Backenstraß, Matthias

Funke, Joachim

Holt, Daniel

Kaiser, Stefan

Rentrop, Mirjam

Rodewald, Katlehn

Roesch-Ely, Daniela

Weißbrod, Matthias

Heidelberger Dokumentenserver

adult age. The latter effect was apparent in post-mortem immuno-histochemical analyses of the cell proliferation marker BrdU and themicrotubule-associated protein DCX, a marker of newborn neuronalcells. Chronic CLZ treatment significantly improved the prenatalPolyI:C-induced working memory deficits, whist at the same time,it negatively affected working memory performance in adultoffspring born to control mothers. These bidirectional cognitiveeffects of clozapine were not paralleled by concomitant effects onadult hippocampal neurogenesis.Discussion: Our findings do not support the hypothesis that theatypical antipsychotic drug clozapine may influence cognitive func-tions by acting on adult neurogenesis in the hippocampus, regardlessof whether the drug is administered to subjects with or without aneurodevelopmental predisposition to adult neuropathology.doi:10.1016/j.schres.2010.02.709Poster 215THE EFFECT OF NON-COMPETITIVE NMDA RECEPTORANTAGONIST MK801 ON HIPPOCAMPUS-PREFRONTAL CORTEXSYNAPTIC RESPONSES AND EXECUTIVE COGNITIVE FUNCTION INRATSKevin Blot1, Shin-ichi Kimura2, Anne Kemp3,Denise Manahan-Vaughan3, Bruno Giros1, Satoru Otani11University of Pierre and Marie Curie-Paris 6, Paris, France; 2HokkaidoHealth Sciences University Ishikari-Tobetsu, Japan; 3Ruhr UniversityBochum, GermanyBackground: Evidence suggests that the pathogenesis of schizo-phrenia cognitive symptom may involve abnormalities in glutama-tergic transmission. Particularly, non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors such as phencyclidine andMK801 are known to cause cognitive states resembling schizo-phrenia in healthy humans and exacerbate preexisting symptoms inthe patients. In rats, the administration of MK801 alters neuronalactivity in the prefrontal cortex (PFC) as well as impairs executivecognitive function. In this study, we tested the effect of MK801 onsynaptic responses of the cognitively important, hippocampus-PFCpathway and on executive cognitive function in rats.Methods: Male Sprague-Dawley rats (350-400 g) were anesthe-tized by urethane (1.5 g/kg, i.p.) and placed in a stereotaxic frame(body temperature maintained at 37±0.1 °C). A recording elec-trode was placed in the mid layer of the prelimbic area (rat PFC),and a stimulating electrode in ventral hippocampus. The electrodepositions were adjusted to obtain the maximum amplitude ofpostsynaptic potential, whose peak appears with an 18.0-20.0 msdelay after stimulus artifact. The intensity of stimulation was set toevoke 60% of the maximum response (300-500 μA). The protocolfor behavioral analysis followed Birrell and Brown (J Neurosci, 20,p4320, 2001).Results: Single injection ofMK801 (0.1 mg/kg i.p.) induced a gradualpotentiation of the evoked responses which reached a significantlevel 2 hours after injection (63±10 at 2 hours, n=12) comparedwith saline control (11±6.6%, n=10, p<0.0005). This MK801-induced potentiation does not require tetanic stimulation unlike thestandard forms of long-term potentiation (LTP). Furthermore,significant MK801-induced LTP was induced even when single teststimuli (at 0.033 Hz) were stopped for 1 hour from the time ofMK801 injection (32±2.8% at 2 hours, n=5, p<0.001 comparedwith saline control, 0.7±2.2%, n=7), suggesting that the MK801-induced LTP occurs in the manner independent of synchronizedsynaptic stimuli. However, MK801-induced LTP appears to share thecommon mechanisms with the standard LTP, since a prior inductionof LTP by tetani (50 pulses at 250 Hz, repeated 10 times at 0.1 Hz;such a trainwas applied twicewith 6 min interval) severely occludeda subsequent MK801-induced LTP (19±7.5, n=7, p<0.005).MK801-induced LTP was blocked also by prior injection of MAPkinase inhibitor SL-327 (10 mg/kg, i.p., 19.2±9.1%, n=5, p<0.01)and of mGluR2/3 agonist LY379268 (3 mg/kg, i.p.; 0.2±2.0%, n=5,p<0.005). Behavioral data showed that the injection of MK801impairs PFC-dependent extra-dimensional set shifting (p<0.05). Inanother series of experiments, we tested the effect of repeatedinjections of MK801 (7 or 14 daily injections) on a subsequentinduction of LTP by tetani. We had verified that tetani delivered 24 hafter single MK801 can induce clear LTP (85±17%, n=5). But tetanidelivered 24 hours after a 7th daily injection of MK801 induced LTPonly in 3 out of 6 animals, and tetani 24 hours after a 14th injectionresulted in no LTP (-11±4.1%, n=7, p<0.001). LTP was still absent72 hours after the 14th daily injection (-3.1±6.4%, n=4, p<0.001).Rats injected with the 14-daily MK801 showed severe impairmentsin the attentional set shifting task.Discussion: These results suggest that MK801 induces an aberrantform of LTP in the hippocampus-PFC pathway. When injection