Extended-release divalproex in bipolar and other psychiatric disorders: A comprehensive review

Bipolar disorder can be a devastating disease state for individuals with the disease and also for family members. Proper recognition and treatment is vital to the successful management of this disease state. Through increased community and practitioner awareness, along with efforts to increase awareness for proper assessment, the rate of diagnosed bipolar disorder is increasing. Recent years have brought about the introduction of several new medications with approved indications for the treatment of bipolar disorder. In addition to new agents, traditional mood stabilizing medications have also been released in different formulations to better enhance tolerability without jeopardizing efficacy. One particular product is extended-release divalproex sodium. In the following article, we review the clinical presentation of bipolar disorder, its epidemiology, and the pharmacokinetics and mechanism of action for divalproex. In addition, we specifically review the role of extended-release divalproex in bipolar disorder through a critical analysis of the currently available published primary literature.     

The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy

The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al. , Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (chi(2)=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6.     

Chronic neuroprotective effects of low concentration lithium on SH-SY5Y cells:possible involvement of stress proteins and gene expression

To investigate the molecular mechanism underlying the neuroprotective effect of lithium on cells, in this study, we exposed SH-SY5Y cells to 0.5 mmol/L lithium carbonate(Li2CO2) for 25–50 weeks and then detected the expression levels of some neurobiology related genes and post-translational modifications of stress proteins in SH-SY5Y cells. cDNA arrays showed that pyruvate kinase 2(PKM2) and calmodulin 3(CaM 3) expression levels were significantly down-regulated, phosphatase protein PP2A expression was lightly down-regulated, and casein kinase II(CK2), threonine/tyrosine phosphatase 7(PYST2), and dopamine beta-hydroxylase(DBH) expression levels were significantly up-regulated. Besides, western blot analysis of stress proteins(HSP27, HSP70, GRP78 and GRP94) showed an over-expression of two proteins: a 105 kDa protein which is a hyper-phosphorylated isoform of GRP94, and a 108 kDa protein which is a phosphorylated tetramer of HSP27. These results suggest that the neuroprotective effects of lithium are likely related to gene expressions and post-translational modifications of proteins cited above.     

No Association Between the Dopamine D2 Receptor Taq I A1 Allele and Earlier Age of Onset of Alcohol Dependence According to Different Specified Criteria

BACKGROUND: The presence of the A1 allele of the dopamine D2 receptor TaqI restriction fragment length polymorphism has been reported to be associated with an earlier age of onset of alcohol dependence as a marker for severity. METHODS: We tested this hypothesis with special regard to the definition of the age of onset of alcoholism in 243 patients with alcohol dependence, according to DSM-IV criteria assessed by the standardized interview Münchner Composite International Diagnostic Interview (M-CIDI), consecutively admitted for detoxification. Additionally, the Addiction Severity Index (ASI) was performed. The TaqIA polymorphism was amplified by polymerase chain reaction (PCR), and the PCR product was digested by the restriction enzyme TaqI. Patients were subsequently divided into an A1 (presence of at least one A1 allele, n = 88) and an A2 group (absence of an A1 allele, n = 155). The following criteria for different definitions of age of onset were used: (1) age of onset of the first occurring symptom necessary for the diagnosis of alcohol dependence according to M-CIDI; (2) age of onset of the last symptom of alcohol dependence according to M-CIDI; (3) age of onset of more than 3 drinking days per week on a regular basis according to ASI; (4) age of onset of more than 3 drinking days-of more than five drinks per drinking day-or at least one binge drinking episode per week on a regular basis according to ASI. RESULTS: The frequency of the A1 allele in our patient sample was 0.208. No statistically significant association between the A1 allele and the age of onset of alcoholism was found. The mean age of onset according to criterion 1 was 30.4 +/- 10.8 years for the A1 group and 30.2 +/- 10.2 years for the A2 group (p = 0.89); for criterion 2, it was 33.3 +/- 10.0 years for the A1 group and 33.9 +/- 10.2 years for the A2 group (p = 0.77); for criterion 3, it was 18.0 +/- 7.5 years for the A1 group and 18.1 +/- 6.1 years for the A2 group (p = 0.92); and for criterion 4, it was 22.3 +/- 9.7 years for the A1 group and 21.8 +/- 8.5 years for the A2 group (p = 0.76). CONCLUSIONS: No association was found between the A1 polymorphism and age at onset of alcohol dependence according to different specified criteria.     

Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen

The vaccination route may influence the success of immunization against pathogens. The conventional intramuscular (i.m.) application of a vaccine containing the hepatitis B virus (HBV) surface antigen (HBsAg) led to protective anti-HBs antibody levels in the majority of vaccine recipients. In this study, we vaccinated healthy volunteers and a group of i.m. vaccine nonresponders via the intradermal (i.d.) route and analyzed the HBV-specific B-cell response as well as class-II- and class-I-restricted T-cell responses by (3)H-thymidine uptake, enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT). The results were then compared with i.m. vaccinated controls. I.d. vaccinations were well tolerated and induced neutralizing anti-HBs antibodies in all naive vaccine recipients and, importantly, all but one former i.m. nonresponder developed protective anti-HBs serum antibody levels after 2 or 3 i.d. immunizations. On the cellular level, i.d. vaccine recipients showed significantly higher anti-HBs producing B-cell frequencies and more vigorous class-II-restricted T-helper (Th) cell responses than i.m. controls. However, although the HBsAg-specific T cells were characterized by their cytokine release as Th1-like cells in both groups, human leukocyte antigen (HLA)-A2+ individuals who received the soluble HBsAg via the i.d. route developed higher peptide-specific cytotoxic CD8+ T cell precursor (CTLp) frequencies. In conclusion, i.d. HBsAg vaccination is more effective even in former i.m. vaccine nonresponders with respect to antibody induction and specific B- and T-cell responses. The induction of virus-specific CTLp may provide the rationale to study the i.d. HBsAg vaccine in the treatment of chronic hepatitis B.     

The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis

Background

Elevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres.

Aims

To investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis.

Methods

Serum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N = 345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma.

Results

Elevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma.

Conclusion

The prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.     

18F-Fluorodeoxyglucose Positron-Emission Tomography (PET) Can Be Used to Assess Inflammation Non-invasively in Crohn’s Disease

Background

Differential therapy requires repeated diagnostic assessment for mapping and monitoring of disease activity in Crohn’s disease (CD).

Purpose

The purpose of this prospective study was to evaluate the accuracy of ¹⁸F-fluorodexyglucose positron-emission tomography (FDG-PET) for non-invasive assessment of disease activity in CD.

Methods

Forty-three patients with CD underwent ileocolonoscopy and hydromagnetic resonance imaging (hydro-MRI) as reference standards. In addition, FDG-PET was performed and correlated with clinical data, hydro-MRI, and endoscopy findings. Diagnostic accuracy was determined for all methods.

Results

Two-hundred and forty-one bowel segments could be analyzed by all methods. Of 80 endoscopically inflamed segments in CD, FDG-PET detected 72 and hydro-MRI 53 segments. Overall sensitivity was 90 % (FDG-PET) versus 66 % (hydro-MRI), and specificity was 92.6 % versus 99 %. In the proximal ileum, hydro-MRI revealed inflammation in eight out of 49 patients and FDG-PET, also, detected all of these inflamed segments. Seventeen stenoses could be identified in 43 CD patients. With regard to assessment as inflammatory or fibrotic stenosis, there was good concordance between colonoscopy, hydro-MRI, and FDG-PET. In one case only, the nature of the stenosis was assessed differently. In contrast with leukocyte numbers and CDAI, there was significant correlation of FDG-PET activity with C-reactive protein and CDEIS levels (P = 0.019 and P = 0.007, respectively).

Conclusion

FDG-PET is able to detect mucosal inflammation in CD with high sensitivity and specificity and to enable proper assessment of inflammatory activity in stenoses. FDG-PET is, thus, a promising non-invasive technique for clinical management of CD.     

Alcohol-induced metabolomic differences in humans

Alcohol consumption is one of the world''s major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values <3.8E−04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies.