3 Thinking ahead: Immunotherapy in the brain 4 Plenary lecture: The official newspaper Paul Harrison discusses of ECNP Congress 2012 a combined approach to schizophrenia therapy Issue 2 6 Blossoming future for mental health with ECNP Monday disruptive innovation 15 October 12 The neural mechanisms of Daily News gambling are put to the test 2012 Keynote lecture starts congress with a bang neuronal death or by inducing a greater proportion of stem cells to reenter mito- sis. Although this demonstrated that this process could be trivially achieved, it is not sufficient simply to have an increased number of brain cells; they need to be organised in a more sophisticated man- ner as well. Professor Blakemore continued: “How could the enlargement of the brain make it more useful? What kind of processes would the brain have to go through in order to be better, simply as a result of being larger? If you look at the way in which the brain changed during the mammalian evolution by extant species representative of different points in the mammalian line, what we see is that the sensory areas – the audio, visual, somatic sensory areas – maintain their relative positions throughout evolution, but they occupy a relatively smaller pro- portion of the cortex in more advanced species. It’s not simply that the brain has uniformly increased in size, but it is that it has introduced more space in between the primary sensory areas and the motor areas. That has generated space for more Colin Blakemore specialised areas and we now know that the whole of the cerebral cortex is a Continuing with an interesting mosaic of specialised areas.” The Keynote Session on Saturday evening was filled perspective of the evolutionary under- How this was achieved throughout with awards, speeches and live entertainment that pinnings of the growth of the hominid the course of mammalian evolution is served as a befitting tribute to the opening of the brain, Professor Blakemore said: “I difficult to ascertain. Using the exam- th think that many of the problems we ple of language, Professor Blakemore landmark 25 ECNP Congress. Of course, a crowning suffer, particularly neurological and proposed: “It is interesting that the moment of the session was the keynote lecture, ‘The psychiatric disorder, are a consequence major language areas occupying the plastic brain’, delivered by prestigious and renowned of two things: our brains are too big, association cortex are strategically placed and we live too long. Having a big brain in between the primary sensory areas – expert Colin Blakemore (Department of Physiology, obviously has its advantages, and these auditory and visual – and the part of the Anatomy and Genetics, University of Oxford, UK). advantages were spotted during the motor cortex responsible for the tongue evolutionary process. The brain size of and the laryngeal movements. It is as hough likely needing no intro- of neurons is progressive. The mamma- hominids has increased enormously in if these areas might have been created duction to most in attendance, lian nervous system can never change size, particularly about 200,000 years because of the additional availability of T Professor Blakemore has been, and reorganise, can never regenerate, ago with a rapid doubling in cerebral brain space and their strategic location in and continues to be, involved in ground- can never adapt from damage, and volume. relation to existing functions. breaking developments in our under- that no neurons are created after birth: “The standard argument is a Darwin- “And I’d like to suggest that this standing of fundamental phenomena in all of these ideas have gone, and there ian one: that there must have been some might have been the way in which much the brain. During his keynote lecture he has been a revolutionary change in our kind of advantage for a very large brain, of the modular organisation of the led us on a journey through the history concept of the brain. which led to the conservation of these cerebral cortex developed, simply being of brain experimentation and of the “We see it now as the most dynamic, changes. These changes of course carry in the right place at the right time, with mammalian brain itself. adaptable and plastic organ in the body disadvantages: the brain is a metaboli- sufficient extra brain to utilise the normal History has a curious way of slipping and indeed so many of its functions cally hungry organ, it is consuming about connectivity and plasticity to begin the from our consciousness, and Professor depend on that plasticity. The sorts of 20% of the oxygen in your blood at the process of evolving new functional Blakemore reminded us of just how far problems that we are interested in – be- moment. So there is a big disadvantage structures. There are so many examples we had come over the past several dec- havioural disorders – are probably due to in having a big brain, but there must of specialisation, particularly in visual ades: “Certainly when I was a student, I aberrations in plasticity in the brain, and have been compensating advantages.” parts of the brain. Our cortex has come learned that every neuron in the brain is paradoxically the plasticity of the brain It has been shown in mice that it up with 35 specialised areas responsible created before birth, that many of them might therefore hold a route to new is possible to double the size of the for ever more refined processing of the die shortly after birth and that the loss treatments for many disorders.” brain, either by reducing developmental Continued on page 2 2 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Keynote lecture

