L. De Picker

906 – Hyponatremia and antidepressants: are they worth their salt? a class-per-class review of the literature

Introduction Hyponatremia due to antidepressant-induced SIADH can cause significant morbidity and serious complications. It is commonly associated with SSRIs, but the frequency and class-specificity are unclear. Objectives To determine the relationship between hyponatremia and antidepressants, defining incidence and odds ratios for antidepressant classes, along with patient risk factors. Methods A review of the literature was performed in Web of Science and Pubmed until April 2012, using combinations of search strings “antidepressants” and antidepressant class and generic drug names with “hyponatr(a)emia”, “SIADH” or “inappropriate antidiuretic hormone secretion”. Results 19 effect studies and over 50 case reports were considered, the majority concerning SSRIs. Variation in study design, population and cut-off values caused divergence of hyponatremia incidences of 0.06-40% for SSRIs and 0.08-70% for venlafaxine. Incidence numbers for mirtazapine and TCAs were tenfold lower. Odds ratios for SSRIs (1.5 -4.0) were consistently higher than for TCAs (1.1-1.9). The risk associated with MAO-inhibitors, reboxetine and bupropion could not be established due to insufficient information. Patient risk factors included older age (OR 6.3) and concommitant use of (thiazide) diuretics (OR 11.2-13.5). Conclusion Hyponatremia is an underdiagnosed and potentially dangerous side-effect of antidepressants and this risk is not exclusive to SSRIs. Current evidence suggests a relatively high risk for hyponatremia with the use of SSRIs or venlafaxine, especially combined with patient risk factors, in which cases clinicians should actively screen for this complication. Mirtazapine and TCAs entail a moderate risk and can be considered as alternative treatment for patients with increased risk or history of hyponatremia.

Preserved SDST Learning in Schizophrenia

Objective Processing speed deficits are very differentiating cognitive impairments in schizophrenia (Brebion 2014) and can be most adequately assessed by a symbol-digit coding task (Dickinson 2007). A digitized version, the Symbol Digit Substitution Test (SDST), allows for the decomposition of processing speed into its motor and cognitive components. Learning performance on both components was compared between schizophrenia patients and age-matched controls. Methods In the SDST, digits were drawn as fast as possible under their corresponding symbol. The task was administered on day 1, 2 and 7 to patients with schizophrenia (N=30) and age-matched controls (N=30) and performed on a digitizing tablet, which allowed precise measurement of the time to write each digit (writing time) and to decode symbols into digits (matching time). Learning was assessed by a change of matching time over sessions and repetition blocks within each session. Results Patients with schizophrenia had a lower test score and a longer writing and matching time compared to controls. Repetitions between and within sessions demonstrated substantial decreases in matching time, while writing time remained constant. Remarkably, the rate of learning was similar between schizophrenia patients and controls. Conclusion Although patients with schizophrenia display both sensorimotor (writing time) and cognitive slowing (matching time), their test results improve similarly to the controls in long and short term. This finding may be attributed to a decrease in matching time, explained by the learning of the symbol-digit relations. Download full-size image

How to Perform Translocator Protein PET-CT Scanning for Microglial Activation in Schizophrenia Patients.

