Opening Lecture

1

Opening Lecture

Sunday 6 June 2010 OL-01. Opening Lecture : It’s all a state of mind jOL-01.001j It’s all a state of mind C.F. Lee. HKU School of Professional, and Continuing Education, Hong Kong SAR, China Through meditation and other means, Buddhism enables practitioners to become mindful of their feelings and thoughts. And when we are mindful of our feelings and thoughts, we are in a better

position to manage them. In other words, we would be in a better position to control our temper. The Buddhist outlook on life also encourages in life, or along one’s career path, particularly when such changes bring along unhappy feeling or disappointment. In essence, we train our mind to better cope with the pressures and mishaps of daily life. Depending on one’s state of mind, one might feel like being in heaven or hell at times, and in fact may mentally feel like going back and forth between them many times everyday. It is all a state of mind. Policy of full disclosure : None.

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2

Plenary Lectures

Monday 7 June 2010 PL-01. Treatment for schizophrenia : Current limitations and future strategies

preparations such as skunk c) starting in early adolescence d) family history and possibly COMT geneotype. Policy of full disclosure : None.

Tuesday 8 June 2010

jPL-01.001j Treatment for schizophrenia : Current limitations and future strategies J. Lieberman. Columbia University Medical Centre, New York, USA While significant progress has been made in the pharmacotherapy of schizophrenia and related psychotic disorders, much remains to be done. Many patients do not respond to even the best current treatments and most are left with significant residual symptoms. Side effect tolerability to and poor patient adherence with treatment further limit the effectiveness of these treatments. In reality despite the proliferation of drugs, there has been little real innovation in terms of novel mechanisms of action. All antipsychotic treatments appear to work principally though the antagonism of dopamine principally at the D2 receptor. Identifying new strategies for treatment development has proven to be a daunting challenge. Recent efforts have largely focused on three approaches. The first is the development of novel agents with affinities for targets other than the D-2 receptor. The second strategy seeks to develop agents as adjunctive treatments to antipsychotic drugs targeting specific symptom domains of the illness (e.g. cognition, psychosis, negative symptoms). This strategy is predicated on the assumption that the various symptom dimensions of the illness may have different pathophysiological bases which no single agent could possibly address. The third strategy is more future oriented and exploratory, and works through the establishment of molecular libraries of neurobiologic targets through the identification of genes associated with schizophrenia, brain development and function, and the identification of candidate molecules. Another exciting line of investigation has been preventive intervention and early detection. This treatment strategy holds tremendous promise for future generations of patients and the possibility of the prevention of disease progression and even the onset of symptoms. Finally, in addition to psychotherapy and pharmacotherapy, another that therapeutic modality holds promise for the treatment of schizophrenia is brain stimulation therapy. Convulsive forms of therapy have historically been used but now studies with R-TMS have shown promising results. Policy of full disclosure : None.

PL-02. Marijuana ; from mellow to madness jPL-02.001j Marijuana ; from mellow to madness R. Murray. Institute of Psychiatry, King’s College London, United Kingdom Objective : People diagnosed as having schizophrenia-like psychoses are more likely to use illicit drugs than the populations from which they are drawn. Two types of drugs have been particularly implicated, the amphetamines and cannabis, the former particularly in Asia and the latter everywhere else. Methods : Cannabis is the most widely used drug in the world and has been causing concern because of a) the general increase in consumption b) increased potency of street preparations available c) decreasing age of first use. Results : Among those with established psychosis, continued consumption is assoicated with worse outcome. In addition, a series of cohort studies have shown that regular use of cannabis increases risk of psychosis in a dose dependent manner. Conclusion : Factors which appear to increase risk include a) having a psychosis prone personality, frequent use of high potency


PL-03. Psychosis, Cognition and Schizophrenia – Back to the Future jPL-03.001j Psychosis, Cognition and Schizophrenia – Back to the Future S. Kapur. Institute of Psychiatry, King’s College London, United Kingdom Objective : The illness now called schizophrenia started its origins as ‘ dementia praecox, ’ a deteriorating cognitive disorder. The first few decades the focus was on its cognitive and associative aspects until the discovery of antipsychotics. For the last half century schizophrenia has been focussed on the study of psychotic symptoms with significant progress. The talk will review our current understanding of the pathophysiology of psychosis and cognition in schizophrenia with a special emphasis on therapeutic strategies. Methods : The talk will focus particularly on studies of antipsychotics and more recent studies of cognitive enhancers. Results : The emerging data supports the view that the major dopaminergic abnormality is a presynaptic one, that this abnormality precedes the onset of psychosis. The data on treatment show a rather close relationship between dopamine blockade and response, and the emerging data suggest that it is the striatal, rather than extra-striatal, regions that best correlate with response. The new data also lay to rest the time-honoured ‘ delayed onset ’ hypothesis regarding antipsychotic action and this opens up new options for clinical trial design, individual treatment and mechanism discovery. However, we may have pushed the dopamine model as far as it can yield new therapeutics – and the problem of cognition in schizophrenia, till now taking a back-seat, is still unaddressed. But, what precisely is wrong with cognition in schizophrenia? Is it a multitude of distinct dysfunctions or is it a single common factor? Does one know enough about the pathophysiology of cognitive dysfunction to design rational treatments? What have been the results of early efforts? Will a drugtreatment of cognition alone in schizophrenia a sensible goal? If not what should it be? Conclusion : The talk will raise and partially address these questions and finish with a model of schizophrenia which embraces both psychosis and cognition and ties it with what is know about psychosis and its treatment. Policy of full disclosure : Grant Support (listed Alphabetically) : AstraZeneca, Bristol-Myers Squibb (BMS), Glaxo Smith Kline Consultant/Scientific Advisor/Speaking Engagements (listed Alphabetically) : AstraZeneca, Bioline, Bristol Meyers Squibb, Eli Lilly, Janssen (Johnson and Johnson), Lundbeck, Otsuka, Organon, Pfizer, Roche, Servier, Solvay, Wyeth.

PL-07. The Ethics of Elective Psychopharmacology PL-04. From understanding neural plasticity to development of cognitive enhancers jPL-04.001j From understanding neural plasticity to development of cognitive enhancers

3 PL-06. Mood dysregulation and stabilization : Perspectives from emotional cognitive neuroscience jPL-06.001j Mood dysregulation and stabilization : Perspectives from emotional cognitive neuroscience

N. Ip. The Hong Kong University of Sc, Kowloon, Hong Kong SAR, China Although a myriad of abnormalities in brain function is observed in various neurological disorders, emerging evidence suggests that they all involve defects in certain aspects of neural plasticity. For example, impairment in migration and integration of neurons in the cerebral cortex is associated with mental illnesses including schizophrenia, whereas loss of synaptic contacts and alteration in synaptic plasticity has been identified as one of the early events for neurodegenerative diseases such as Alzheimer’s disease. Thus, elucidating the signaling mechanisms underlying the establishment of neuronal connections is pivotal for identifying new targets and developing neurotherapeutic agents. Our laboratory has been interested in the signal transduction mediated by receptor tyrosine kinases, such as Ephs and TrkB, in synapse development and plasticity. In this talk, I will discuss how these cell surface receptors and their downstream effectors such as Rho GTPase regulators modify circuit assembly through regulation of neuronal migration and synapse development. Furthermore, we have leveraged our research strengths in molecular neuroscience and traditional Chinese medicine (TCM) to establish a focused knowledge-based drug discovery program to search for novel drug leads. A TCM-based strategy has been adopted whereby the vast knowledge accumulated on TCM herbs is leveraged to identify potential therapeutic agents against neurological disorders. Using cell-based bioassays, novel lead compounds have been identified, such as those that modulate synaptic functions. These compounds have been found to not only improve the cognitive skills of memoryimpaired mice, but also exhibit anti-depressant activities. They are currently undergoing pre-clinical investigations towards development of therapeutics for neurological disorders. Policy of full disclosure : None.