cortex. He said: “Changes like this are Keynote lecture starts congress with a bang being demonstrated even after a few days of practice.” Continued from page 1 He concluded his keynote presen- visual image. And that seems to have tation by marking out the potential been a hallmark of human sensory therapeutic uses of these fascinating evolution: that we just found new ways discoveries, saying: “Cortical plasticity of reprocessing, again and again, the continues throughout life, but it is not same information that enters the primary necessarily always adaptive. However, visual cortex.” we know that during early development, Professor Blakemore tested the role of the rapid plasticity of sensory areas can plasticity as a critical factor in the evolu- actually make the brain vulnerable. tion of cortical growth in mammals by Children who have unequal stimulation addressing whether that intrinsic process of their two eyes can suffer in cortical would be plastic enough to be able to organisation by losing input from both utilise increases in cortex size that have eyes. Language disorders, which develop occurred during evolution. With evidence from insufficient exposure to language, of cortical reorganisation following the seem to be due to the fact that there is removal of half of one brain hemisphere a language-sensitive period – perhaps up during a critical developmental phase in to seven or eight years of age. experimental animals, it is clear that this “If it is not utilised, the cortex can may well be the case, as he explained: never fully develop language function. “If this sort of adaptive relationship is Dyslexia too: perhaps some forms could utilised in normal development, it could be explained by disorders in the plasticity easily have been used in the evolutionary that lead to the formation of structures process, because additional brain would that come to acquire the computa- automatically be filled by this adap- tional capacity tive process of projection. If there were for reading. And projections, then that pattern of connec- “Perhaps utilising plasticity, also in learning: tions between neurons might turn out to developing methods IQ is dependent be useful to the individual. to capture and reapply on stimulation: as “After birth, very different forms of much as a 30 IQ plasticity begin to happen. There are plasticity in the brain point difference two main phases: an early stage, usually might be a route to can be produced in called the sensitive period (although children who have there are many, many sensitive periods) ment; kittens that were only exposed to different forms it prevention or therapy.” been very socially in which sensory areas of the brain seem vertical lines had denser, more active and may take: “There deprived in early Colin Blakemore (Department of to be programmed by their own sensory larger areas relating to those vertical sen- are now so many life compared with input. It starts at birth (even before birth sory phenomena than areas devoted to examples of the Physiology, Anatomy and Genetics, normal children. in the case of the auditory system) and other orientations. Professor Blakemore ways in which the University of Oxford, UK) Perhaps in condi- it’s completed quite quickly – in weeks in described the significance of these find- adult cortex can tions like PTSD and monkeys and perhaps a year in humans, ings with regard to the classic dichotomy change dramatically as a result of learn- reactive depression, because there is very with sensory areas learning about the of genes and environment, saying: “So ing – of attentive learning of particular good evidence of a gene-environment statistics of the outside world, and the cortex is adapting itself for its own tasks.” A dramatic demonstration of this interaction in individual depressive changing their properties – their recep- world. This is a sophisticated physiologi- was the representation of the somatic episodes, these may be examples of tive field characteristics to match the cal property; sensory cortex plasticity gone wrong. outside world.” it cannot be and the neigh- “If this is the case, perhaps utilis- Further experiments in sensory depri- accidental. “I have tried to remind you bouring motor ing plasticity, developing methods to vation in cats identified that the develop- “So that of how important plasticity cortex in the capture and reapply plasticity in the ment of sensory areas depended largely leads to the brains of in- brain might be a route to prevention on the nature of sensory stimuli that conclusion is, to reinforce the view that dividuals that or therapy. There are very early but kittens were exposed to during develop- that although what we are has depended had started promising developments in that area, this form of completely on the fact that to learn a using transcranial magnetic stimulation, plasticity has an stringed or transcranial direct current stimula- our brains are plastic, and can tion, to try to reactivate developmental ECNP Daily News environmental instrument, dependence, be reorganised during our starting at or normal plastic mechanisms to try to Publishing and Production it is nurture at different ages. reorganise damaged or disordered brains MediFore Limited work, it must evolution as well as during By measuring in order for them to recover. I have tried President depend on our individual development.” the difference to remind you of how important plastic- Joseph Zohar nature, on the in the degree ity is, to reinforce the view that what we Editor-in-Chief genetics of Colin