isrepeated, MK801 blocks a subsequent LTP induced by tetanicstimuli. We are currently testing the role of PFC dopamine receptorsfor the MK801-induced LTP.doi:10.1016/j.schres.2010.02.710Poster 216TARGETING PLANNING AND PROBLEM SOLVING VERSUS BASICCOGNITION IN COGNITIVE REMEDIATION FOR PATIENTS WITHSCHIZOPHRENIAKatlehn Rodewald1, Mirjam Rentrop1, Daniel Holt2,Daniela Roesch-Ely1, Matthias Backenstrass1, Joachim Funke2,Matthias Weisbrod1,3, Stefan Kaiser1,41Section of Experimental Psychopathology, Department of GeneralAdult Psychiatry, Centre for Psychosocial Medicine, University ofHeidelberg, Heidelberg, Germany; 2Departmentof Psychology,Universityof Heidelberg, Heidelberg, Germany; 3SRH Klinikum Karlsbad-Langensteinbach, Germany; 4Psychiatric University Hospital, Zurich,SwitzerlandBackground: The importance of cognitive impairment for functionaloutcome in patients with schizophrenia has led to the development ofcognitive remediation programs designed to improve cognition. Theseinterventions have targeted a wide range of cognitive functions.However, there arenodirect comparisons between treatmentprogramsaddressing cognitive functions on different levels of complexity in arehabilitation setting. The purpose of this studywas to assesswhether aplanning and problem solving training is more effective in improvingfunctional capacity in patients with schizophrenia than a traditionaltraining program addressing basic cognitive functions.Methods: Eighty-nine patients with schizophrenia or schizoaffec-tive disorder were randomly assigned either to a training ofplanning and problem solving or a training of basic cognition. Thedependent variables included functional capacity as a proxymeasure for functional outcome, problem solving and planningability. Assessment of the primary outcome was blind to groupallocation. Participants received computer-assisted cognitive train-ing three times a week over a three week period.Results: Amain effect of time indicated that both groups improved infunctional capacity during the study. Calculation of the reliable changeindex suggests that this improvement is clinically significant. Contraryto our main hypothesis, no significant time x group interaction wasAbstracts 393found for functional capacity suggesting that both types of training canimprove functional capacity similarly. Measures of planning andproblem-solving showed a similar pattern with an advantage forplanning and problem solving training on one measure.Discussion: Our results are in line with previous studies reportingan improvement of functional capacity when cognitive remediationis combined with other rehabilitation methods. However, adifferential effect of targeting different cognitive functions onfunctional capacity remains to be established.doi:10.1016/j.schres.2010.02.711Poster 217FEASIBILITY STUDY OF MULTI-SITE COGNITIVE REMEDIATION INTHE SCHIZOPHRENIA TRIALS NETWORK (CRSTN)Richard Keefe1, Sophia Vinogradov2, Alice Medalia3, Peter Buckley4,Stanley Caroff5, Deepak D'Souza6, Phillip Harvey7, Karen Graham8,Steve Marder9, Del Miller10, Steve Olson11, Jayendra Patel12, DawnVelligan13, Trina Walker1, Adam Haim14, Scott Stroup31Duke University Medical Center, Durham, NC, USA; 2University ofCalifornia San Francisco, San Francisco, CA, USA; 3Columbia UniversityCollege of Physicians and Surgeons, New York, NY, USA; 4Medical College ofGeorgia Augusta, GA, USA; 5Veterans Affairs Medical Center, University ofPennsylvania School of Medicine, Philadelphia, PA, USA; 6Yale UniversitySchool of Medicine, New Haven, CT, USA; 7Emory University School ofMedicine, Atlanta, GA, USA; 8University of North Carolina at Chapel Hill,Chapel Hill, NC, USA; 9Semel Institute at UCLA and VA Desert Pacific MentalIllness Research, Educational, and Clinical Center, Los Angeles, CA, USA;10University of Iowa Carver College of Medicine, Iowa City, IA, USA;11University of Minnesota, Minneapolis, MN, USA; 12University ofMassachussets Medical School, Worcester, MA, USA; 13University of TexasHealth Science Center at San Antonio, San Antonio, TX, USA; 14NationalInstitute of Mental Health, Bethesda, MD, USABackground: The NIMH MATRICS Project and related efforts havestimulated the initiation of several studies of treatments for cognitiveimpairment in schizophrenia. Cognitive remediation may provide anexcellent platform for the provision of new learning opportunities andthe acquisition of new skills for patients who are engaged inpharmacologic trials to improve cognition. However, it is not clearwhether cognitive remediation intervention would be feasible forlarge trials involving sites without specific cognitive remediationexpertise. We sought to address the feasibility of a multi-site trial ofcognitive remediation in schizophrenia, called the Cognitive Remedia-tion in the Schizophrenia Trials Network (CRSTN) study.Methods: Nine sites from the