Wednesday 9 June 2010 PL-05. Individual differences and evidence based psychopharmacology

S. Yamawaki. Hiroshima University School, Department of Psychiatry & Neurology, Japan Mood is a relatively long-lasting emotional state that directly impacts mental health. The development of neuroimaging methods has enabled significant advances toward elucidating the mechanism of emotion regulation and its dysregulation in mood disorders. The neural networks that regulate emotion include the prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala, hippocampus, hypothalamus, and ventromedial parts of basal ganglia. A major depressive episode is thought to reflect the failure of these multi-region networks to appropriately regulate activity under stressful circumstances. It has been suggested that in depressed patients low PFC activity is correlated with impairment in attention and working memory ; ventral striatum/nucleus accumbens hypoactivity with lack of motivation and anhedonia ; and subgenual ACC hyperactivity with the production of sad emotion. However, the question of how the dopaminergic and serotonergic systems interact with these neural networks to regulate emotion remains obscure. In this lecture, after a brief review of the current research on emotion regulation, I shall discuss four aspects of our neuroimaging studies employing functional magnetic resonance imaging (fMRI) on the basis of emotion processing. These include (1) the study using various visual emotional tasks on gender differences in cognitive emotional processing and neural mechanisms of coping with stressful events ; (2) the study on predictors for treatment response and functional recovery from depression ; (3) the study using future reward prediction tasks on the role of dopaminergic and serotonergic systems in cognitive emotional behaviors such as impulsivity and hedonia. Psychotherapy including cognitive behavioral therapy (CBT) improves depressive symptoms by helping to alter psychological processing associated with problemsolving capacity, self-perception and emotion. I shall present (4) the study of psychological support and CBT on emotional and self-referential processing of negative stimuli. In conclusion, I shall discuss the future direction of the emotional cognitive neuroscience of mood disorder. Policy of full disclosure : None.

jPL-05.001j Individual differences and evidence based psychopharmacology R. Belmaker. Ben Gurion University Negev, Division of Psychiatry, Beersheva, Israel Considerable controversy surrounds the question as to whether all or most decisions in psychopharmacologic treatment can be evidence based. While large placebo controlled trials, mostly for registration purposes, clearly provide important evidence for the clinician, many patients do not fit the criteria for such trials and the results of such trials are not always applicable to such patients. Major findings in psychopharmacology and biological psychiatry have not been replicated consistently and thus the clinician is faced with a question of judgment as to when to change his clinical practice based on a new finding. Moreover, research results in psychopharmacology are almost always published as mean effects. Examples of individual differences in biological and psychopharmacological studies are presented. These individual differences do not disappear even when inbred genetically identical mouse strains are used and molecular studies have confirmed the existence of consistent individual differences even in genetically identical cell lines maintained under identical conditions. These facts suggest that the history of the individual patient may be at least as important in determining the best clinical treatment for that patient than the existing evidence on large heterogeneous clinical patient samples. The implications of this for developing guidelines and algorithms are discussed. The possible use of a new Bayes’ Theorem based algorithm is proposed.

Thursday 10 June 2010 PL-07. The Ethics of Elective Psychopharmacology jPL-07.001j The Ethics of Elective Psychopharmacology B. Sahakian. University of Cambridge, School of Clinical Medicine, United Kingdom Cognitive enhancing drugs are needed to treat the cognitive impairments associated with debilitating neuropsychiatric disorders, such as Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder (Sahakian and Morein-Zamir, 2007). Such treatments will improve the quality of life and wellbeing for patients and their families and reduce the financial burden on society (Beddington et al. 2008). Cognitive enhancement is of great interest to the general public and has implications for society, particularly in regard to the increasing use of cognitive enhancing drugs in school age children, and in young adults and academic staff at University (Greely et al., 2008 ; Maher, 2008 ; Sahakian and Morein-Zamir, 2007). Therefore, it is important to consider the potential harms of these drugs, for example substance abuse, unknown effects on the developing brain or coercion at school or work. Nevertheless, with the rapidly developing field of pharmacogenomics we may be able to gain maximum benefits with minimum harms to the individual and society as a whole. Certainly,


4 the benefits of safe and effective cognitive enhancing drugs to society, including the ageing population and people with neuropsychiatric disorders and brain injury, are great (Beddington et al. 2008 ; The Academy of Medical Sciences Report, 2008). It is therefore important to engage the public in discussions of these neuroethical issues. Policy of full disclosure : Barbara J Sahakian consults for Cambridge Cognition Ltd., and a number of pharmaceutical companies.


Plenary Lectures, Thursday 10 June 2010 J Beddington et al. 2008 The mental wealth of nations. Nature 455, 1057–1060 H Greely et al. 2008 Towards responsible use of cognitive enhancing drugs by the healthy. Nature 456 702–705 B Maher 2008 Poll results : Look who’s doping. Nature. 452 674–675 B Sahakian and S Morein-Zamir 2007 Professors little helper Nature 450 1158–1159 The Academy of Medical Sciences Report on Brain science, addiction and drugs 2008

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Symsposia

Monday 7 June 2010 S-01. Predictors, moderators, and mediators of symptom improvement in MDD jS-01.001j Predictors, moderators, and mediators of symptom improvement in major depressive disorder : Overview, definition, and significance G. Papakostas. Massachusetts General Hospital, Boston, USA Major Depressive Disorder (MDD) is a prevalent illness that is frequently associated with significant disability, morbidity, and mortality. Despite the development and availability of numerous treatment options for MDD, studies have shown that antidepressant monotherapy yields only modest rates of response and remission. Clearly, there is an urgent need to develop more effective treatment strategies for patients with MDD. One possible approach towards the development of novel pharmacotherapeutic strategies for MDD involves identifying subpopulations of depressed patients that are more likely to experience the benefits of a given (existing) treatment versus placebo, or versus a second treatment. Attempts have been made to identify such ‘‘subpopulations ’’, specifically by testing whether a given biological or clinical marker also serves as a moderator, mediator (correlate), or predictor of clinical improvement following the treatment of MDD with standard, 1st-line antidepressants. During the course of this lecture, the discussant will present the definitions of predictors, moderators, and mediators of clinical improvement in MDD, followed by a discussion regarding the potential applications of such elements on clinical practice as well as future drug development. Policy of full disclosure : Lifetime disclosure, as of November 23rd, 2009 Dr. Papakostas has served as a consultant for AstraZeneca PLC, Bristol-Myers Squibb Company, Eli Lilly Co., GlaxoSmithKline, Evotec AG, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Shire Pharmaceuticals, and Wyeth, Inc. Dr. Papakostas has received honoraria from Astra Zeneca PLC, Bristol-Myers Squibb Company, Eli Lilly Co., Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Shire Pharmaceuticals, Titan Pharmaceuticals, and Wyeth Inc. Dr. Papakostas has received research support from Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc., and Ridge Diagnostics (formerly known as Precision Human Biolaboratories). Dr. Papakostas has served on the speaker’s bureau for BristolMyersSquibb Co and Pfizer, Inc.

jS-01.002j Personality and Neuroimaging Mediators S.H. Kennedy. University Health Network, University of Toronto, Ontario, Canada The pursuit of personalized medicine requires the identification of pretreatment variables (moderators) that accurately predict antidepressant response. In addition, changes that occur during treatment and correlate with treatment outcome (mediators) can also be important predictors to guide treatment selection and management. Preliminary data suggest that personality factors may act as mediators of antidepressant response, whereby reduction in harm avoidance actually precedes the alleviation of depressive symptoms (Quilty et al. 2010). Neuroimaging methods can also be used to identify potential mediators of treatment response. Based on positron emission tomography (PET) measuring glucose metabolism, pretreatment hypermetabolism in the subgenual cigulate cortex was associated with non-response to venlafaxine or cognitive behaviour therapy (Konarski et al. 2005). This presentation will examine personality domains and functional neuroimaging variables as mediators of response to

antidepressant monotherapy, including cognitive behaviour therapy combination pharmacotherapy and neurostimulation. Considering early symptom improvement (usually defined as a symptom reduction of 20 % or more at an early stage) is a predictive mediator for positive treatment outcome (Szegedi et al. 2008), the interaction between personality and neuroimaging mediators with early improvement will also be explored. Policy of full disclosure : Funding for original trials discussed in this presentation came from St. Jude Medical, Eli Lilly, and Wyeth. The author has also received funding in the past three years from AstraZeneca, Biovail, GlaxoSmithKline, Janssen-Ortho, Lundbeck and Servier.