Blakemore (Department of Physiology, of reorganisa- are has depended completely on the fact Peter Stevenson the neurons. Anatomy and Genetics, University of Oxford, tion between that our brains are plastic, and can be Editor There must UK) controls and reorganised during our evolution as well Ryszarda Burmicz be something those who as during our individual development. ECNP Office special about had started Aberrant plasticity might be at the heart Petra Hoogendoorn the neurons of the visual and other to learn, Professor Blakemore explained of many disorders. Utilising and enhanc- Design sensory cortices early in life that make that the earlier learning starts, the more ing plasticity might lead us to new forms Peter Williams those cells capable of regulating their dramatic the reorganisation of the of remediation and prevention.” Head Office connections as a result of activity: that’s Woodside Villa, 11 Sydenham Hill genetics. Genetics endows neurons with London SE26 6SH the ability to acquire new properties and Telephone: +44 (0) 208 244 0583 new connections as a result of activity in [email protected] the environment. So there isn’t a sharp www.medifore.co.uk distinction between nature and nurture; Copyright © 2012: ECNP. All rights reserved. No part of this publication may be reproduced, nature provides the capacity for nurture stored in a retrieval system, transmitted in to influence the brain.” any form or by any other means, electronic, mechanical, photocopying, recording or This naturally led to the identifica- otherwise without prior permission in writing to tion of several genes involved in the ECNP and its organisers. regulation of developmental plasticity The content of ECNP Daily News does not necessarily reflect the opinion of ECNP 2012 using knock-out mice. However, plasticity Congress Chairman, ECNP Scientific Advisors continues throughout life, and Profes- or Collaborators. sor Blakemore acknowledged the many www.ecnp.eu Monday ECNP Daily News 15 October 2012 3

Immunotherapy in neurodegenerative disorders Monday October 15 14.30 Hall D Thinking ahead: Immunotherapy in the brain

The use of antibody-based treatments to we can really intervene – this is combat neurodegenerative disorders is a open at the moment.” Regarding the course that promising avenue of research that needs Alzheimer’s research has taken, more focus, and financial support, delegates Professor Bayer cautioned: will hear this afternoon during a session “With Alzheimer’s, a big disadvantage has been that that will explore the cutting-edge status of one or two big pharmaceuti- immunotherapy in the brain. cal companies jumped into development too early, basing studies on unpromising scientific o-chairing the ses- “There are several speakers grounds.” sion will be Thomas with hands-on experience on Referring to the recent data C Bayer (Department for different proteinopathies, pre- that suggests soluble oligomers Psychiatry, Göttingen University, senting ideas about preventing of Aß, not Aß plaques, are the Germany) a biologist by training ALS amytrophic lateral sclerosis toxic species that form a key who found himself fascinated and other ‘tauopathies’, a therapeutic target in Alzheimer’s by the discovery of the first generic term for brain disorders pathology, he continued: “Now mutation in a gene related to where the tau protein is af- there is a strong paradigm shift, Alzheimer’s pathology. That a fected,” he said. and the big companies are single gene could have such “Einar Sigurdsson has shown aware that removing plaques is tremendously devastating con- that active or passive immunisa- not a good idea.” sequences in the brain inspired tion works, even for proteins Professor Bayer concluded him to develop transgenic inside cells, and this approach with a positive yet realistic model systems to mimic the has also been tried for prion summary about what is yet to disorder. diseases – the only infectious be achieved in proteinopathy Speaking to ECNP Daily disease in this symposium – with therapies: “We need to bring News ahead of the congress, unfortunately less success.” antibodies into the brain, and Professor Bayer technical improvements are summarised the needed there. Alternatively, commonalities “We need to bring antibodies into the there are antibodies that work between different brain, and technical improvements Thomas Bayer in the peripheral blood system neurodegenerative in Alzheimer’s, which appar- disorders, referring are needed there... There is no lack of antibodies. show immense promise for ently is sufficient to remove Aß to the develop- information; everything is available. He has also treating them effectively in their in the brain. There is no lack of ments in his own cloned these very early stages. “This body information; everything is avail- area of expertise There is a lack of money to perform antibodies of research clearly opens up a able. There is a lack of money to and offering insight all of the experiments that need to be into viruses new research line: how to tackle perform all of the experiments into the current and then proteinopathies, and not just that need to be done, and to state, and future done.” injected the Alzheimer’s; it has a very broad carry out clinical trials at least promises, that the Thomas Bayer (Department for Psychiatry, Göttingen virus into the application,” added Professor until phase II.” field of immuno- brain. This is a Bayer. University, Germany) therapy offers. gene therapy Distinguishing immuno- Professor Bayer will co-chair He began by approach that therapies from existing drugs the