Schizophrenia Trials Network, formerlythe Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)schizophrenia trial,were involved in the study. Each sitewas expected toenroll six patientswith chronicDSM-IV schizophrenia over the course ofapproximately3 months, estimating a reasonable rate of recruitment fora large-scale efficacy trial. Raters were certified on the MATRICSConsensus Cognitive Battery (MCCB) as the primary outcomemeasure,the 2nd edition of the UCSD Performance-based Skills Assessment(UPSA-2) as a co-primary measure, and key secondary measuresincluding the Cognitive Assessment Interview (CAI) and trained on thePositive and Negative Syndrome Scale (PANSS). Patients met thefollowing criteria: age 18-55; not fully satisfied with current level offunctioning and able to identify functional goals; no hospitalization inlast 8 weeks; no change in medication regimen in last 4 weeks; PANSSdelusion and hallucination item scores ≤5, conceptual disorganizationitem score≤4, and CalgaryDepression Scale total score≤10;WTAR>5.Patients were randomized to one of two treatment conditions: 1. thePositScience Brain Fitness auditory training program with weekly'bridging groups' adapted from the Neuropsychological EducationalApproach to Remediation (NEAR), that help patients to learn howcognitive improvement can be applied to functional benefit in everydaylife; or 2. a control condition that involved computer games andweeklyhealthy lifestyles groups. Patients were expected to complete the one-hour auditory training intervention or computer game activities 3-5times per week until study end, which was 40 sessions or 12 weeks,whichever came first. Efficacy with theMCCB and UPSA-2was assessedafter 20 sessions and study end. The key indicator to evaluate thefeasibilityof this studywas rateof enrollment, retention, andcompletionrate of primary outcome measures.Results: Within the 3-month enrollment period, 67 patients signedconsent, 60 patients were screened, and 53 were enrolled, one shortof the maximum allowed. As of the date of abstract submission, 3patients (1 receiving cognitive remediation) had terminated thestudy, and 32 patients had completed the trial. Of these, 26completed the maximum 40 sessions and the other 6 patientscompleted an average of 30 sessions in 12 weeks.Weekly attendancein the bridging groupswas excellent. Efficacy datawill be available atthe time of this presentation.Discussion: In terms of training, enrollment and study completion,multi-site trials of cognitive remediation using the PositScienceauditory training program with the NEAR method of weeklybridging groups appear to be feasible, supporting large-scaleefficacy trials of cognitive remediation and the use of cognitiveremediation as a potential platform for large-scale drug trials.doi:10.1016/j.schres.2010.02.712Poster 218CONCEPTUAL BACKGROUND OF IMAGING STUDIES INPSYCHOTHERAPY RESEARCH: THE EXAMPLE OF CBTINTERVENTIONS IN PATIENTS WITH SCHIZOPHRENIATilo Kircher1, Axel Krug1, Henrik Walter2, Georg Winterer3,Bernhard Müller4, Jutta Herrlich5, Georg Wiedemann6, Kai Vogeley7,Andreas Wittorf8, Alexander Rapp8, Stefan Klingberg81Philipps-University Marburg, Department of Psychiatry, Marburg,Germany; 2University of Bonn, Department of Medical Psychology,Bonn, Germany; 3Heinrich-Heine-University, Department of Psychiatry,Düsseldorf, Germany; 4University Duisburg-Essen, Department ofPsychiatry, Essen, Germany; 5University Frankfurt, Departmentof Psychiatry, Frankfurt, Germany; 6Klinikum Fulda, Department ofPsychiatry, Fulda, Germany; 7University Cologne, Department ofPsychiatry, Cologne, Germany; 8Eberhard Karls University, Tübingen,GermanyBackground: Cognitive behavioural therapy (CBT) is an importanttreatment in conjunction with psychopharmacotherapy in schizo-phrenia. However, there is only very little research on the effects ofsuch interventions on brain function. Recent studies have suggestedthat jumping to conclusions and a specific attributional style is apredominant cognitive style in patients which might lead to thedevelopment of delusions.Methods: In this multi-centre fMRI trial, we investigated the effectof CBT on neural correlates of "jumping to conclusions" and the"attributional style" in patients with schizophrenia. Eighty patientsand 80 control subjects were recruited in six centres and measuredwith 3-Tesla functional magnetic imaging (fMRI) before and after9 months of cognitive behavioural therapy.Results: It could be shown that CBT ameliorates differences in brainactivations between patients and controls after nine months.Abstracts394

Targeting planning and problem-solving versus basic cognition in cognitive remediation for patients with schizophrenia

Targeting planning and problem-solving versus basic cognition in cognitive remediation for patients with schizophrenia

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