a difference between the patients weight gaining and nonweight gaining (p > .05). While a significant correlation between BMI and serum leptin levels was found in the study group (r = .704; p = .003), it was not significant in the control group (r = .330; p = .211). In conclusion, our findings showed that long-term use of VPA did not cause weight gain in a group of prepubertal children receiving VPA and, parallel to this, serum leptin levels were similar in both the control and study group.     

Reduced plasma leptin concentrations in bulimia nervosa

Leptin is a protein produced by the ob-ob gene which inhibits food intake. Plasma levels have previously been reported to be altered in obesity and anorexia nervosa (AN) but not bulimia nervosa (BN). We measured fasting plasma leptin levels by radioimmunoassay in 53 subjects carefully studied at NIMH, including 37 women meeting DSM-III-R criteria for BN [10 with concurrent AN (body mass index (BMI)=14.1+/-1.4), 27 without AN (BMI=20.4+/-1.6)] and 16 normal control women (NCs) (BMI=21.1+/-2.0). Patients were medication-free and abstinent from bingeing and purging for three to four weeks prior to study. Plasma leptin levels were significantly correlated to BMI (r=0.41, P<0.002), weight (kg, r=0.43, P<0.001), and percent average body weight (%ABW, r=0.45, P<0.001) in the total group. Plasma leptin levels were lower in the BN subjects (3.4+/-2.5 ng/ml) compared to the NCs (6.1+/-2.6 ng/ml, P<0.001, ANCOVA) even after controlling for BMI and weight. There was no significant difference between BN subjects with AN (n=10, 2.6+/-2.6 ng/ml) and those without AN (n=27, 3.8+/-2.4 ng/ml), despite lower BMI in BN with AN. Furthermore, leptin levels were decreased in BN without AN compared with healthy controls, even though BMI was comparable in these two subgroups. Plasma leptin concentrations were negatively correlated with baseline plasma cortisol levels (n=49, r=-0.49, P<0.001) and positively correlated with prolactin responses following L-tryptophan (n=49, r=0.37, P<0.009) and m-chlorophenylpiperazine (n=52, r=0.24, P<0.09). This is the first known report of decreased plasma leptin levels in BN. The decrement in leptin concentration is not related to BMI, body weight, or the presence or absence of BN. HPA axis activation as well as serotonin dysregulation may be related to decreased leptin levels, which may in turn contribute to disinhibited eating in BN. Although current leptin levels were not correlated with self-reported previous binge frequency, the role of leptin in the pathophysiology of BN deserves further study.     

Brief Clinical Report DOES LONG-TERM USE OF VALPROATE CAUSE WEIGHT GAIN IN PREPUBERTAL EPILEPTIC CHILDREN?

In this experiment, we studied the effect of valproate (VPA) on weight gain, and serum leptin levels in prepubertal epileptic children receiving VPA. Our purpose was to determine whether or not long-term use of VPA causes weight gain in childhood, and to evaluate serum leptin levels in a group of prepubertal children receiving VPA. Our study included 15 patients (9 males, 6 females) with new diagnosed epilepsy and 16 healthy age-matched controls (9 males, 7 females). The subjects ages ranged from 9 months to 12 years. Weight gain was noted in 9 (60%) of 15 patients in the study group, and 8 (50%) of 16 subjects in the control group (p >. 05). There was no difference between the groups for body mass index (BMI) and serum leptin levels. Although higher serum leptin levels were found in the patients treated with VPA weight gaining (5.65 &#45 3.06 ng/ml vs. 3.28 &#45 1.69 ng/ml), we did not find a difference between the patients weight gaining and nonweight gaining (p >. 05). While a significant correlation between BMI and serum leptin levels was found in the study group (r =. 704; p =. 003), it was not significant in the control group (r =. 330; p =. 211). In conclusion, our findings showed that long-term use of VPA did not cause weight gain in a group of prepubertal children receiving VPA and, parallel to this, serum leptin levels were similar in both the control and study group.     

