Impact of Type and Duration of Use of Antipsychotic Drugs on Plasma Levels of Selected Acute-Phase Proteins in Patients with Major Mental Illnesses.

Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer

Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients

Objective: This study examined ethnic disparities in antipsychotic therapy in a population with significant Asian representation. Methods: Using a cross-sectional retrospective study design, self-reported ethnicity data pooled from three cycles of the Canadian Community Health Survey were linked to 2005 administrative data on physician, hospital, and pharmaceutical use in British Columbia, Canada. Logistic regression was used to model the association between ethnicity and the likelihood of filling one or more prescriptions for any antipsychotic, with controls for sex, age, residence, immigrant status, income, health status, and diagnoses of schizophrenia, bipolar disorder, depression, and dementia. Results: Of the 27,658 individuals in the sample, 2.2% filled at least one antipsychotic prescription. The proportion varied across ethnic groups: Chinese, 1.0%; other Asians, 1.2%; whites, 2.3%; nonwhite non-Asians, 2.8%; and mixed ethnicity, 4.3%. After adjustment for patient characteristics and diagnoses of schizophrenia and bipolar disorder, the likelihood of filling a prescription was found to be lower among Chinese (odds ratio [OR]=.47, 95% confidence interval [CI]=.24–.90) and higher among persons of mixed ethnicity (OR=3.19, CI=1.49–6.83). Further adjustment for depression and dementia diagnoses did not significantly change the ORs for the Chinese (OR=.49, CI=.25–.98) and the mixed ethnic groups (OR=2.97, CI=1.30–6.80). Conclusions: Consistent with the existing literature on ethnic disparities in antipsychotic therapy, the study found evidence of persistent disparities in a population that has a significant number of Asians. Further studies should be done to identify possible causes of these disparities and to identify potential interventions that may reduce or eliminate them. (Psychiatric Services 62:1026–1031, 2011)

Long-term use of antipsychotics among community-dwelling persons with Alzheimer׳s disease: A nationwide register-based study

Patients with malignant tumors complicated by venous thromboembolism (VTE) face high mortality rates because of a lack of effective diagnostic and predictive markers. Plasminogen activator inhibitor 1 (PAI-1) and tissue-type plasminogen activator-inhibitor complex (t-PAIC) may contribute to VTE formation in these patients. To evaluate the diagnostic and predictive value of peripheral blood PAI-1 and t-PAIC levels in patients with malignant tumors complicated by VTE and to develop a new thrombosis risk score model (NRS) based on PAI-1 levels. This study included 216 patients with malignant tumors (lung, colorectal, ovarian, breast, and gastric cancers). The correlation between PAI-1 and t-PAIC levels was explored. The predictive value of PAI-1 and t-PAIC, combined with the COMPASS-CAT risk score, Khorana risk score, and Padua risk score, was assessed for postoperative VTE risk. Differences in PAI-1 and t-PAIC levels across tumor types were also analyzed. The PAI-1 and t-PAIC levels were positively correlated. Preintervention PAI-1 levels independently predicted VTE risk, and the new thrombosis risk score model could effectively predict the occurrence of concurrent VTE in patients with malignancy. PAI-1 and t-PAIC have better diagnostic value for VTE than D-dimers. Combining these markers with the COMPASS-CAT risk score, Khorana risk score, and Padua risk score improves the risk prediction of VTE. PAI-1 levels were significantly associated with VTE risk in colorectal cancer, whereas t-PAIC levels were significantly associated with VTE risk in breast cancer. Peripheral blood PAI-1 and t-PAIC levels have excellent predictive and diagnostic value for VTE in patients with malignancy.

Blood levels of the clotting factor fibrinogen and tissue plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of fibrinolysis, have been positively linked to risk of coronary heart disease. The authors have reported previously that plasma fibrinogen appears to rise after menopause and to be reduced with use of postmenopausal hormonal therapy. There is also evidence to suggest that sex hormones may influence PAI-1. To examine whether plasma fibrinogen and PAI-1 antigen levels differ among older postmenopausal women according to use of hormone therapy and by blood level of estrogen and androgens, these variables were assessed among 277 healthy women aged 65-82 years, one half of whom were receiving therapy. The study population was drawn from the Study of Osteoporotic Fractures, Pittsburgh, Pennsylvania, during 1986-1988. Overall, results showed median PAI-1 levels to be lower on average with oral and transdermal use of hormone therapy (25.0 vs. 33.5 ng/ml, p < 0.01) and mean fibrinogen levels to be lower (279 vs. 295 mg/dl, p < 0.02) with use of oral estrogen (but not transdermal) therapy compared with women not receiving therapy. Among women not receiving therapy, PAI-1 and fibrinogen levels were not related to endogenous sex hormone levels, with the exception of a modest positive relation between PAI-1 and serum estrone concentrations (rs = 0.29). In addition, a markedly higher PAI-1 level was found for women with a preponderance of upper body fat, independent of obesity. In sum, results showed that older women receiving postmenopausal hormone therapy had more favorable plasma levels of the hemostatic factors PAI-1 and fibrinogen than did those not receiving therapy, which can be explained in large part by differences between the two groups in obesity and body fat distribution.