jS-01.003j Neurophysiologic biomarkers for predicting response and remission during treatment for major depression A.F. Leuchter. David Geffen School of Medicine at UCLA, Los Angeles, USA Approximately 50 % of patients with Major Depressive Disorder (MDD) respond to the first antidepressant medication prescribed, and fewer than one-third experience remission of symptoms. The most significant challenge therefore is selection of the antidepressant medication that is most likely to lead to patient response or remission. There is growing evidence that certain clinical neurophysiologic techniques may be useful for selecting the medication that is most efficacious. Use of low resolution electromagnetic tomography (LORETA), loudness dependent auditory evoked potentials (LDAEP), and resting state quantitative electroencephalography (QEEG) in the clinical setting is increasingly supported by studies indicating that these techniques may help identify particular medications that are most likely to lead to response or remission. One putative neurophysiologic biomarker, the Antidepressant Treatment Response (ATR) index, is based upon QEEG data collected on two occasions, at pretreatment and at the end of one week of medication treatment. ATR is based upon a change in frontal brain electrical activity integrated and scaled from 0 (low probability of response or remission to the medication) to 100 (high probability). In a study of 73 MDD subjects treated with escitalopram, ATR predicted response and remission with 74 % overall accuracy. A low ATR value not only predicted non-response to escitalopram, but also subsequent response to the antidepressant bupropion. Subjects with ATR values above the threshold were over 2.4 times as likely to respond to escitalopram as those with low ATR values (68 % vs. 28 %, p=0.001). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone than those who remained on escitalopram treatment (53 % vs. 28 %, p=0.034). ATR is recorded with a laptop computer-based system and can be performed in 10–15 minutes in any office-based setting. ATR therefore could constitute a translatable clinical tool if preliminary results are confirmed. Policy of full disclosure : Andrew Leuchter, M.D. has provided scientific consultation or served on advisory boards for Aspect Medical Systems, Bristol-Myers Squibb, Eli Lilly and Company, Merck & Co., Otsuka Pharmaceuticals, and Pfizer. He has served on a speaker’s bureau for Bristol-Myers Squibb, Eli Lilly and Company and Wyeth-Ayerst Pharmaceuticals. He has received research/ grant support from the National Institute of Mental Health, the National Center for Complementary and Alternative Medicine, Aspect Medical Systems, Eli Lilly and Company, Wyeth-Ayerst Pharmaceuticals, Merck & Co., Pfizer, Sepracor, Vivometrics, and MedAvante. He also is a former equity shareholder in Aspect Medical Systems.


Symsposia, Monday 7 June 2010

6 jS-01.004j Pharmacogenetical approach to prediction and personalized medication in major depressive disorder treatment

body are very similar to the biochemical changes induced by drugs. This new way of thinking may have profound implications both for clinical trials and for medical practice. Policy of full disclosure : None.

M. Kato. Kansai Medical University, Dept. of Neuropsychiatry, Osaka, Japan Objective : The genetically determined investigation of pharmacological responses would be helpful to evaluate the best therapeutic tool for each depressed patient. However, the growing body of research in this field and heterogeneity across those studies could make it difficult for these candidates to be translated into treatment recommendations. Among others variety of ethnicity and therapeutic agents could play an important role as confounder in pharmacogenetic result. To contribute to personalized medication for depression we should clarify the complicated effect of these confounders. Methods : Therefore we performed meta-analysis of pharmacogenetic studies with consideration of efficacy of some factors to detect the difference of genetic influence on antidepressant response between Asian and Caucasian based on our previous meta-analysis. We also performed randomized clinical trail (RCT) in Japanese subject ‘‘ fluvoxamine vs. paroxetine vs. milnacipran ’’ stratified by interesting genetic factor such as functional polymorphisms of the serotonin transporter gene (SERTPR) and the alpha 2A-adrenergic receptor gene (ADRA2A), that we previously observed different contribution to each antidepressant. Results : From the meta-analysis, clearly different results between ethnicities were observed with HTR1A-1019C/G, HTR2A-1438A/G (102T/C) and TPH1 218A/C independent from efficacy of type antidepressant possibly due to efficacy of other polymorphisms, different allele frequency, differential effect depending on specific symptoms, and cultural or social differences between Asians and Caucasians. As for 5-HTTLPR, inconsistent result could not be observed between ethnicities but SSRIs prescribed study and others. RCT showed that in patient having both SERTPR Sk/Sk and ADRA2A-1297C allele, fluvoxamine was significantly less effective compared to paroxetine and milnacipran, while in patient with SERTPR Lk allele and ADRA2A1297G/G, milnacipran was significantly less effective compared to paroxetine and fluvoxamine. Conclusion : Pharmacogenetic approach could contribute to, at least partially, to predict antidepressant response and personalized medication in depression with consideration of possible confounders. Policy of full disclosure : None.

jS-02.002j Emergence and source of placebo response in schizophrenia trials L.D. Alphs. Ortho-McNeil Janssen, Psychiatry, Titusville, USA Objective : An increasing placebo response has been observed in trials of antipsychotic agents over the past few decades. This effect may derive from a response to the therapeutic setting, or biases introduced during patient selection, evaluations or ratings, or from the patient. Because placebo response impacts the observed placebo-adjusted effect of antipsychotic therapy, outcomes of clinical trials can be dramatically influenced by this effect. This presentation will examine placebo effect seen in clinical trials conducted in schizophrenia and schizoaffective disorder trials to identify predictors of this effect. Methods : Post-hoc analyses of several clinical trials were completed to explore the extent of placebo response over time. Potential associated factors that might represent risk factors or predictors of an exaggerated placebo response over time were evaluated. Results : A pronounced increase in placebo response relative to active treatment was been observed during the past decade. Further, although the increasing placebo effect has been global, a decrease in the drug-placebo effect has been particularly prominent in the United States. Some demographic and clinical characteristics were identified in this analysis as possibly associated with placebo response. Conclusion : The origin of the observed increase in placebo response in clinical trials is likely to be multi-factorial and not easily addressable with changes to patient selection criteria. Increased placebo response has implications for clinical trial design, interpretation and generalizability of trial results. Policy of full disclosure : I am an employee of Ortho-McNeil Janssen a Division of Johnson & Johnson.

jS-02.003j Methodological concerns surrounding S-02. Placebo-related response in clinical trials : what is driving this phenomenon and what can be done to minimize it? jS-02.001j The neurobiological bases of placebo responses F. Benedetti. University of Turin, Medical School Italy Objective : The placebo effect, or response, has evolved from being thought of as a nuisance in clinical and pharmacological research to a biological phenomenon worthy of scientific investigation in its own right. The study of the placebo effect and of its negative counterpart, the nocebo effect, is basically the study of the psychosocial context around the treatment and the patient, and it plays a crucial role in the therapeutic outcome. Methods : In recent years, different types of placebo responses have been analyzed with sophisticated biological tools, such as neuropharmacology, neuroimaging, in vivo receptor binding, and singleneuron recording from awake subjects, that have uncovered specific mechanisms at the anatomical, physiological, biochemical and cellular level. Results : Most of our knowledge about the neurobiological mechanisms of the placebo response comes from pain and Parkinson’s disease, whereby the neuronal circuits involved in placebo responsiveness have been identified. In the first case, opioidergic, dopaminergic and cholecystokinergic networks have been found to be involved. In the second case, dopaminergic activation in the striatum and neuronal changes in basal ganglia circuitry have been described. Conclusion : This recent research has revealed that these placeboinduced biochemical and cellular changes in a patient’s brain and


placebo-controlled trials in schizophrenia W.W. Fleischhacker. Medical University Innsbruck, Dept. of Biological Psychiatry, Austria Objective : Placebo response is a common and well appreciated phenomenon in clinical trials in all fields of medicine. It has a number of potential negative consequences including, among others, the economical and scientific burden of failed, negative or uninterpretable trials. Historically, placebo response in trials involving schizophrenia patients has been fairly low but it appears that it may be increasing. Clearly, placebo response occurs both in placebo-controlled studies and in clinical trials without a placebo control. Methods : Concerns regarding placebo-controlled trials are based on ethical and methodological considerations, the latter have focussed on the feasibility of such studies and the generalizability of results obtained from them. Patient and centre selection have been studied in this context. Results : Legal restrictions as well as a decreasing acceptance of patients to participate in placebo-controlled studies impact on both problems as well. The fact that placebo-controlled studies have larger drop out rates than studies which involve active controls also impacts on the generalizability problem. Conclusion : All of these concerns taken together have fuelled the ongoing debate on the usefulness of placebo-controlled clinical trials and possible alternatives. Policy of full disclosure : W. Wolfgang Fleischhacker has received research grants from Janssen Cilag, Servier, Eli Lilly, BMS/Otsuka. He has received honoraria for educational programmes from Pfizer and AstraZeneca, speaking fees from AstraZeneca, Pfizer, Janssen cilag, BMS/Otsuka and advisory board honoraria from BMS/Otsuka, Wyeth, Janssen Cilag and AstraZeneca.