Introduction Activated microglia express translocator protein (TSPO) on the outer mitochondrial membrane. PET ligands targeting TSPO allow in vivo non-invasive visualization and quantification of neuroinflammation. Whereas inflammation in schizophrenia was previously studied using 11 C-PK11195, 18 F-PBR111 is a novel second-generation tracer, with high specific TSPO binding and longer half-life. Objective To establish a protocol for 18 F-PBR111 TSPO PET in schizophrenia. Methods A pilot study on a Siemens Biograph mCT PET-scanner in healthy controls and schizophrenia patients (n=9). Results Subjects underwent a 90-minute dynamic brain PET-CT, following i.v. bolus injection of 214±13 MBq 18 F-PBR111. An arterial input function was measured using continuous blood sampling (Twilite, Switzerland) with discrete samples for metabolite analysis. The metabolite corrected plasma input function (IPF) was calculated from the whole blood input function, individual plasma to whole blood and parent fraction data as determined by a SEP-PAK procedure. Dynamic PET data were reconstructed and a post-reconstruction motion correction was applied. Regional tissue time activity curves (TACs) were extracted from the PET images for regions of interest determined from individual MRI images. Total volume of distribution (V T ) was then calculated from fitting a reversible two-tissue compartmental model to the measured TACs using the individual IPF. Prior genotyping for TSPO receptor polymorphism (rs6971) allowed to exclude low-affinity binders (estimated 10% of European population). The procedure was well tolerated. Conclusions We established a protocol for 18 F-PBR111 TSPO PET in healthy subjects and schizophrenia patients, thereby providing useful information for others considering 18 F-PBR111 TSPO PET imaging for evaluation of neuroinflammation.

EPA-0445 – Procedural learning in stable schizophrenia patients compared to healthy young and elderly controls in two variations of the rotary pursuit.

Objective To compare sensorimotor learning in stable schizophrenia patients, healthy age- and sex-matched controls and elderly controls in two variations of the classic Rotary Pursuit. Method In Circle Pursuit (true motor learning), a target circle, rotating along a predictable circular path on the computer screen, must be followed by manipulating the pen on the writing tablet. The task consists of two trials of six rotations each, with target speed gradually increasing. In the eight-trial Figure Pursuit (motor and sequence learning), subjects learn to draw a complex figure by following a target circle that moves at a fixed speed along an invisible trajectory around several goals. Tasks were administered thrice (interval 2-7days) to 32 stable schizophrenia patients (S), 16 healthy age- and sex-matched controls (Y) and 16 elderly controls (>65y; E) and recorded with a digitizing tablet and pressuresensitive pen (200Hz frequency; 0.2mm spatial accuracy). Learning speed was assessed in a repeated-measures ANOVA of outcome variable accuracy (% of time cursor is within target). Results All groups exhibited learning effects and significant group differences in accuracy existed (E Conclusion In our Pursuit continuous sensorimotor task, group differences exist between schizophrenia patients and elderly and young healthy controls. When a sequence learning component is added (Figure Pursuit), there is also significant difference in the amount of learning.

EPA-0759 - Multi-immunostaining for microglial activation in schizophrenia

Background Activation of microglial cells is currently explored in schizophrenia pathophysiology. Post-mortem immunohistochemistry remains the most accurate method to investigate microglial morphology and function, since high microglial plasticity limits extrapolation of in vitro and animal research results to the human brain. Method To investigate microglial morphology and activation patterns, we performed immunohistochemistry with specific microglial markers: Iba1 (marker of resting and activated microglia), CD68 (marker of microglial lysosomes, indicative of phagocytic microglia) and CD64 (FcγRI, binds IgG) on formalin fixed paraffin embedded brain tissue from the Corsellis Collection (BRAIN UK), in 15 schizophrenia cases and 15 nonneurological controls. Immunostaining was quantified by image capture and analysis (Image J, NIH, US) to provide a measure of protein load. We also reviewed existing literature on microglial immunostaining in schizophrenia using Pubmed. Results Few studies have examined post-mortem microglia in schizophrenia, mostly with HLA-DP/DQ/DR markers. Although frequently studied in neurological disorders Iba1, but also CD64 were never previously investigated in schizophrenia patients. Two studies explored CD68, but results were misinterpreted for resting state tissue macrophages. Our pilot study shows Iba1, CD68 and CD64 can detect microglial cells in schizophrenia brain tissue, but considerable heterogeneity exists both in patients and controls, probably due to confounding by clinical variables, e.g. age and cause of death. Conclusion Future research needs careful selection of cases and controls to minimize heterogeneity due to confounding clinical variables. Highly specific microglial markers such as Iba1, CD64 and CD68 are very useful and ought to be introduced into schizophrenia research.