Normalization of circulating leptin levels by fasting improves the reproductive function in obese OLETF female rats

In order to examine a possible detrimental effect of hyperleptinemia on the reproductive system, we examined whether a decrease in circulating leptin levels by fasting affects the estradiol/progesterone-induced luteinizing hormone (LH) and prolactin (PRL) surges in genetically obese OLETF (Otsuka-Long-Evans-Tokushima-Fatty) rats. Experiments were performed on both normally fed and 3-day starved groups from ovariectomized OLETF rats and their controls LETO (Long-Evans-Tokushima-Otsuka). Starved LETO rats, whose leptin levels were less than 0.5 ng/ml, did not show a significant surge of either LH or PRL. Normally fed OLETF rats, whose leptin levels were 9.7 +/- 1.8 ng/ml, showed a significant but small surge for both LH and PRL. Interestingly, starved OLETF rats, whose leptin levels (4.1 +/- 0.7 ng/ml) were similar to those in normally fed LETO rats (3.3 +/- 0.4 ng/ml), had significantly greater surges of both hormones than normally fed OLETF group. This study demonstrates for the first time that the normalization of circulating leptin levels in female OLETF rats augments the steroid-induced LH and PRL surges, and also suggests a deleterious effect of hyperleptinemia on the reproductive axis.     

Relationship between weight loss and dysphagia in patients with Parkinson's disease]

The purpose of this study was to investigate the relationship between weight loss and dysphagia in Parkinson's disease. We compared the height, body weight and the data of self-administered questionnaires concerning food intake and deglutition feelings in patients suffering from Parkinson's disease with normal controls. A structured interview was performed by nutritionists and nutrient intakes were calculated from the reported food intake over 5 days. Biochemical parameters were chosen from the chart. The subjects were 105 patients with Parkinson's disease, 34 males with a mean age of 67.7 +/- 8.6 years and 71 females with a mean age of 69.1 +/- 10.0 years (Hoehn-Yahr stage I6, II25, III51, IV20, V3). In addition, 47 family members were used as control subjects: 26 males, 70.6 +/- 7.6 years and 21 females, 64.9 +/- 7.7 years. Body mass index (BMI) in females with Parkinson's disease (20.2 +/- 3.5 kg/m2) was significantly lower (p < 0.005) than that in control females (23.0 +/- 3.0 kg/m2). There was no significant difference in BMI in males. The BMI was 21.9 +/- 3.0 kg/m2 in male patients with Parkinson's disease and 22.6 +/- 3.1 kg/m2 in controls. The occurrences of symptoms such as choking, cough, sputum, food in sputum, wet voice and pharyngeal discomfort following food intake in patients with Parkinson's disease vs. those in controls were 22% vs. 6%, 16% vs. 2%, 7% vs. 4%, 2% vs. 0%, 5% vs. 2% and 11% vs. 0%, respectively. Concerning symptoms such as choking, cough and pharyngeal discomfort, the occurrence was significantly more frequent in patients with Parkinson's disease than in controls (p < 0.05, p < 0.05, p < 0.05). We defined the dysphagic Parkinson patients as those who have at least one symptom of dysphagia such as choking, cough, sputum, food in sputum, wet voice and pharyngeal discomfort following food intake. The dysphagic subjects were present in 31% of Parkinson patients and in 7% of control subjects (p < 0.005), although half of the dysphagic Parkinson patients did not recognize it. No relationship between the occurrence of dysphagic symptoms and the Hoehn-Yahr stage was found. In patients with Parkinson's disease. BMI in the dysphagic group (19.1 +/- 3.6 kg/m2) was significantly lower than that in the non-dysphagic group (21.6 +/- 3.0 kg/m2) (p < 0.005). There was no relationship between BMI and the dose of levodopa. Patients in the dysphagic group showed significantly lower carbohydrate intake (186 +/- 49 g) than those in the non-dysphagic group (215 +/- 52 g) (p < 0.05). Biochemical nutritional parameters were lower in the dysphagic group than those in the non-dysphagic group; 6.6 +/- 0.7 g/dl vs. 6.9 +/- 0.4 g/dl (p < 0.005) in serum total protein, 3.8 +/- 0.5 g/dl vs. 4.1 +/- 0.4 g/dl (p < 0.01) in albumin and 173.4 +/- 33.0 mg/dl vs. 199.7 +/- 40.7 mg/dl (p < 0.05) in total cholesterol. These findings suggest that dysphagia, especially unrecognized dysphagia, plays a role in weight loss in Parkinson's disease.     

Increased cardiovascular risk markers in obesity are associated with body adiposity: role of leptin

Epidemiological studies have shown that obesity is associated with increased blood concentrations of proinflammatory factors and markers of endothelial dysfunction such as fibrinogen, C-reactive protein (CRP), and von Willebrand factor (vWF). We analyzed the association of these markers with percentage of body fat (BF), and the influence of leptin in a cross-sectional study of 1,089 subjects (366 men) aged 44 (34-53) [median (interquartile range)] years, who were classified as obese or nonobese according to BF estimated by whole-body air displacement plethysmography. Obesity was defined as BF >or= 25% in men and >or= 35% in women. Compared with non-obese subjects (mean +/- SD), obese patients had higher concentrations of fibrinogen (312 +/- 78 vs. 342 +/- 81 mg/dl, P < 0.001), CRP (0.41 +/- 0.75 vs. 0.75 +/- 1.04 mg/l, P = 0.014), vWF (107 +/- 29 vs. 123 +/- 55%, P < 0.001), and leptin (10.4 +/- 6.5 vs. 37.5 +/- 26.1 ng/ml, P < 0.0001). A positive correlation was observed between BF and fibrinogen (r = 0.266; P < 0.0001), logCRP (r = 0.409; P < 0.0001), and vWF (r = 206; P < 0.0001). Leptin was correlated with fibrinogen (r = 0.219, P < 0.0001), logCRP (r = 0., P < 0.0001), and vWF (r = 0.124, P = 0.002), but the statistical significance was lost after including BF in adjusted-correlation and multivariate analysis, suggesting that they are not regulated by leptin per se. In conclusion, the obesity-associated increase in the circulating concentrations of fibrinogen, CRP, and vWF is highly associated to BF and apparently not determined by leptin.     

Sexual diergism of baseline plasma leptin and leptin suppression by arginine vasopressin in major depressives and matched controls

Leptin inhibits appetite by activating several neuroendocrine systems, including the hypothalamo-pituitary-adrenal cortical (HPA) axis. In turn, chronically elevated glucocorticoids increase circulating leptin. HPA axis hyperactivity occurs in 30-50% of patients with major depression, but the few prior reports of leptin measurements in this illness have shown inconsistent results. We, therefore, measured plasma leptin in 12 female and 8 male unipolar major depressives and 12 female and 8 male individually matched normal controls administered low-dose physostigmine (PHYSO) and arginine vasopressin (AVP) to stimulate the HPA axis. The subjects underwent four test sessions 5-7 days apart: PHYSO (8 microg/kg IV); AVP (0-08 U/kg IM); PHYSO+AVP; and saline control. Serial blood samples were taken before and after pharmacologic challenge and analyzed for leptin, ACTH(1-39), cortisol and AVP. Estradiol and testosterone also were measured at each test session. PHYSO and AVP produced no side effects in approximately half the subjects and predominantly mild side effects in the other half, with no significant patient-control differences. Correlations between side effects (absent or present) after PHYSO or AVP and the corresponding leptin responses were non-significant in all groups. Baseline plasma leptin concentrations (mean+/-S.D.) were significantly higher in the female patients compared to the female controls (22.5+/-13.9 ng/ml vs. 12.3+/-9.7 ng/ml), whereas they were similar in the male patients and the male controls (3.9+/-1.4 ng/ml vs. 3.6+/-2.0 ng/ml). Leptin concentrations following PHYSO remained unchanged from baseline, indicating that the short-lived ACTH and cortisol increases produced by PHYSO did not affect leptin secretion. In contrast, AVP administration, while also increasing ACTH and cortisol, significantly suppressed leptin, more so in the women than in the men. Baseline leptin and the leptin decrease after AVP were moderately positively correlated with the Hamilton Depression Scale 'somatization' factor in the female patients (r=0.50) and more strongly correlated with the 'mood-depression' factor in the male patients (r=0.81). These findings indicate a sexual diergism (functional sex difference) in plasma leptin measures between major depressives and matched normal controls.     