S-03. Treatment of methamphetamine addiction : A global perspective jS-02.004j Minimization of placebo response in clinical trials J.M. Kane. The Zucker Hillside Hospital, Glen Oaks, USA Clinical trials in schizophrenia fail more frequently than they should, and the rate has been worsening. This presentation will focus on two potential root causes : first, some patients enrolled into clinical trials may be inaccurately diagnosed and/or insufficiently ill to benefit from the treatments being tested ; and second, assessment methods for detecting efficacy may be inadequate and/or inconsistent. One potential root cause is subject selection. Depression and anxiety studies have shown that up to 50 % of patients enrolled in trials may not meet initial severity criteria. New data from ongoing schizophrenia studies show that up to 56 % of patients enrolled in trials may not meet initial severity criteria. New data on diagnosis at study entry in ongoing psychiatric trials show that an additional cohort of patients may be inaccurately diagnosed. A second potential root cause is variability of outcomes assessments. Data will be reviewed showing that >50 % of assessments of primary efficacy scales were inadequately performed in one study, and that assessment quality decayed over the life of another trial. One potential solution to both of these possible problems is centralized assessments of diagnosis and symptom severity by a small group of highly-trained, continuously calibrated raters. Careful selection of study participants may result in optimized outcome measures, as well as a minimization of placebo response. An alternative to centralized assessments by videoconference is to videotape assessments performed at dispersed trial sites for review by a highlytrained, continuously calibrated group of clinicians. Initial data from this later approach show improvement in diagnostic and outcomes assessments from clinical trials in various psychiatric indications. Policy of full disclosure : Dr. Kane disclosure statement. Consultant and Advisory Board : Bristol-Myers Squibb, Otsuka, Eli Lilly and Co., Janssen, Johnson & Johnson PRD, MDS Pharma Services, Pfizer Inc., Solvay Pharmaceuticals Inc., Wyeth Pharmaceutical, Lundbeck, Vanda Pharmaceutical, Astra-Zeneca, Cephalon, Dainippon Sumitomo, GlaxoSmithKline, Intracellular Therapeutics, PGxHealth, Proteus, Takeda. Shareholder MedAvante. Speakers Bureau : Bristol-Myers Squibb, Janssen.

S-03. Treatment of methamphetamine addiction : A global perspective jS-03.001j Addictive disorders : Treatment of methamphetamine addiction : A global perspective R. Rawson. UCLA, Integrated Substance, Los Angeles, USA Objective : Review Current Behavioral Treatments For Methamphetamine Dependence. Methods : At present there is no pharmonacotherapy will established efficacy for the treatment of methamphetamine (MA) disorders. Research on medications including bupropion, modafinil and amphetamine appears promising but more research is needed to establish efficacy. There are several behavioral treatment which have data to support their use for treatment of MA dependence. Results : Contingency management (CM) has the most substantial data to support its use for treating MA users. Studies by Roll, Rawson and others have demonstrated that CM reduces MA use, promotes extended periods of MA abstinence and retains MA users in treatment. Cognitive Behavioral Therapy (CBT) also has been shown to be useful with MA users. Various durations of CBT have been shown to be useful to MA users (Lee and others) and that CBT produces a sustained benefit to patients beyond the active treatment period. The Matrix Model a multi-component behavioral model has been evaluated in comparison to a treatment as usual condition. The Matrix approach resulted in better treatment retention and more MA-free urine samples during treatment than the comparison group. At one year and 3 years post treatment, outcomes from the two treatment conditions were comparable. Conclusion : The major limitation to all of these treatment approaches is that they require a trained cadre of clinicians and training in CBT and especially the Matrix Model is very time intensive and lacks feasibility in many parts of the world. Although CM is relatively easy to train, requires that the treating clinician has access to resources

7

to provide as incentives. In many parts of the world this is also a significant limitation. There is a great desire to identify treatments for MA dependence that can be practical and effective, As yet, the options are limited. Policy of full disclosure : None.

jS-03.002j Pharmacological treatment of methamphetamine addiction A. Elkashef. NIDA, Division of Pharmacotherapies, USA Amphetamine type stimulants are major public health problem worldwide, with an estimated 40 million users globally. Major areas of concentration are in southeast Asia, Australia and eastern Europe. In the united states there is an estimated 2 million users mostly in the western states and Hawaii. Chronic use is associated with serious medical, behavioral and psychiatric problems. Psychosocial interventions represent the main treatment modalities in many countries ; however the relapse rate is high. Pharmacological interventions are showing promise in early proof of concept trials. Bupropion 150 mg SR, B.I.D, was significantly efficacious in improving abstinence in the mild to moderate users. Modafinil 200 mg/day was efficacious in nonopiate dependent methamphetamine users especially patients who attended the psychosocial treatment sessions offered during the trial. Concerta 54 mg/day was significantly better than placebo and aripiprazole in facilitating abstinence from methamphetamine use. These signals are highly encouraging and are being pursued in confirmatory trials. Lobeline and vigabatrin are two other promising medications based on their preclinical profile that are in early phase development for stimulants addiction. This presentation will cover pharmacological treatment of methamphetamine addiction ; highlight findings from recently completed studies and overview promising medications in the pipeline as well as immunotherapy concepts that may be of use for methamphetamine addiction treatment. Policy of full disclosure : None.

jS-03.003j International differences in stimulant use : Comparison of cocaine, methamphetamine and MDMA using wastewater analysis J. White1, R. Irvine2, C. Kostakis3, P. Felgate3, E. Jaehne2, E. Zuccato4, R. Fanelli4. 1 School of Pharmacy, and Medical Sciences, Adelaide, Australia ; 2 Univeristy of Adelaide, Pharmacology, Australia ; 3 Forsensic Sciences, Adelaide, Australia ; 4 Mario Negri, Pharmacological Research, Milan, Italy Objective : Trends in drug use are increasingly international, with the spread across borders of drugs and drug production methods. International comparisons of drug use are therefore valuable in predicting future drug trends and hence the need for services and other responses. Current data suggests that use of the three main stimulants, cocaine, methamphetamine and MDMA (‘ ecstasy ’), varies significantly across countries. For example, MDMA and methamphetamine use is high in Australia, but lower in the US and UK and much lower in Italy, whereas cocaine use is highest in the US, followed by England, Italy and Australia. However, these data are based on selfreport surveys with their associated problems of limited access to marginalised groups, under-reporting and non-standard mthodology. Methods : In order to provide a more accurate means of comparison we have used an objective method for quantifying drug use that relies on sampling sewage inflow as a means of obtaining population urine samples. We have conducted these analyses in Italy and Australia ; data are also available for the UK. Results : Cocaine was highest in Milan, followed by London, with an approximate 20-fold lower concentration in Adelaide. In contrast, methamphetamine and MDMA use were highest for Adelaide with rates approximately 10-fold lower in Milan and London. Conclusion : These results reveal striking differences in amounts of drugs used across different locations that may be significantly underestimated by current survey methods. This approach has the potential to be widely used to quantify our understanding of drug use in populations and should be further developed to improve the data that inform prevention and treatment programs. Policy of full disclosure : None.