session ‘Immunotherapy in giving a brief overview of the Elaborating on the results requires only a single injection, for Alzheimer’s disease, he also neurodegenerative disorders’ at symposium’s speakers and their in ALS that pave the way for not a series of them.” emphasised that there is much 14.30 this afternoon in Hall D. progress in developing differ- similar research, Professor These developments present work yet to be done. He said: The session will be immediately ent kinds of immunotherapies Bayer continued: “Dr Julien has a clear future for addressing “Existing drugs are not really followed by a scientific café on for proteinopathies – a term several approaches that target the causes of many age-related causally active, they only treat neurodegenerative disorders at used to describe disease in the ALS, using active and passive diseases and, along with the symptoms. We need to de- 16.10 in the foyer GH. brain with protein aggregation. immunisation with single chain improvements in diagnostics, velop these drugs to show that

Live from ECNP ECNP Neuropsychopharmacology Award 2012 unday’s keynote session featured the ECNP Neu- therefore divide the prize.” ropsychopharmacology Award – an honour that Introducing the first recipient Paul Harrison (Depart- S recognises innovative and distinguished research ment of Psychiatry, University of Oxford, UK), Professor achievements in neuropsychopharmacology and closely Goodwin said: “The first is my colleague from Oxford, related disciplines. Amongst other prizes, the recipients he is Professor of psychiatry, and he has been working of the award are invited to present a plenary lecture at in Oxford now for quite a number of years. Probably the 25th ECNP Congress, as well as the submission of more than he wants to remember! a review article for publication in European Neuropsy- “He originally trained there and did research in chopharmacology. London, and he made his reputation initially by working Guy Goodwin (Department of Psychiatry, University in what was described as the ‘graveyard of pathology’ of Oxford, UK) hosted during the award ceremony which was the post-mortem studies of the schizophren- which, for this year, would see two recipients take the ic brain. Paul is one of the very few people who has stage. “We have had a difficult time in the committee been able to make sense and produce sensible results because we ended up not being able to make up our from those kinds of studies which greatly influence our minds,” said Professor Goodwin. Guy Goodwin field. “Those of you that have sat in committees will “He’s moved on from that to look the consequences know that this is not uncommon. But in the case of this sion. I observed deliberations which eventually came of the abnormal kinds of gene expression that one sees kind of award, it is rather critical one does reach a deci- to the right answer: invite two people to accept, and Continued on page 10 4 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Schizophrenia: from pathophysiological understanding to novel treatments Monday 15 October 11.00 Hall D 2012 ECNP Neuropsychopharmacology Award Lecture A combined approach to schizophrenia therapy

athophysiological understanding should take isoforms or variants of the Neuregulin gene, so the bal- centre stage alongside preclinical data and ance of signalling that different forms of Neuregulin are P experiential animal models in the quest for carrying out in the brain are probably altered, and that novel schizophrenia treatments, delegates will hear on may be one of the mechanisms. And then you can say Monday morning in the second of two plenary lectures ‘ok, well is directing that, or normalising it, likely to be delivered by the 2012 ECNP Neuropsychopharmacology therapeutically useful?’” Award winners at the congress. However, despite the identification of genes such “The central theme of the lecture is the extent to as Neuregulin, does Professor Harrison agree that which findings in schizophrenia while new genes are actively itself can or should contribute in being discovered, they are deciding what treatment targets “Neuregulin was an still largely elusive in their to investigate,” joint 2012 function or effect? “Yes – award winner Paul Harrison example of a finding in and whether something is a (Department of Psychiatry, Uni- the illness that might be gene that puts you at risk of versity of Oxford, UK) explained the illness or not – whether to ECNP Daily News. relevant therapeutically. that in itself is therapeutically Expanding on this idea, In other words, it’s a relevant – is a matter of some Professor Harrison explained that debate,” he said. there is now great interest in gene that at least some “Clearly I think, other ascertaining to what extent the studies show is associated things being equal, it is a Paul Harrison differences exhibited between genetically. Then the good thing – because you patients and controls (for a cer- can then sort of think that “Now, that drug has never been tested in people in tain parameter) will be useful in question is what is it you are targeting one of this regard, so there is a lot of work to be done, but it developing novel therapeutics. that is different in the the causes of the illness. is an example of where therapeutics developments can “Now, to me that seems However, it is not necessary. come based upon the dissection of genetic pathways fairly obvious, but I think it’s form of the gene that There are plenty of effective and the biochemistry that they contribute to.” been, in some ways, a relatively is associated with the