The deletion (D) allele of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is strongly associated with an increased level of circulating ACE. The ACE gene polymorphism may influence the production of angiotensin II (Ang II). It has been shown that Ang II modulates fibrinolysis, that is, Ang II increases plasminogen activator inhibitor-1 (PAI-1) mRNA and plasma PAI-1 levels in vitro and in vivo. Considered together, we tested the hypothesis that the deletion allele of the ACE gene might be associated with increased levels of PAI-1. We related the ACE genotype to PAI-1 antigen levels in 603 men and 221 women attending a routine health screening. As a whole, the plasma PAI-1 level was not strongly associated with ACE genotype. Since the PAI-1 level was significantly influenced by well-known risk factors for coronary artery disease (CAD), we further analyzed the data after excluding subjects with major cardiovascular risk factors. In low-risk male subjects, the DD genotype had significantly higher levels of plasma PAI-1 (DD: 20.3 +/- 2.2; DI: 13.9 +/- 1.1; II: 13.6 +/- 1.3 ng/mL, P = .010 by ANOVA). In low-risk female subjects, the DD genotype showed a tendency to a high level of plasma PAI-1 without statistical significance. When analysis was restricted to postmenopausal women (age > or = 55 or FSH > or = 35 ng/mL), the DD genotype showed a significantly higher level of PAI-1 than subjects with the DI and II genotypes (27.7 +/- 6.2 versus 15.6 +/- 1.8 ng/mL, P = .028). The DD polymorphism of the ACE gene is associated with high PAI-1 levels in male and possibly in postmenopausal female subjects who have lower conventional cardiovascular risk factors. These results suggest that the increased ACE activity caused by DD polymorphism may play an important role in elevating the level of plasma PAI-1. Our data support the notion that the genetic variation of ACE contributes to the balance of the fibrinolytic pathway.

EFFECT OF BEZAFIBRATE ON HYPERCOAGULABILITY ASSESSED BY FLUOROGENIC PROTHROMBIN TIME IN HYPERLIPIDEMIC PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES MELLITUS

Plasminogen Activator Inhibitor-1 and Vitronectin Levels in Children with Acute Lymphoblastic Leukemia, and Their Relationship with Risk Groups

Trends in Use of Antipsychotics and Mood Stabilizers Among Medicaid Beneficiaries With Bipolar Disorder, 2001-2004

This study aimed to determine the prevalence of prescribing antipsychotics to adults without schizophrenia or bipolar disorder and to identify factors associated with such off-label use. Patients with at least one prescription for an antipsychotic medication from the Department of Veterans Affairs (VA) during fiscal year (FY) 2007 were identified in national VA administrative databases. Rates of off-label antipsychotic use were determined along with average doses. Multivariate logistic regression models identified sociodemographic and clinical characteristics associated with off-label use. Of the 279,778 individuals in FY 2007 who received an antipsychotic medication, 168,442 (60.2%) had no record of a diagnosis for which these drugs are approved. The most common mental illness diagnoses among patients given prescriptions for antipsychotics off label were posttraumatic stress disorder (PTSD, 41.8%), minor depression (39.5%), major depression (23.4%), and anxiety disorder (20.0%). Among VA patients with mental illness other than schizophrenia or bipolar disorder, the proportion who received prescriptions for antipsychotic medications ranged from a low of 9.1% among patients with adjustment reaction; to about 20% for those with depression, dementia, or PTSD; and to a high of 40.7% among patients with other psychoses. Doses were low, with over half of patients who received off-label quetiapine, risperidone, or first-generation antipsychotics receiving doses below those recommended for schizophrenia. In logistic regression models, patients diagnosed as having other psychosis or dementia had the highest odds of receiving an antipsychotic medication off label. Off-label use of antipsychotic medications was common. Given that these drugs are expensive, have potentially severe side effects, and have limited evidence supporting their effectiveness for off-label usage, they should be used with greater caution.