8 jS-03.004j A relationship of mania to methamphetamine experiences J. Rybakowski. University of Medical Sciences, Dept. of Adult Psychiatry, Poznan, Poland Excessive use of methamphetamine (MA) can produce symptoms similar to bipolar mood disorder, i.e. manic symptoms after acute intake and depressive symptoms during abstinence period. A co-existence of these two conditions (methamphetamine dependence and bipolar disorder) is also not so rare phenomenon. In recent years, a concept of bipolar-stimulant spectrum has been introduced where sub-threshold bipolar traits are complicated by stimulant abuse, eventually leading to pathology characteristic of both disorders. Similarities in the underlying neurobiological mechanisms and aspects of treatment between MA dependence and bipolar mood disorder are multifarious. Genetic predisposition to both disorders is characterized by a commonality of various candidate genes such as catechol-O-methyltransferase (COMT), dopamine receptor D4 (DRD4) or brain-derived neurotrophic factor (BDNF). The occurring of psychotic symptoms both in MA dependence and bipolar illness may be associated with a polymorphism of the dysbindin gene, previously shown to be connected with schizophrenia. BDNF plays an important role in both neurobiological mechanisms and clinical aspects in both disorders which has been confirmed both in experimental and clinical studies. Concerning mood-stabilizing drugs which make the forefront of treatment of bipolar illness, it has been shown that lithium and carbamazepine reduce MA-induced regional Fos protein expression in the rat brain and that lithium may enhance the effect of MA on circadian rhythms in the mouse. Atypical antipsychotic drugs such as quetiapine and risperidone have been efficacious in the treatment of co-occurring bipolar disorder and stimulant dependence. A promising effects of D-amphetamine and methylphenidate in the treatment of MA dependence have raised a question whether psychostimulants can be a treatment option in mania. The efficacy of aripiprazole, a partial D2 receptor agonist, in the treatment and prophylaxis of mania has been demonstrated, and experimental and clinical studies of its utility in stimulant dependence are under way. Policy of full disclosure : None.

S-04. Chromatin remodeling by HDAC inhibition in neuropsychiatric and neurodegenerative disorders jS-04.001j The mood stabilizer valproate induces protective effects in neurodegenerative and neuropsychiatric models through HDAC inhibition D.-M. Chuang1, Z. Wang1, C.-T. Chiu1, G. Liu1, P. Leeds1, Y. Leng1. 1 National Institute of Mental Health, Bethesda, USA Objective : The interplays between histone acetyltransferases (HATs) and histone deacetylases (HDACs) have prominent roles in chromatin remodeling and transcriptional regulation, and their abnormalities have been implicated in the pathogenesis of neurodegenerative and neuropsychiatric disorders. Valproic acid (VPA), a mood stabilizer and anticonvulsant, was found to be a direct inhibitor of class I and class IIa HDACs. Our study investigated the role of VPA-induced HDAC inhibition in the induction of neuroprotective/neurotrophic proteins and protection against excitotoxicity in vitro. We also studied the beneficial effects of VPA in rodent models of brain disorders. Methods : Glutamate-induced, NMDA receptor-mediated death in primary cultures of neurons was used as a model of excitotoxicity. Rat middle cerebral artery occlusion (MCAO) was used as an ischemic stroke model. N171-82Q and YAC128 transgenic mice were employed as models of Huntington’s disease. In all cases, therapeutically relevant doses of VPA were administrated to assess its beneficial effects. Levels of histone acetylation served as an index of HDAC inhibition. Results : VPA treatment, through HDAC inhibition, protected neurons from excitotoxicity via multiple mechanisms including induction of BDNF, GDNF, VEGF and surprisingly alpha-synuclein. In the MCAO model, post-insult VPA treatment reduced infarct volume, neuroinflammation and behavioral deficits. In addition, VPA


suppressed breakdown of the blood-brain barrier and stimulated neurogenesis and angiogenesis. In the Huntington’s disease models, N171-82Q and YAC128, dietary VPA administrations showed multiple beneficial effects including prevention of hypo-locomotion, improvement of rotarod performance, amelioration of depression and anxiety-like behaviors and prolongation of survival. In general, these effects were potentiated by co-treatment with lithium, another mood stabilizer. Conclusion : VPA-induced HDAC inhibition activates transcriptional capacity to induce a number of neurotrophic and neuroprotective factors, and exhibits robust neuroprotective effects in cultured neurons and animal models of CNS disorders. Our research suggests that VPA may have utility in treating multiple brain diseases, in addition to bipolar disorder. Policy of full disclosure : Biosketch : De-Maw Chuang, Ph.D. Dr. De-Maw Chuang is the Chief of the Section on Molecular Neurobiology in the Mood and Anxiety Disorder Program of the National Institute of Mental Health at the National Institutes of Health. He obtained his Ph.D. degree from the Molecular and Cellular Biology Program of the State University at Stony Brook and received his postdoctoral training in the Roche Institute of Molecular Biology at Nutley, New Jersey. Since 1999, he has been holding the current position of a Section Chief. He has worked throughout his career as a neuroscientist, pharmacologist and molecular biologist. Dr. Chuang’s current research centers on the neurobiology of mood stabilizing drugs, notably lithium, valproic acid and lamotrigine, which are used to treat bipolar mood disorder. His pioneering work demonstrated that treatment with lithium robustly protects cultured CNS neurons from glutamate-induced NMDA-receptor-mediated excitotoxicity, which has been implicated in a variety of neurodegenerative and neuropsychiatric diseases. His recent research provided evidence that lithium and valproic acid, by inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, elicited neuroprotective, neurotrophic, anti-inflammatory and mood stabilizing effects. His laboratory also reported the downstream mechanisms mediating these actions. His past and current work showed that lithium and valproic acid have beneficial effects in multiple animal models of neurodegenerative and neuropsychiatric disorders. His research goal is to explore the possibility that mood stabilizers have utility in treating neurodegenerative diseases, in addition to bipolar disorder. Dr. Chuang has received many honors and awards, including the NIH Director’s Award in 1997 in recognition of ‘‘his superb leadership and innovative research which advances the understanding of basic mechanisms involved in neurodegenerative and neuropsychiatric disorders ’’. He is the recipient of the 2002 NARSAD Distinguished Investigator Award. He was also inducted to the Academia Sinica in Taiwan in 2006. Dr. Chuang is an Adjunct Professor of Psychiatry and Neuroscience at the Uniformed Services University of the Health Sciences in Bethesda, and a member of many scientific societies including the ACNP, FASEB and the Society for Neuroscience. He has published over 220 scientific articles in peerreviewed journals including PNAS, Science, Nature Medicine, J Neuroscience, Mol Psychiatry and J Biol Chem.

jS-04.002j HDAC inhibitors induce GAD67 expression and reduce promoter methylaion D. Grayson1, Y. Chen2, E. Dong2, A. Guidotti2. 1 Univ. of Illinois at Chicago, The Psychiatric Institute, USA ; 2 Univ. of Illinois at Chicago, Department of Psychiatry, USA Objective : The down-regulation of reelin, NMDA receptor subunit and GAD67 mRNAs in GABAergic neurons of schizophrenia cortex is well established. Defective excitatory signaling through NMDA receptors on GABAergic interneurons results in reduced synaptic GABA release innervating cortical pyramidal neurons. In addition, there is increased expression of DNA methyltransferase (DNMT) 1 in these GABAergic neurons. We have shown that the reelin promoter is hypermethylated in schizophrenia subjects. The inverse relationship between Dnmt1 and reelin/GAD67 expression suggests that DNMT1 may function in establishing DNA methylation patterns in neurons and in regulating gene expression. Methods : We have focused on dissecting the human GAD67 promoter to understand its regulation and how epigenetic drugs impact expression. Promoter deletion analyses were used to identify

S-05. Positron Emission Tomography Treatment Developments in Psychiatry cis-acting regulatory elements. In addition, we have used methyl DNA immunoprecipitation (MeDIP) in combination with real time qPCR, chromatin immunoprecipitation (ChIP) to analyze promoter methylation after treating NT2 cultures with chromatin remodeling drugs. Results : Transfection experiments revealed the presence of regulatory regions downstream of the GAD67 start site. MeDIP studies showed that this region is methylated when the gene is inactive. The HDAC inhibitor MS-275 increased demethylation and reduced MeCP2 binding to downstream regulatory elements. The increased GAD67 expression is accompanied by the dissociation of MeCP2 from the promoter. Conclusion : We suggest that the down-regulation of mRNAs in GABAergic neurons of schizophrenia brain may be the result of promoter hypermethylation. Drugs that inhibit methylation as well as histone deacetylation activate the expression of reelin and GAD67. This appears to occur through a mechanism that involves promoter demethylation and the release of repressor proteins from the region. Based on our findings, we suggest that components of the DNA methylation cascade may represent novel therapeutic targets for pharmaceutical development. Policy of full disclosure : None.