Serum leptin levels are higher in females affected by frontotemporal lobar degeneration than Alzheimer's disease

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.     

Changes in the fibrinolytic system in patients with peripheral arterial occlusive disease undergoing percutaneous transluminal angioplasty.

We have investigated fibrinolytic parameters in 33 patients with peripheral arterial occlusive disease (PAOD) before and 6, 24, and 48 hours after percutaneous transluminal angioplasty (PTA) as well as in 35 gender-matched healthy controls, whose mean age was not significantly different from the mean age of the patients. PAOD patients had significantly higher plasma levels of t-PA antigen (12.0+/-4.9 vs. 9.2+/-5.5 ng/ml), PAI-1 antigen (34.8+/-22.1 vs. 27.2+/-23.6 ng/ml), PAI-1 activity (10.0+/-6.5 vs. 8.0+/-8.0 U/ml), PCI (188.2+/-55.6 vs. 134.1+/-75.5% as compared with normal human plasma), and fibrinogen (420.2+/-92.6 vs. 261.9+/-32.7 mg/dl) as compared with controls. After angioplasty, fibrinolytic parameters and fibrinogen levels increased, reaching higher than preintervention levels 24 and 48 hours after the intervention. Six months after initially successful PTA, restenosis was demonstrated in 14 out of 33 patients (42%). Patients with late restenosis had significantly higher levels of PAI-1 activity 24 and 48 hours after PTA, as compared with patients with late patency (24 hours: 16.1+/-8.0 vs. 10.0+/-7.4; 48 hours: 16.5+/-7.9 vs. 12.0+/-7.0; p<0.05 for both time points). The results suggest that impaired fibrinolysis early after PTA might be a cause or marker of a disturbed repair process of vascular injury, leading to restenosis.     

The effect of TNF-alpha, PMA, and LPS on plasma and cell-associated IL-8 in human leukocytes

INTRODUCTION/AIM: This study was performed to examine the proficiency of mononuclear cells (MNC) and polymorphonuclear cells (PMN) in a whole blood model to expressing interleukin-8 (IL-8) in response to various stimuli. METHODS: Isolated cells that had been recombined with heparinized plasma were incubated with lipopolysaccharide (LPS), phorbol myristate acetate (PMA) and tumor necrosis factor (TNF)-alpha. RESULTS: IL-8 release by MNC was most potently induced by LPS, reaching significant levels after 2-h incubation in the presence of 0.2 ng/ml LPS. In contrast, 5.0 ng/ml LPS was required for PMN to release significant amounts of the cytokine (P<0.001). When PMN and MNC were coincubated (MNC/PMN), LPS-induced IL-8 release was reduced compared to the release from MNC alone, regardless of the concentration of LPS used. IL-8 release by PMN was much more strongly induced by TNF-alpha, increasing by 1050% in the presence of 10 ng/ml TNF-alpha (P<0.005), whereas MNC or MNC/PMN subjected to this stimulus alone did not significantly enhance their IL-8 release. PMA had no effect on IL-8 release from either cell type. Since a high portion of IL-8 in blood is associated with cells, the IL-8 levels in isolated and lysed cell suspensions were also quantified. Thus, a considerably higher level of IL-8 was found in freshly isolated PMN (0.58+/-0.09 ng/ml) than in MNC (0.010+/-0.007 ng/ml). PMN remained the main source for cell-associated IL-8 after 2-h incubation in the absence of any added stimuli, harbouring a relatively high level of the cytokine (3.37+/-1.38 ng/ml), which was significantly enhanced in the presence of TNF-alpha (8.99+/-1.46 ng/ml, P<0.001). CONCLUSION: This study shows that LPS is an effective inducer of IL-8 in MNC, whereas TNF-alpha is a potent agonist for IL-8 release from PMN. The main portion of cell-associated IL-8 is present in PMN when the cells are stimulated in their normal environment of plasma.     

Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1

Rakocevic Stojanovic V, Peric S, Lavrnic D, Popovic S, Ille T, Stevic Z, Basta I, Apostolski S. Leptin and the metabolic syndrome in patients with myotonic dystrophy type 1.
Acta Neurol Scand: 2010: 121: 94–98.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – To evaluate serum leptin concentration and its relation to metabolic syndrome (MSy) in non‐diabetic patients with myotonic dystrophy type 1 (DM1). Materials and methods – This study included 34 DM1 patients, and the same number of healthy subjects matched for age, sex and body mass index (BMI). Results – DM1 patients had increased BMI and insulin resistance, and increased leptin and insulin concentrations, but the other features of MSy such as diabetes, glucose intolerance and hypertension were not detected in DM1 patients. Serum leptin levels were higher in patients with DM1 than in healthy controls (8.5 ± 6.6 ng/ml vs 3.6 ± 2.9 ng/ml in men, and 13.9 ± 10.0 ng/ml vs 10.9 ± 6.9 ng/ml in women, respectively). In DM1 patients, leptin levels correlated with BMI, fasting insulin and insulin resistance (HOMA) (P < 0.01). Conclusions – The leptin overproduction correlated with insulin resistance in DM1 patients but the significance of this finding remains unclear.     

Haemostatic abnormalities, cardiac involvement and serum tumor necrosis factor levels in X-linked dystrophic patients

Left ventricular thrombosis and systemic emboli have been demonstrated to complicate cardiomyopathy in Duchenne and Becker muscular dystrophy (DMD, BMD). We investigated plasma levels of prothrombin fragment 1+2 (F1+2). thrombin-antithrombin III complex (TAT) and circulating levels of tumor necrosis factor-alpha (TNF-alpha), a procoagulant cytokine that has been shown to be elevated in patients with depressed cardiac function, in 20 patients with DMD and 12 patients with BMD as compared with 30 age-matched control subjects. Significantly elevated levels of F1+2 (DMD: 1.4+/-0.8 nmol/l; BMD: 1.8+/-0.8 nmol/l vs. controls: 0.7+/-0.2 nmol/l, p <0.01 and p <0.001, respectively), TAT complexes (DMD: 4.7+/-2.7 microg/l, BMD: 5+/-2.3 microg/l vs. controls: 1.6+/-0.5 microg/l, p <0.001) and TNF-alpha (54+/-9 vs. 25+/-7 pg/ml, p <0.001) were observed in patients with the dystrophic disease compared to control subjects. A significantly negative correlation was also found between F1+2 and TAT complexes and left ventricular ejection fraction (r = -0.65, p <0.0001; r = -0.80, p < 0.0001, respectively) and a positive correlation between F1+2 and TAT complexes and serum TNF-alpha levels (r = 0.67, p <0.0001; r = 0.70, p <0.0001, respectively). Our results indicate a hypercoagulable state in X-linked dystrophic patients. A possible relationship between haemostatic activation, left ventricular dysfunction and TNF-alpha system upregulation may be suggested.     

Immunoassays for the quantitation of porcine PAI-1 antigen and activity in biological fluid samples

