P.5.a.001 Dropouts due to other reasons than adverse events during clinical trials in Alzheimer's disease

P.5.a Dementia and neurological disorders - Dementia (clinical) criteria for groups B and D than group C, potentially making group C a rate-limiting factor for the diagnosis of PTSD. Criterion F (Impairment) has been examined in an analysis of two prospective longitudinal studies of PTSD and was found to have a major impact on the rate of PTSD. The impact of changes in PTSD diagnostic criteria were examined using a Canadian PTSD epidemiological sample Method: The rates of PTSD and its correlates were evaluated in a nationally representative random sample of 3006 individuals aged 18 years and over. DSM-III, DSM-III-R, DSM-IV and ICD10 criteria were employed. DSM-III, DSM-III-R and ICD-1O rates were re-evaluated, adding Criterion E The effect of changes in the definition of Criterion F on rates of PTSD was also examined. Results: The prevalence rates of lifetime PTSD ranged from 13.4% (DSM-III) to 13.0% (lCD-10), to 12.2% (DSM-III-R) to 9.2% (DSM-IV); all rates differed significantly from each other. Regardless of diagnostic criteria, most people reported more than one year duration of symptoms, although rates were significantly higher in those with DSM-IV PTSD (68.2%, P < 0.0001). Rates of comorbid major depression, alcohol and substance abuse and dependence were also significantly higher when using the DSM-IV PTSD criteria and those with DSM-IV PTSD reported significantly higher rates of help seeking. When Criterion F was added to earlier DSM versions, lifetime PTSD rates became much closer to those obtained in DSM-IV: 10.2% (DSM-III), 9.6% (DSM-IIIR) and 8.4% (lCD-l 0). Rates of PTSD were the lowest when Criterion F was defined as having both functional impairment and psychological impairment, followed by a criterion F definition of psychological distress only and finally, functional impairment only. Having either psychological or functional impairment yielded the highest rates of PTSD. Conclusion: The rate of PTSD declined with successive definitions of the DSM. In contrast to previous versions, DSM-IV PTSD identifies a more severe disorder given the significantly higher rates of comorbidity, symptom duration and help seeking behaviour. Interestingly, changes in Criterion A do not appear to have as much influence on the rates of PTSD as does the addition of Criterion E This information may be useful for the architects of DSM-Y. References [1] EIhai, JD, Grubaugh, AL, Kashan, TB and Frueh, BC., 2008 Empirical examination of a proposed refinement to DSM-IV posttraumatic stress disorder symptom criteria using the national comorbidity survey replication data. J Clin Psychiatry 69: 597--602. [2] North, CS, Suris, AM, Davis, M, and Smith, RP., 2009 Toward validation of the diagnosis of posttraumatic stress disorder. Am J Psychiatry. 166: 34-41. [3] Solomon, Z and Horesh, D., 2007 Changes in diagnostic criteria for PTSD: Implications from two prospective longitudinal studies. Am J Psychiatry. 77 92): 182-188.

Ip.4.f.0021 The absence of one-trial tolerance on a new animal model of anxiety

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called "one-trial tolerance" (OTT). Here, we present a new and very simple animal model to evaluate benzodiazepine-induced anxiolysis and demonstrate that such model does not exhibit the phenomenon of one trial tolerance. Specifically, this animal model of benzodiazepine-induced anxiolysis consists in the ability of these drugs (at ineffective doses per se) to increase cocaine- or amphetamine-induced hyperlocomotion by inhibiting their anxiogenic effects. Methods: 78 adult male swiss mice were exposed to an open field (OF) for 3 consecutive days (15 minutes each day) and their locomotor activity (LA) was quantified every day (DAYl, DAY2, DAY3). On the fourth day, the animals were randomly allocated to 6 groups (n = 13) which were treated with saline + saline (sal + sal), 5 mg/kg chlordiazepoxide + saline (cdp + sal), saline + 2mg/kg amphetamine (sal + amph), 5mg/kg chlordiazepoxide + 2mg/kg amphetamine (cdp + amph), saline + 30mg/kg cocaine (sal + coc) and 5 mg/kg chlordiazepoxide + 30 mg/kg cocaine (cdp + coc). Thirty minutes after the injection of cdp (or saline), 15 minutes after the injection of amphetamine (or saline) and 5 minutes after the injection of cocaine (or saline) animals were exposed to OF for 5 minutes for LA quantification. Results: The paired T-test revealed that the LA of the animals on DAY2 (75.74±3.84) [t= 10.82; P < 0.001] and on DAY3 (62.87±4.34) [t= 12.40; p < 0.001] was significantly decreased when compared with DAYI (116.08±3.64), demonstrating a significant habituation to the apparatus. One way ANOVA followed by the post-hoc Duncan test revealed significant differences among groups [F(5,72)= 18.45; P < 0.001]. Indeed post-hoc Duncan test showed that although the 5 mg/kg dose of cdp per se was ineffective in modifying LA (cdp + sal: 80.65±7.56) in relation to the control group (sal + sal: 60.72±7.99), cdp significantly increased LA in both amphetamine (cdp + amph: 183.37±22.20) and cocaine (cdp + coc: 452.35±64.12) treated mice in relation to the animals treated with amphetamine alone (sal + amp: 76.59±1O.04) or cocaine alone (sal + coc: 198,44±47.68), respectively. Conclusion: the present study shows that an ineffective dose of a benzodiazepine drug when administrated alone can increase locomotor activity in amphetamine-or cocaine-treated animals by inhibiting the anxiogenic effects produced by these psychostimulants. This finding may provide a very simple animal model to evaluate benzodiazepine anxiolysis. In addition, the model does not undergo the phenomenon of one trial tolerance since it is observed in mice previously habituated to the OF apparatus.