jS-04.003j Maternal care, gene expression and epigenetic programming of stress responses M. Meaney. McGill University, Douglas Institute Research, Montreal, Quebec, Canada Maternal care alters adaptive behavioral and endocrine responses to stress in the rat. The mechanisms for these ‘ maternal effects ’ involve stable changes in gene expression. Thus, the adult offspring of mothers that exhibit increased pup licking/grooming (LG) show increased hippocampal glucocorticoid receptor (GR) mRNA expression. The differences in GR expression associate with effects at the level of both negative feedback inhibition and HPA responses to stress. Studies of the mechanisms for maternal effects on GR expression focus on DNA methylation within a brain-specific GR gene promoter. These studies reveal sustained effects of maternal behavior on the cytosine methylation of the consensus binding sequences for specific transcription factors that regulate GR gene expression. Pharmacological manipulations that reverse the maternal effect on cytosine methylation of the GR promoter also eliminate the effect at the level of both GR expression and HPA responses to stress. The maternal effect on DNA methylation involves an active demethylation at specific CpG dinucleotides targeted by intracellular signals driven by pup LG. Such processes reveal experience-dependent plasticity in the chemistry of the DNA and chromatin structure. Finally, recent studies suggest that a comparable process may occur in humans ; thus, studies with postmortem human hippocampus reveal that a history of child maltreatment associates with increased methylation of the exon 1F GR promoter and decreased GR expression. Policy of full disclosure : None.

jS-04.004j Effect of histone deacetylase inhibition on cocaine self-administration by rats : Behavioral and gene profiling studies J. Zwiller. Centre de Neurochimie, Institut National de la Sante´, Strasbourg, France Objective : Regulation of gene expression is known to contribute to the long-term adaptations taking place in brain structures in response to drugs of abuse. Recent studies highlight the regulation of gene transcription in neurons by chromatin remodeling, a process governed by the interplay of DNA methylation and post-translational modifications of histones. Methods : To test the involvement of epigenetic regulation on drug reinforcing properties, we submitted rats to the cocaine self-administration paradigm. We then investigated alterations in gene expression in dopaminergic structures of rats self-administering cocaine and treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TsA). We also used the oligonucleotide microarray technology that revealed 722 probe sets in the cortex and 136 probe sets in the nucleus accumbens differentially expressed between vehicle and TsA-treated rats that self-administered cocaine.

9

Results : Using the fixed-ratio 1 schedule, we found that HDAC inhibitors TsA and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both TsA and depudecin significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. Cocaine self-administration was accompanied by an increased synthesis of epigenetic parameters, such as Mecp2, HDAC2 and HDAC11 and by the nuclear export of HDAC5. The latter mechanism was further addressed by the demonstration of an enhanced expression of MEF2C transcription factor. Microarray data were validated by real-time PCR for seven genes. Using immunohistochemistry, we further investigated the expression of Lis1 and reelin genes, since they belong to the same signal transduction pathway and mutations within both genes cause lissencephaly. Conclusion : The data indicate that the two proteins, and the signal transduction pathway to which they belong, contribute to establish neurobiological mechanisms underlying brain plasticity whereby TsA lowers the motivation for cocaine. Policy of full disclosure : None.

S-05. Positron Emission Tomography Treatment Developments in Psychiatry jS-05.001j Positron emission tomography treatment developments in psychiatry 1

N. Mori , K. Suzuki2, Y. Iwata2, Y. Ouchi2. 1 Hamamatsu University School, of Medicine, Japan ; 2 Hamamatsu University School, Dep. of Psychiatry, Neurology, Japan Objective : The pathogenesis of most psychiatric illnesses is likely multifactorial, although animal and human data have implicated common pathophysiologic pathway abnormalities including dysregulations in monoamine signaling, reduced neuroplasticity and dysfunction in brain circuitry as important processes. To what extent are these processes a cause of the disease, or part of a chain of events in the pathophysiology? In vivo imaging offers an opportunity to identify relationships between the timing of symptoms, and the timing of abnormalities to better understand how some of these phenomena are connected. In the symposium, I will give an introduction on recent developments in molecular imaging using PET to close existing gaps between basic research in psychopathology, neurobiology and treatment with the ultimate goal to translate basic research into clinically relevant findings. Subsequently, I will present our recent study on autism as an example showing usefulness and advantage of PET to identify the current symptoms and the molecular changes in brain of psychiatric illnesses. Results : We have recently measured the binding of serotonin transporter which is a highly selective marker for the serotonergic system, using PET (Nakamura et al. Arch Gen Psychiatry 2010 ; 67 : 59–68). The most important finding was significantly lower binding in serotonin transporter throughout the brain in autistic individuals. Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition, while that in the thalamus was associated with repetitive and/or obsessive behavior and interests. Elucidation of molecular mechanism associated with the decreased serotonin transporter binding observed by the PET study may open a new window for further understanding neurobiology of autism. Policy of full disclosure : None.

jS-05.002j Brain serotonin and dopamine transporter bindings in adults with high-functioning autism G. Sugihara. Hamamatsu University, School of Medicine, Japan Objective : Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. To determine the occurrence of changes in the binding of



10 serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. Methods : Using positron emission tomography (PET), we measured the binding of brain serotonin and dopamine transporters with the radioligands [11C](+)McN-5652 and [11C]WIN-35,428, respectively, in 20 men with autism and 20 age- and IQ-matched control subjects. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Results : Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls. Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the subjects with autism. A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus. In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group. In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding. Conclusion : The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Policy of full disclosure : None.

jS-05.003j Abnormalities in the serotonergic system in panic disorder : Evidence from neuroimaging studies D. Cannon1, J.M. Klaver2, S.A. Peck3, P.J. Carlson3, M. Ichise4, W.C. Drevets3. 1 National University of Ireland, Department of Psychiatry, Galway, Ireland ; 2 National Insitutes of Health, MD, USA ; 3 National Institutes of Health, MD, USA ; 4 Columbia University, NY, USA Objective : The central serotonergic system has been implicated in the pathophysiology of panic disorder (PD) by evidence of abnormally elevated serotonin-turnover, reduced pre- and post-synaptic 5-HT1A-receptor sensitivity and binding, increased susceptibility to panic following tryptophan depletion, and clinical improvement during administration of agents that enhance serotonergic transmission. Sex effects are compatible with evidence that polymorphisms in genes that putatively play roles in serotonergic neurotransmission increase the vulnerability for developing PD specifically in males. The objective was therefore to test the hypotheses that 5-HTT-binding, which generally parallels 5-HT neurotransmission, is elevated in PD subjects versus healthy-controls in regions where 5-HT-release increases during anxiety, and that the extent of this difference depends upon sex. Methods : Outpatient volunteers with current PD (n=24) and psychiatrically healthy controls (n=24) were studied at the NIH. The non-displaceable 5HTT binding-potential (BPND) was measured using PET and the 5-HTT selective radioligand, [11C]DASB. PD severity was assessed using the PD Severity Scale. Results : The 5-HTT-BPND was increased in males with PD relative to male controls in the anterior cingulate cortex (F=9.02, p=0.004) and anterior insula (F=7.10, p=0.011). In contrast, BPND did not differ between females with PD and female controls in any region examined. Conclusion : The finding that 5-HTT-binding is elevated in males but not in females with PD converges with other evidence suggesting that dysfunction within the central serotonergic system exists in PD, but that such abnormalities are influenced by sex. These data suggest that the compensatory elevation in 5-HT transmission expected in response to the stress or fear associated with PD occurs more prominently in males than females. This hypothesis appears compatible with evidence that SSRIs show greater efficacy in females than males with PD, since inhibition of 5-HTT-sites would augment 5-HT neurotransmission during periods of increased 5-HT-release. Policy of full disclosure : None.