Two monoclonal antibody-based enzyme-linked immunosorbent assays (ELISAs) for the quantitation of porcine plasminogen activator inhibitor-1 (PAI-1) antigen and activity in plasma were constructed and validated. The intra-assay, interassay, and interdilution coefficients of variation were 4.3, 13, and 8%, respectively, for the antigen ELISA and 5, 16, and 11% for the activity assay. Assay recoveries, in the antigen ELISA. of either latent or active recombinant porcine PAI-1 (10 and 50 ng/ml) added to plasma were 86 +/- 9% and 92 +/- 22%, respectively, for the latent form and 89 +/- 99% and 87 +/- 7% for the active form (mean +/- SD, n = 3 to 4). In the immunofunctional assay, recoveries for the same concentrations of active PAI-1 were 108 +/- 16% and 92 +/- 21%, respectively. In male porcine plasma the level of PAI-1 antigen was 31 +/- 11 ng/ ml and the activity, 34 +/- 16 ng/ml (mean +/- SD, n = 10). In female plasma PAI-1 antigen levels were 20 +/- 5.2 ng/ml and the PAI-1 activity 42 +/- 17 ng/ml (n = 13). A linear correlation was found between PAI-1 antigen and activity levels in male (r = 0.60) and female (r = 0.70) plasma. Immunodepletion resulted in a decrease of >95% of the original PAI-1 antigen or activity levels. Incubation of plasma samples at 37 degrees C for 16 h resulted in a significant decrease (70 to 85%) of PAI-1 activity. Under these conditions (37 degrees C, 16 h) PAI-1 antigen levels remained unchanged in males whereas the response of the female samples in the PAI-1 antigen assay increased two-fold. In lysed platelet-rich plasma males had 990 +/- 470 ng/ml antigen and 160 +/- 80 ng/ml activity and females, 920 +/- 500 ng/ml antigen and 150 +/- 98 ng/ml activity corresponding to 2.1 +/- 0.77 fg PAI-1 antigen per platelet. Only 16% of PAI-1 released from platelets was found to be active. Linear correlations between PAI-1 antigen and activity were found for both males (r = 0.61) and females (r = 0.67). The assays are both sensitive and specific and may, therefore, aid the elucidation of the pathophysiological role of PAI-1 in swine experimental models of atherosclerosis and other thrombotic disorders.     

Cerebrospinal fluid levels of selenium in patients with Alzheimer's disease

Summary. We compared CSF and serum selenium levels, measured by atomic absorption spectrophotometry, in 27 patients with Alzheimer's disease (AD) (13 females, 14 males, mean ± SD age 73.6 ± 7.4 years) without major clinical signs of undernutrition, and 34 matched controls (18 females, 16 males, mean ± SD age 70.7 ± 7.8 years). CSF and serum selenium levels did not differ significantly between AD-patient (11.4 ± 7.8 ng/ml and 28.5 ± 13.0 ng/ml, respectively) and control groups (13.3 ± 7.0 ng/ml and 22.5 ± 17.5 ng/ml). These values were not correlated with age, age at onset, duration of the disease, and scores of the MiniMental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that CSF selenium concentrations are apparently unrelated with the reported oxidative stress processes in patients with AD. Received May 5, 1998; accepted September 9, 1998     

Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine

This open-label, prospective, 4-month study in hyperprolactinemic patients with schizophrenia explored whether prolactin levels decrease after switching antipsychotic therapy to olanzapine. A secondary objective was to determine if reproductive morbidities and sexual dysfunction occurring with hyperprolactinemia improved with prolactin normalization. Clinically stable patients with schizophrenia, who had hyperprolactinemia defined as >18.8 ng/ml for males and >24.2 ng/ml for females, were randomized to: remain on current therapy (n=27) or switch to olanzapine, 5-20 mg/day, (n=27). Baseline prolactin levels in female patients randomized to receive olanzapine (n=14) were 66.3+/-38.7 ng/ml and were 82.0+/-37.6 (p=.32) in those remaining on their pre-study antipsychotic medication (n=14). In male patients, baseline prolactin levels were 33.7+/-12.1 and 33.5+/-13.8 ng/ml (p=.97), respectively, for those randomized to olanzapine (n=13) or remaining on pre-study treatment (n=13). At study end, patients switched to olanzapine experienced significant reductions in mean serum prolactin levels of 19.8+/-18.1 ng/ml in males (p=.02), and 32.3+/-47.5 ng/ml in females (p=.01), but prolactin continued to be elevated in patients who remained on pre-study antipsychotic treatment. After switching to olanzapine treatment, male patients experienced significantly (p=.03) increased free testosterone levels but there were no significant improvements in total testosterone levels; some female patients experienced improved menstrual cycling, as well as resolution of galactorrhea and gynecomastia, and sexual functioning was significantly improved in both genders. Patients switched to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement. Treatment-emergent adverse events did occur in both treatment groups; however, they were not significantly different between groups. Olanzapine-treated patients experienced significantly lower eosinophil counts and higher elevations in low-density lipoproteins and standing blood pressure than non-switched patients. Olanzapine treatment may offer sustained reduction in serum prolactin and improvement in sexual and reproductive comorbid symptoms in patients with schizophrenia who have treatment-emergent hyperprolactinemia.     