The authors examined prevalence, incidence, and duration of antipsychotic drug use in the northern and eastern regions of the Netherlands between 1997 and 2005 among youths in regard to age, gender, and class of drug. Prescription drug dispensing data were collected from community pharmacies in the northern Netherlands (www.iadb.nl). Prevalence, incidence, and duration of use were studied among roughly 100,000 youths ranging in age from infancy to age 19 years, calculated by age group (zero to four years, five to nine years, ten to 14 years, and 15 to 19 years), for boys and girls, and for first- and second-generation antipsychotics. Duration of use was compared between youths who started antipsychotic treatment in 1998-1999 and those who started in 2001-2002. From 1997 to 2005, prevalence increased from 3.0 to 6.8 per thousand. Prevalence was highest among ten-year-olds to 14-year-olds (11 per thousand), especially among boys (17 per thousand). The increased prevalence was mainly attributable to an increased use of second-generation antipsychotics and to a longer duration of use. Median duration of use doubled from .8 year in 1998-1999 to 1.6 years in 2001-2002. Second-generation antipsychotic drugs were increasingly prescribed, and for longer periods of time, to younger children, probably because of new indications. This practice increases the exposure of a young population to (partly unknown) risks.

Prior studies have demonstrated a cross-sectional association between elevated plasminogen activator inhibitor-1 (PAI-1) levels and nonalcoholic fatty liver disease (NAFLD). However, there are no prospective longitudinal assessments of the association between PAI-1 and NAFLD. We aimed to describe the association between PAI-1 levels in early adulthood with NAFLD in midlife. Among the 5115 participants in the coronary artery risk development in young adults (CARDIA) study, participants were randomly selected from a subset that was free of obesity, diabetes and hypertension at the 1992-1993 exam and attended the 2005-2006 exam (n=996). A subset of participants (n=896) also had CT liver fat measured (2010-2011). Participants with secondary causes of steatosis were excluded (n=87). NAFLD was defined as liver attenuation ≤51 Hounsfield units. Logistic regression models assessed the association between PAI-1 and NAFLD. Of 809 participants, 53% were female, 37% black with a mean age of 32years. Median PAI-1 level at 1st assessment (1992-1993) was 23.4ng/mL among participants with NAFLD vs 11.9ng/mL among those without NAFLD (P<.0001). Median PAI-1 level at 2nd assessment (2005-2006) was 55.6ng/mL among participants with NAFLD vs 19.5ng/mL among those without NAFLD (P<.0001). Higher PAI-1 levels were independently associated with NAFLD (1st assessment adjusted OR [AOR] 2.16 per 1 standard deviation higher log(PAI-1) level (95% confidence interval [CI] 1.63-2.85); 2nd assessment AOR 2.71 (95% CI 2.03-3.61)). Plasma PAI-1 levels in young adulthood were independently associated with NAFLD in midlife. Further studies may indicate whether PAI-1 plays a role in NAFLD pathophysiology.

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3-5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non-DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long-standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI-1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti-aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.

Patients with inflammatory bowel disease (IBD) have an increased risk of thromboembolic events. Imbalance of fibrinolysis has been suggested as one of the possible pathogenetic mechanisms. As plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) are inhibitors of fibrinolysis, we studied TAFI as well as PAI-1 plasma levels in IBD patients compared with healthy controls. A total of 132 IBD patients [68 ulcerative colitis (UC) and 64 Crohn's disease (CD)] and 50 healthy controls were enrolled. PAI-1 and TAFI plasma levels were assessed by commercially available enzyme-linked immunosorbent assay kits. Their relationship with clinical parameters of UC and CD was assessed. Mean plasma PAI-1 levels were significantly higher in both UC patients (3.9+/-1.3 IU/ml) and CD patients (4.0+/-1.5 IU/ml) compared with healthy controls (3.1+/-1.1 IU/ml) (P=0.01). On the other hand, mean plasma TAFI levels were significantly lower in both UC patients (14.7+/-3.1 microg/ml) and CD patients (13.3+/-3.4 microg/ml) compared with healthy controls (17.4+/-3.0 microg/ml) (P<0.0001). Patients with active disease had significantly higher PAI-1 levels compared with patients with inactive disease for both diseases (P=0.03 and P=0.01, respectively). No significant association between plasma TAFI levels and disease activity was also found. Plasma TAFI levels were significantly lower in patients with ileal CD compared with patients with colonic CD. PAI-1 plasma levels are increased whereas TAFI levels are decreased in IBD patients. These results suggest an imbalance of fibrinolysis in IBD.