jS-05.004j Pet imaging reveals novel mechanisms in the neurobiology of PTSD C. Czermak1, R. Carson2, S. Kasserman3, B. Planeta-Wilson2, S. Henry3, Y.-S. Ding2, H. Yuang2, J. Krystal2, A. Neumeister2. 1 LKH Sigmund Freud, Institute of Pathophysiology, Graz, Austria ; 2 New Haven, USA ; 3 West Haven, USA Objective : Although, based on empirical data, selective serotoninreuptake inhibitors are used as first-line drugs for the treatment of posttraumatic stress disorder (PTSD), little is known on the respective neurobiological rationale. The serotonin-1B (5-HT1B) receptor is a key component of the serotonergic system, as it is expressed both presynaptically and postsynaptically, and as a presynaptic receptor it controls for the release of serotonin. 5-HT1B receptors can be also found in the midbrain raphe regions. In our studies we aimed to further investigate possible serotonergic alterations in PTSD. Methods : Using [11C]P943, a selective, high affinity 5-HT1B receptor antagonist, we studied 5-HT1B receptor expression in PTSD patients without and with an additional diagnosis of major depressive disorder (PTSD only, n=30, and PTSD+MDD, n=15, respectively), relative to healthy control subjects (HC, n=26). The use of a high resolution PET scanner also permitted assessment of serotonin-1B receptor expression in the midbrain raphe regions. Results : Significant differences between the groups were found for the anterior cingular cortex (ACC) and the dorsal striatum. In both regions, PTSD+MDD but not PTSD only patients showed reduced 5HT1B expression relative to HC (ACC : p=0.13, and dorsal striatum : p1000 genes involved in these disorders. However, the etiology of many rare disorders remains unknown because either the number of patients is too small for genetic studies, or the disorder is so heterogeneous that many families carry essentially private mutations, but are usually not large enough to by themselves permit gene identification. In addition, risk for most psychiatric disorders is thought to be influenced by a multitude of genetic variants, each with a small effect. Only a small fraction of the genetic heritability is currently explained by the genetic variants identified. The past years have seen an unprecedented growth in genetics, genomics, and other yomics technologies. Methods : We propose that combining these yomic technologies with genetic studies will facilitate gene identification in both rare and common neuropsychiatric disorders. We will show results from combining genetic linkage and association studies with gene expression. Results : In this manner, we have identified DIAPH3 as the mutant gene in a rare form of deafness, AUNA1, by combining traditional linkage analysis with gene expression in lymphoblastoid cell lines. Similarly, we combined the results from large genome-wide association studies (GWAS) of Bipolar Disorder with gene expression analysis of cis variants in many different relevant brain regions, including a large haplotype block associated with bipolar and other mood disorders. Conclusion : While the causative mutant genes could be identified in common Mendelian disorders using purely genetic techniques, more heterogeneous and complex disorders such as psychiatric disorders require a combination of approaches. So far, we and others applied this yomic approach to combining genetic with gene expression studies. Future studies may combine genetic linkage and association with linkage disequilibrium, next generation sequencing, proteomics, and biochemical pathway analysis. Challenges include how to combine datasets in vastly different formats and to assign significance when technologies are combined. Policy of full disclosure : The author is a member of The Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. An agreement exists between the fund and the Universities involved to encourage the development of appropriate findings for research and clinical applications.

jS-12.002j Exploring systems medicine using translational bioinformatics A. Butte. Stanford University, School of Medicine, USA Objective : With the end of the United States NIH budget doubling and completion of the Human Genome Project, there is a need to translate genome-era discoveries into clinical utility. The difficulties in making bench-to-bedside translations have been described : comprehensive molecular studies on patients are expensive, and hospitals are not phenotypers. The nascent field of translational bioinformatics may help. Methods : I will highlight three recent translational bioinformatics projects from the laboratory with direct implications for medicine, in the process redefining how we consider and treat diseases. Results : (1) Genome-wide association studies (GWAS) are a popular and powerful method to decipher the architecture of complex diseases, though they are limited by inconsistent findings. I will show how a new data-driven method to find new candidate genes – enabled by the community sharing of molecular measurements – could be

17 used to find the rest of the ‘‘long tail ’’ of genes associated with complex disorders. (2) Modern day use of DNA sequencing has enabled the re-organization of species in the taxonomical trees that date back to Linnaeus. But Linnaeus was also among the first to suggest a taxonomical classification for diseases, or nosology. I will show how a new genome-data driven nosology has led us to find novel biomarkers for solid-organ transplant rejection, and suggests novel roles for drugs in the treatment of disease. (3) Our lab has successfully built novel ‘‘ clinical microarrays ’’ from quantitative electronic medical record data on 60,000 patients over 7 years. We have used these clinical microarrays to find novel biomarkers and genes associated with human aging. Conclusion : Despite their limitations, it is remarkable that in the fifteen years since their creation, gene expression microarrays have already been used to study so many human diseases. It is only because data from these experiments are publicly-available, that we can now start to comprehensively reconsider the nature of disease itself. Policy of full disclosure : Dr. Butte’s research is supported by grants from the Howard Hughes Medical Institute, the NIH, the Pharmaceutical Research and Manufacturers of America Foundation, and the California Institute for Regenerative Medicine. Dr. Butte is a consultant for NuMedii, Johnson and Johnson, Tercia, and Genstruct. Dr. Butte has been a speaker for Siemens and Lilly.

jS-12.003j Combinatorial, multimodal biomarkers from large variable datasets findings from the addneuromed study S. Lovestone1, M. Thambisetty2, D. Kronenberg3, A. Hye3, S. Furney3, A. Simmons3, A. Guntert3, C. AddNeuroMed4. 1 King´s College London, Institute for Psychiatry, United Kingdom ; 2 National Institute on Aging, Baltimore, USA ; 3 King´s College London, United Kingdom ; 4 London, United Kingdom Objective : Biomarkers for Alzheimer’s disease are urgently needed. To date most efforts in biomarker discovery have been hypothesis led, focussed on single analytes and use diseased case versus normal control experimental design. The AddNeuroMed study is a large European collaboration with ADNI like protocols and using data-led discovery with large variable datasets and with novel experimental design in the search for blood based biomarkers. Methods : The AddNeuroMed study has, thus far, used three different study designs. In the first, cases with AD were compared to cognitively normal controls. In the second phase we used endophenotypes and indicators of disease severity as the test variables and in the third phase we compared samples from stable MCI with MCI converter cases. Analytical techniques included proteomics and protein arrays, genomics and analysis of structural MRI using automated processing pipelines. Results : In the first phase, using proteomics we identified a series of proteins in plasma that were elevated in AD, although we also found that single protein measures alone do not have robust accuracy as diagnostics. In the second phase we used endophenotypes of brain pathology as a test variable and found, using proteomics, clusterin as a plasma marker reflecting brain pathology. The role of clusterin as a aetiopathological agent was confirmed by genomics. Other analyses have combined genomics and imaging. In the third phase we compared MCI converters to non-converters and identified a combinatorial, multimodal marker set of regional MRI measures and proteins that has 93 % accuracy in predicting conversion in an otherwise indistinguishable group. Conclusion : AddNeuroMed data suggests 1) that there is a signature in plasma that has utility as a biomarker, 2) that study design is critical and that very large variable datasets should be used in biomarker discovery and 3) that a true biomarker is likely to be combinatorial and multi-modal. Policy of full disclosure : Some of the authors have participated in intellectual property protection by their institutions related to biomarkers for AD.


Symsposia, Tuesday 8 June 2010

18 jS-12.004j GWAS and personalized medicine in China L. He. Shanghai Bio-X-Center of Jiao Tong University, China Objective : Common complex diseases, including psychiatric diseases, cancer, cardiovascular diseases, diabetes, etc., cause major problems for the Chinese society given the large size of the population. As the etiologies of those diseases are multiple, and the genetic backgrounds vary in different populations, it is essential to study genetic factors for these disorders separately in each population. Methods : In recent years, Chinese researchers have carried out a series of genome-wide studies including genome-wide association, CNV, epigenomics, and microRNA-based work to uncover the genetic etiology of some complex diseases in these Chinese samples. Results : In the first half of my presentation, I will show recent advances with several large studies mainly focusing on psychiatric diseases, based on genome-wide studies of complex diseases in the Chinese population. Conclusion : In the second half of my presentation, I will give a brief overview on ‘‘ Personalized Medicine in China : Opportunities and Challenges ’’. The adverse drug reaction (ADR) monitoring system in China has improved greatly ; blood samples from ADR patients are being collected and cell lines constructed ; the establishment of the personalized medicine system in the Chinese population is on the way. Policy of full disclosure : None.