P.5.a Dementia and neurological disorders - Dementia (clinical) 1P.5.a.0011 Dropouts due to other reasons than adverse events during clinical trials in Alzheimer's disease

L.H.E Zanlorenci"., R. Wuo-Silva 1 , R.p. Souza 1 , T.E Trombin 1 , C.S. Oliveira 1 , L.T.C. Ribeiro 1 , D.E Fukushiro 1 , M.B. Calzavara 1 , R. Frussa-Filho 1 . 1Federal University of Slio Paulo, Pharmacology, Slio Paulo, Brazil

C. Kani 1 , A. Pehlivanidis/ • , K. Papanikolaou'[, Z. PapadopoulouDaifoti", 1 University ofAthens, Department ofPharmacology Medical School, Athens, Greece; 2University of Athens, 1st Department of Psychiatry Eginition Hospital, Athens, Greece; 3 University of Athens, Department of Child Psychiatry "Agia Sophia" Children s Hospital, Athens, Greece

Purpose: The elevated plus-maze is probably the most widely used animal model of anxiety. An intriguing finding in the elevated plus-maze is that several anxiolytic drugs do not induce anxiolysis in animals with previous plus-maze experience, a phenomenon

Purpose: Dropouts play a significant role in the extraction and interpretation of results of clinical trials showing a moderate effect. As Cholinesterase Inhibitors (ChEls) and memantine have been found to be moderately clinically effective in the treatment

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P.5.a Dementia and neurological disorders - Dementia (clinical)

of AD [1], the purpose of the present review was to exami~e whether reasons of dropouts, other than adverse events (AEs), In clinical trials of at least 6 months duration, can result to further reduction of their efficacy. Methods: Dropouts due to other reasons than AEs were extracted from total dropouts minus dropouts due to AEs, already calculated in a meta-analysis of ChEIs and memantine, being under publication elsewhere [2]. Additiona!ly, inclu~ed tria~s in ~e meta-analysis were screened if they detailed specific aetiologies for dropouts due to other reasons and relevant data were extracted. Percentages with relevant measures of dispersion were calculated. Due to expected variation, emerged from the wide variations found in AD and in the treatment response, a random effects model was used to calculate combined estimates for dichotomous outcomes. Results: Dropouts due to other reasons than AEs were extracted from 21 trials (9 trials of donepezil, 3 trials of galantamine, 4 trials of rivastigmine and 5 trials of memantine). Dropouts due to other reasons than AEs for ChEIs, as a class, were 10.42%±5.63 vs 11.28%±5.93 and for memantine 9.31%±3.1O vs 11.96%±3.98 for treatment arms and placebo, respectively. No statistically significant differences were observed among ~eatment arms. ~d placebo through meta-analysis. 18 trials provided data detailing the specific reasons, which leaded to dropouts due to other causes than AEs. These included, mainly: medication non-compliance, protocol violation, patients unavailable for follow up, patient consent withdrawal, insufficient response and other (non categorized) reasons. Patients' informed consent withdrawal and protocol violations were reasons with highest frequencies (5.50%±3.38, 2.14%±1.33 and 5.85%±3.75, 2.35%±1.73 for treatment and placebo arms, respectively). Medicati~n ~on-com~liance ~d. insufficient response rates had lower incidences In the clinical trials settings. More specifically, percentages of subjects withdrew due to non-compliance were available only from ChEIs trials (1.32%±1.26, for ChEIs treatment vs 1.12%±0.78 for placebo, respectively). Insufficient response percentages were 0.38%±0.11 for treatment vs 1.62%±0.32 for placebo for galantamine trials. The respective odds ratios for galantamine were 0.30 (95% CI 0.08-1.10, p=0.07). Conclusions: The use of ChEIs and memantine was associated in clinical trials for AD also with dropouts due to other reasons than AEs. The percentages are almost the same with dropouts due to AEs (14.14% vs 7.46% for ChEIs and 9.55% vs 10.08% for memantine, for treatment and placebo arms, respectively) and cannot be negligible. The insufficient response estimate implies that treatments with low efficacy can increase the number of dropouts from placebo arms. However, it should be taken into account that data for the present study have been extracted from clinical trials settings and should be cautiously generalized as conditions in naturalistic settings usually differ in long-term, neurodegenerating diseases. References [1] Raina, P., Santaguida, P., Ismaila, A., Patterson, C., C;owan, D., Levine, M., Booker, L., Oremus, M., 2008. Effectiven.ess ~f Cholinesterase Inhibitors and Memantine for Treatmg Dementia: EVIdence Review for a Clinical Practice Guideline. Ann Intern Med 148, 379-397. [2] Kani, C., Papanikolaou, K., Pehlivanidis, A. Bonovas, S., Papado:poulo.uDaifoti Z 2009 Cholinesterase Inhibitors and Memantine in Alzheimer's Disease: a systematic review and meta-analysis of randomized controlled trials. Alzheimer. Realidades e Investigaci6n en Demencia 42, under publication.