The cerebrospinal fluid level of glial fibrillary acidic protein is increased in cerebrospinal fluid from Alzheimer's disease patients and correlates with severity of dementia.

To gain insight of the underlying mechanisms of astroglial response to Alzheimer's disease (AD), the level of glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) from controls and AD subjects were immunochemically determined, and the correlation between that level and dementia severity of AD patients was evaluated. Means and SD of CSF levels of GFAP for the young control group (from 1 to 25 years, mean +/- SD 14.2 +/- 5.0, n = 13) adult control (from 26 to 55 years, 41.6 +/- 10.1, n = 9) and senescent control (older than 56 years, 65.4 +/- 8.0, n = 8) were 2.96 +/- 1.04, 2.80 +/- 1.46 and 3.99 +/- 1.55 ng/ml, respectively, and the CSF level of GFAP was not dependent on age (ANOVA, p = 0.17). While that of the AD patient group (n = 27, 70.8 +/- 8.0 years) was 8.96 +/- 7.80 ng/ml, significantly higher than that of both the all-control (3.19 +/- 1.39 ng/ml, t test, p < 0.001) and age-matched senescent (3.99 +/- 1.55 ng/ml, t test, p < 0.005) control groups. The receiver-operator characteristic (ROC) curve revealed that the GFAP concentration at 5 ng/ml in CSF could serve as a cutoff value. The CSF level of GFAP in the moderately to severely demented patients (MMSE /= 18, 6.85 +/- 5.76 ng/ml, n = 18; ANOVA, p < 0.05). These findings together with our previous report on an increase in the CSF level of apolipoprotein E suggest that degeneration and stimulation of astrocytes takes place concurrently in the AD brain.     

Association between major Multidrug Resistance 1 (MDR1) gene polymorphisms and plasma concentration of prolactin during risperidone treatment in schizophrenic patients

An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR1gene. The rate of P-glycoprotein efflux transport can mediate brain penetration of lipophilic drugs. We therefore studied the effects of major polymorphisms of MDR1 gene on plasma concentrations of prolactin. Subjects included 175 schizophrenic patients (68 males, 107 females) who were receiving 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in females were significantly higher than in males (54.3+/-27.2 versus 126.8+/-70.2 ng/ml, p<0.001). There was no difference in mean (+/-SD) plasma concentration of prolactin between C3435T genotypes [C/C, C/T, T/T; 62.3+/-33.3, 49.4+/-15.6, 53.2+/-33.2 ng/ml, ns] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 58.0+/-27.7, 58.5+/-35.0, 46.1+/-20.7 ng/ml, ns] in males nor between C3435T genotypes (123.6+/-65.0, 127.8+/-79.2, 130.4+/-49.7 ng/ml, ns) or G2677T/A genotypes (123.3+/-67.0, 97.7+/-71.2, 144.9+/-69.9 ng/ml, ns) in females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized beta=0.540, p<0.001) and negatively with age (standardized beta=-0.183, p<0.01). No correlations were found between prolactin concentration and MDR1 genotypes. These findings suggest that prolactin concentrations in females are much higher than in males but the major MDR1 variants are not associated with the plasma concentration of prolactin.     

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome

Background: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone. Methods: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol. Results: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029). Conclusions: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.     

Involvement of an altered 5-HT -{6} receptor function in behavioral symptoms of Alzheimer's disease

We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02 +/- 27.53 pmol/mg prot.) compared to controls (823.33 +/-196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT_{6} receptor density was significantly lower (p< 0.01) in AD (6.67 +/- 0.83) compared to controls (16.67 +/- 3.33). Splitting these results by sex, 5-HT_{6} receptor activation was significantly lower (p< 0.01) in AD females compared to males (121.67 +/- 30.02 vs. 231.67 +/- 34.17 pmol/mg prot). 5-HT_{6} density and 5-HT levels were significantly correlated (p < or = 0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT_{6} activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.