Schizoaffective disorder: diagnostic issues and future recommendations

Objective:  Difficulties surrounding the classification of mixed psychotic and affective syndromes continue to plague psychiatric nosology. This paper addresses the controversy regarding the diagnostic validity of schizoaffective disorder (SAD), a diagnosis that is used in both DSM-IV and ICD-10 and one that encroaches on both schizophrenia (SCZ) and bipolar disorder (BD).
Methods:  A systematic synthesis of clinical and empirical literature, including evidence from cognitive, neurobiological, genetic, and epidemiological research, was undertaken with the aim of evaluating the utility of the SAD classification.
Results:  Distinctions between the diagnostic categories of SCZ, SAD and BD are not clearly demarcated by findings from neuropsychological, neuroimaging, molecular neurobiology, or genetic epidemiology studies. On the contrary, convergent evidence purports overlap across current diagnostic boundaries in the heritability and pathophysiology of psychotic and affective disorders. However, there are some disorder-specific findings.
Conclusions:  Schizoaffective disorder is a prototypic boundary condition that epitomizes the pitfalls of the current categorical classification system. Future revisions to the DSM should consider the implementation of one of two alternative models to account for individuals presenting with mixed psychotic and affective symptoms. These include the views that (i) SAD is a comorbid set of symptoms that occur as a by-product of two separate disorders (SCZ and BD) or, that (ii) SAD exists as the mid-point on a continuum between SCZ and BD, such that the incorporation of these two disorders onto one dimension may be a suitable alternative. Hence the category SAD should be omitted in future revisions of DSM, allowing the development of meaningful nomenclature that rests upon further rigorous investigation of differences and similarities between disorders.     

Distribution of cyclosporine in blood of a renal-transplant recipient with type V hyperlipoproteinemia

A patient with severe type V hyperlipoproteinemia and chronic end-stage renal disease received a renal transplant and therapy with cyclosporine. Concentrations of the drug in plasma as determined by liquid chromatography appeared extraordinarily high for the dose ingested. When we measured the drug in the plasma, plasma cleared by ultracentrifugation, leukocytes, erythrocytes, and whole blood, we found that the high concentrations of cyclosporine were associated with the chylomicrons that always were present in this patient's blood. Cyclosporine added directly to this patient's plasma was less associated with the plasma lipids. Isolated lymphocytes and kidney slices incubated with plasma from this patient bound no more drug than when incubated with nonhyperlipemic plasma containing cyclosporine at a normal therapeutic concentration. We conclude that the cyclosporine associated with the chylomicrons in this patient was not biologically available to either lymphocytes or kidney tissue. We strongly recommend the use of chylomicron-cleared plasma for therapeutic drug monitoring of cyclosporine in type V hyperlipoproteinemic patients.     

Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation

The inability of transplanted cells to proliferate in the normal liver hampers cell therapy. We considered that oxidative hepatic DNA damage would impair the survival of native cells and promote proliferation in transplanted cells. Dipeptidyl peptidase-deficient F344 rats were preconditioned with whole liver radiation and warm ischemia-reperfusion followed by intrasplenic transplantation of syngeneic F344 rat hepatocytes. The preconditioning was well tolerated, although serum aminotransferase levels rose transiently and hepatic injury was observed histologically, along with decreased catalase activity and 8-hydroxy adducts of guanine, indicating oxidative DNA damage. Transplanted cells did not proliferate in the liver over 3 months in control animals and animals preconditioned with ischemia-reperfusion alone. Animals treated with radiation alone showed some transplanted cell proliferation. In contrast, the liver of animals preconditioned with radiation plus ischemia-reperfusion was replaced virtually completely over 3 months. Transplanted cells integrated in the liver parenchyma and liver architecture were preserved normally. These findings offer a paradigm for repopulating the liver with transplanted cells. Progressive loss of cells experiencing oxidative DNA damage after radiation and ischemia-reperfusion injury could be of significance for epithelial renewal in additional organs.     

Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity

BACKGROUND: Elevated circulating free fatty acids (FFA) contribute to the development of hepatic steatosis and promote hepatocyte apoptosis by incompletely defined mechanisms. Although the death ligand TRAIL has been implicated in a variety of pathological liver diseases, the role of TRAIL in mediating apoptosis of FFA induced steatotic hepatocytes is unknown. AIM: We examined TRAIL cytotoxicity in an in vitro model of hepatocyte steatosis induced by FFA. METHODS: Hepatocytes (Huh 7 cells, HepG2 cells, and primary rat hepatocytes) were rendered steatotic by incubation with oleic acid. Apoptosis was assessed morphologically and biochemically by caspase activity. TRAIL receptor regulation was examined using immunoblot analysis and siRNA for targeted knockdown. c-jun N-terminal kinase (JNK) inhibition was attained with SP600125. RESULTS: Oleic acid sensitised the cells to TRAIL but not TNF-alpha cytotoxicity. FFA sensitisation to TRAIL occurred at much lower concentrations than required for FFA mediated sensitisation to Fas, or FFA induced lipoapoptosis. Oleic acid treatment led to upregulation of the cognate TRAIL receptor death receptor 5 (DR5) but not death receptor 4 (DR4). The upregulation of DR5 was JNK dependent. siRNA targeted knockdown of either DR5 or DR4 demonstrated that DR5 was responsible for FFA sensitisation to TRAIL killing. DR5 expression was enhanced in steatotic human liver samples. CONCLUSION: Our results suggest that FFA induced hepatocyte steatosis sensitises to TRAIL by a DR5 mediated JNK dependent mechanism.     

Regional gray matter changes in bipolar disorder: a voxel-based morphometric study

OBJECTIVE: To investigate structural abnormalities in bipolar disorder (BD) using optimized voxel-based morphometry (VBM) in closely matched patients and controls, and to examine the relationship of clinical features with regional gray matter (GM) volumes. METHODS: Twenty-four patients (six male) aged 19-59 years (mean=38.21 years, SD=11.04 years) with DSM-IV bipolar I disorder were compared with 25 control subjects, matched on age, sex, and years of education. VBM analyses were conducted on high-resolution T1-weighted brain magnetic resonance imaging to detect regional GM volume differences between groups, ensuring statistical correlation for age, sex and total intracranial volumes. Within the patient groups, regional GM changes were also investigated. RESULTS: Compared to controls, BD patients had increased GM volume in left parahippocampal gyrus and decreased GM volume in left middle temporal gyrus. Family history, psychotic symptoms and lithium status were associated with regional GM abnormalities in BD patients. CONCLUSIONS: This study presents evidence of gray matter volume abnormalities in adults with bipolar I disorder. Regional variation in relation to clinical factors suggests a neurobiological basis for clinical heterogeneity and posits the possibility of trait deficits.     

Do cognitive deficits in juvenile bipolar disorder persist into adulthood?

This article reviews neuropsychological research in adults with bipolar disorder and compares the findings with emergent data on neuropsychological function in juvenile bipolar disorder. Despite a recent surge of interest in childhood onset bipolar disorder, there remains a scarcity of neuropsychological literature investigating this population. From the study of adult bipolar disorder a substantial body of literature points to the existence of trait deficits in verbal and executive function that are detectable even during euthymia. In the nascent literature on neuropsychology in early onset bipolar, there is growing evidence to suggest that some of the deficits apparent in adults are also discernible in adolescents. Precise knowledge about when, how, and why these deficits appear requires future research of prodromal changes in neurocognition in childhood and adolescent bipolar disorder.