1P.5.a.0021Imaging of muscarinic acetylcholine receptors with 11C·3NMPB in vascular dementia and Alzheimer's disease K. Nagata1 ., D. Takano 1, T. Maeda 1, T. Nakase 1, T. Yamazaki", H. Saitoh/. 1 Research Institute jorBrain and Blood Vessels, Neurology, Akita, Japan; 2Tokyo Metropolitan Ebara Hospital, Rehabilitation, Tokyo, Japan Objective: Acetylcholine neurotransmission plays an important role in the treatment of Alzheimer's disease (AD) and vascular dementia (VaD). We have developed a new ligand (+)N-[11C]methyl-3-piperidyl benzilate (11C-3NMPB) which has a specific affinity to the muscarinic acetylcholine receptor (mAChR). In the present study, to clarify the integrity of the acetylcholine neurotransmission in patients with AD and Val? we analyzed the integrity ofmAChR using 11C-3NMPB and positron emission tomography (PET) in patients with patients with AD and VaD. Subjects and Methods: Present study was.bas~d on I? pati~nts with probable VaD who had subcortical multiple ischemic lesions on MRI and were diagnosed according to the NINDS-AIREN criteria, 11 patients with probable AD who were diagnosed according to the NINCDS-ADRDA criteria, and 7 age-matched normal volunteers served as normal control (NC). The mean age was 70.2 years, 69.5 years and 62.7 years for VaD, AD and NC group, respectively. None of them were on acetylcholine est~rase inhibitors (AChEIs) at the timing of PET study. All subjects underwent mAChR imaging using llC-3NMPB and 1.5T MRI. The regional llC-3NMPB uptake was evaluated by the ratio relative to the cerebellum and regions of interest (ROIs) were set up in the right frontal cortex, basal ganglia, thalamus, temporal cortex, occipital cortex, parietal cortex, posterior cingulated gyrus and anterior cingulated gyrus on both sides. The llC-3NMPB uptake was also compared by the 3D statistical surface projection method among 3 subject groups. Result: The mAChR binding rate was greatest in the bilateral basal ganglia, and smallest in the thalamus. As compare~ with NC group, mAChR binding was not significantly reduced In any ROI in the AD group, whereas mAChR binding was significantly reduced in the thalamus and anterior cingulated gyrus, but not in other cerebral cortices in the SC group. As compared with the NC group, mAChR binding was not significantly red~ced i~ any ROI in AD patients. In those with VaD due to cortical lesions, mAChR binding was reduced in the infarcted areas. On the other hand, mAChR binding was significantly reduced in the thalamus and anterior cingulated gyrus on both ROI-based and 3D-statistical analyses, but not in other cerebral cortices ~ patients w,ith V~ due to subcortical lesions. As compared With those WIth mild white matter(WM) lesions, mAChR binding was mildly reduc~~ in a patchy fashion over the frontal, parietal, temporal and OCCIpItal cortical regions in those with severe WM lesions, but none of these brain regions showed a significant difference. Conclusion: Since the remaining acetylcholine receptor activity was considered to be indispensable for the treatment with AChEIs in dementia patients, the preservation of the muscrinic receptor activity in the surviving cortical areas indicates possible effects from AChEIs in AD patients as well as in VaD patients with subcortical ischemic lesions.