S-13. Novel therapeutical developments in dementia jS-13.001j Modeling of Alzheimer’s disease in mice and identification of novel therapeutic targets B. De Strooper. Katholieke Universiteit, Leuven, Belgium Objective : Alzheimer’s disease is a major burden for our aging societies. Finding a cure is highly desirable but also a very big challenge. In the brain accumulations of protein deposits, known as amyloid plaques and neuronal tangles, are observed. These pathological signs, together with massive neuronal loss, provide a clue towards the understanding of the molecular pathways underlying the disease. The tangles consist of twisted filaments build by the microtubules binding protein tau, while the amyloid plaques contain mainly amyloid fibrils build from a short peptide, the amyloid-betapeptide or Abeta. We focus on the mechanisms generating the Abeta peptide. Methods : We use the genes identified in patients to create mouse models. We study gain and loss of function of those genes. Results : The Abeta peptide is proteolytically cleaved from a larger amyloid precursor protein (APP) by the secretases. Very strong support for the amyloid cascade hypothesis claiming that the Abeta peptide provides the trigger for the disease process came from the study of familial Alzheimer patients. Mutations both in the substrate (APP) and in the catalytic subunit of the gamma-secretase (Presenilin) cause Alzheimer’s Disease. All these mutations change the biophysical properties of the Abeta peptide, so that the generation of neurotoxic Abeta peptide oligomers is favored. Presenilin/Gammasecretase is an obvious drug target as inhibition would result in reduced Abeta oligomer formation. Gamma-secretase is however an intramembrane cleaving protease and therefore also part of important signaling pathways including Notch. We will discuss how mouse models have helped to understand the role of Presenilin and to find ways to modulate Gamma-secretase in ways that do not affect Notch signaling. Conclusion : Gamma-secretase constitutes an attractive drug target, but the problem of notch signaling needs to be circumvented. We will present recent insights in the heterogeneity of the complex and in its regulation by GPCR that provide likely new ways to modulate this activity in a safer way. Policy of full disclosure : None.


jS-13.002j Epigenetic mechanisms regulating synaptic plasticity and memory formation in health and disease L.-H. Tsai. Massachusetts Institute, of Technology, USA Objective : Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. However, effective therapeutic strategies for restoring cognition in these patients are currently lacking. We have therefore been exploring alternative methods that facilitate re-establishment of learning ability and access to long-term memories. Methods : The CK-p25 transgenic mice previously created in our lab allows temporally and spatially restricted induction of neuronal loss and learning/memory impairment which serves as an ideal model for testing therapeutic strategies. Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wildtype mice as well as in mouse models of Rubinstein-Taybi syndrome, a developmental brain disorder. Results : We found that increased histone acetylation as a result of HDACi treatment reinstated learning behavior and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred in the CK-p25 mice. Moreover, increased histone acetylation by HDACi induced dendritic sprouting and increased synapse numbers ; thus, long-lasting remodeling of neural circuits may underlie the beneficial effects of HDACi on cognition. Through a combination of genetic and pharmacological approaches, we have identified histone deacetylase 2 (HDAC2) as a major HDAC in regulating synaptic plasticity and memory formation. HDAC2-deficient mice exhibit facilitated long-term potentiation (LTP), whereas HDAC2 overexpressing mice exhibit impaired learning and hippocampal LTP. Moreover, HDAC2-deficient mice are refractory to the beneficial effects of HDACis in enhancing cognition. Recent work points to additional roles of HDAC2 in regulating neuronal function outside the hippocampal circuitry. Conclusion : Collectively, these results suggest that targeting HDAC2 may benefit multiple neurological disorders associated with learning and memory impairments. Policy of full disclosure : None.

jS-13.003j Rationale approaches and obstacles to targeting abeta and abeta aggregates in AD T. Golde. Center f. Translational, Research in Neurodegenerative, Gainsville FL, USA Objective : Amyloid Beta peptide (Abeta) accumulation within senile plaques, cerebral blood vessels walls, and diffuse immunoreactive deposits is a hallmark of Alzheimer’s disease (AD) pathology. The accumulation of aggregated ABeta is thought to initiate a pathological cascade that results in cognitive decline. As to what Abeta aggregates are the toxic entities in AD is highly debated. Methods : During this talk I will highlight several recent unpublished studies from my laboratory. Results : The first study will show that the most effective window for treatments (e.g., gamma-secretase inhibitors, GSI) that target Ab production is in the pre-plaque phase, and that even GSI therapy that is discontinued prior to onset of plaque deposition is effective with respect to effects on amyloid deposition up to 10 months later. A second study will highlight our studies on substrate targeting gammasecretase modulators (GSMs) (4). I will present data showing that additional GSMs target substrate, and also data showing that the GSM binding site is a critical mediator that determines where gamma-secretase cleaves APP. Finally I will discuss the rationale for development of anti-amyloid antibodies and anti-amyloid vaccines that do not recognize monomeric Abeta (5). Data will be presented that demonstrates in vivo efficacy of the recombinant anti-approach and also discuss how a heterologous amyloid vaccine can be used to generate an anti-amyloid response antibody in the absence of an anti-Ab antibody response. Conclusion : Mutliple ways exist to target Abeta in Alzheimer’s disease, but current therpeutic trials in humans may not result in optimal efficacy.

S-14. Clinical Psychopharmacology of Eating Disorders : Research Update Policy of full disclosure : Grants : NIH, Lunbeck, Myraid Consutlant : Elan, Sonexa Patents : Inveton on mutlpole patents relating to GSMs and anti-amyloid immunotherapy.

jS-13.004j BACEs for AD pathogenesis and drug development W. Song. University of British Columbia, Vancouver, Canada Objective : Alzheimer’s disease is the most common neurodegenerative disorders leading to dementia. Senile neuritic plaques, neurofibrillary tangles, and neuronal losses in the brain are the hallmarks of AD pathology. A central component of the neuritic plaque consists of the 40–42 amino acid residue Ab. Ab is generated from beta-amyloid precursor protein (APP) by the beta- and gamma-secretases. Abnormal APP processing by b- and c-secretase has been shown to be closely associated with AD pathogenesis. Beta-site APP cleaving enzyme 1 (BACE1) is the b-secretase in vivo. Specifically blocking the cleavages of APP by beta-secretases inhibitors has enormous therapeutic potential for AD therapy. This study examined the mechanism underlying BACE1 gene expression and the effect of BACE1 inhibition on AD pathogenesis and treatment. Methods : BACE1 and BACE2 stably-transfected cells were established. BACE1 and BACE2 gene transcription and translation regulation were examined by promoter assay, real-time qRT-PCR and Western blot. Human brain tissues were also assayed. AD transgenic mouse models were used to examine the role of BACE1 processing of APP and Abeta production in AD pathogenesis and treatment. Results : BACE1 trafficking and maturation were altered in Down Syndrome and overproduction of Abeta in Down syndrome is caused by abnormal BACE1 level. Hypoxia, the major consequence of stroke, facilitates AD pathogenesis by upregulating BACE1 expression. BACE2 has distinct transcription and function from BACE1. We identified that BACE2 functions as a novel theta-secretase to cleaves APP within Abeta, and increase in BACE2 expression neuronal cells can significantly reduce Abeta production. Furthermore, we found that modulation of BACE1 expression could significantly inhibit AD pathogenesis in APP/PS transgenic mice. Conclusion : Our studies demonstrate that inhibition of BACE1 or potentiation of BACE2 could be valid targets to develop drugs to prevent and treat Alzheimer’s disease. Policy of full disclosure : None.

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comparison to previously reported results for 28 female controls, study participants had significantly elevated baseline ratings of obsessive-compulsive symptoms (p

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