treatments in medicine that Continuing in his discussion of novel treatment neglected or difficult area to are not targeting causative pathways, Professor Harrison also referred to the contribute fully to,” continued illness?” genes. And secondly there are comparative measurement of enzyme activity in post- Professor Harrison. “So the Paul Harrison (Department of plenty of causative genes that mortem brains of both patients and controls. “One lecture is going to explore those don’t turn out to be effective example is an enzyme called D-amino acid oxidase, or Psychiatry, University of Oxford, UK) issues.” therapeutic targets for one DAO,” he said. One recent finding that has reason or another. But yes I “We and a number of other groups have studies been placed under the spotlight think that is one example of a that enzyme, and it turns out that that enzyme’s activity is Neuregulin 1, a growth factor involved in neurode- role that the genetics of schizophrenia may be able to in increased in patients with schizophrenia (when com- velopment and plasticity that has been identified as play in advancing treatments. pared to control subjects). A number of drug compa- a schizophrenia candidate gene.1 “Neuregulin is a He continued: “Just to take the Neuregulin story nies are studying DAO inhibitors for schizophrenia, and good example – it became of interest to schizophrenia further, Neuregulin sets off a particular signalling so the argument there is: well that might be a good because of genetic association to the illness,” said pathway, and following up on the original observations thing because the inhibitors could then bring down the Professor Harrison. about Neuregulin and schizophrenia from former col- excessive activity back to normal.” “That was an example of a finding in the illness that leagues of mine that now work in the States, they have might be relevant therapeutically. In other words, it’s a traced this pathway down to three or four components ECNP Neuropsychopharmacology Award lecture: gene that at least some studies show is associated ge- further downstream and they found again an abnor- ‘Schizophrenia: from pathophysiological understanding netically. Then the question is what is it that is different mality in patients with schizophrenia in this signalling to novel treatments’; 11.00, Monday 15 October, Hall D in the form of the gene that is associated with the ill- pathway, and they’ve then used a drug that corrects Reference ness? How does that affect the biology of Neuregulin? that change in an animal model, and it corrects some 1 H Deakin et al. Transgenic Overexpression of the Type I Isoform of Neu- regulin 1 Affects Working Memory and Hippocampal Oscillations but “So we and others did studies suggesting that what of the animal behaviours that are considered to be like not Long-term Potentiation. Cereb. Cortex. 2011 (In press: Accessed is different is that you express different amounts of behaviours seen in schizophrenia. August 30, 2011)

The immune–brain axis: a concept gaining momentum Monday October 15 14:30 Hall IK Taking a journey from immunity to psychology

he influence of the immune sor Schäfer described how these effects bance has been found. An increase of system over the brain’s emergent might be transmitted to the brain: pro-inflammatory cytokines with second- T characteristics has long been ap- “There are a variety of proposed mecha- ary changes in the monoamine system preciated, yet much remains to be under- nisms, including humoral and neural has also been related to these mood stood about this intricate relationship, routes, through which microbiota can changes.” not least when it comes to complex psy- modulate signalling along the brain-gut Professor Schäfer moved on to chiatric disorders. Speaking to ECNP Daily axis. For example, recent studies suggest describe three key mechanisms by which News, Martin Schäfer, Director of the a role for both the vagus nerve and the pro-inflammatory cytokines stimulate Department of Psychiatry, Psychotherapy modulation of systemic tryptophan levels the brain: The humoral pathway, via and Addiction Medicine and associated in relaying the influence of both resident activated monocytes and macrophages Professor for Psychiatry at the Charité- and exogenous microflora along this through ‘leaky’ areas of the blood-brain University Berlin, Germany, described the bidirectional communication axis,” he barrier; the neural pathway, via the vagus Martin Schäfer intriguing findings that drive this thriving explained. nerve; and the cellular pathway, via the research area, drawing together the Stress in the gut can cause distur- stimulation of microglia, leading to the immune system can influence the brain immune interactions of current therapies bances in the central nervous system production of monocyte chemoattractant and behaviour. In the context of inflam- with the future of psychoimmunological (CNS), and vice-versa. He added: protein-1 (MCP-1) and the recruitment of mation, pro-inflammatory cytokines can treatments. “Interestingly in most immune related monocytes into the brain. access the CNS and interact with a cy- The innate immune response is disorders, an increased incidence of He continued: “There has been tokine network in the brain to influence related to the maintenance of enteric psychiatric problems such as depression, an explosion in our knowledge of the virtually every aspect of brain function flora within the gut lining, and Profes- anxiety, fatigue and cognitive distur- pathways and mechanisms by which the relevant to behaviour, including neuro- www.ecnp.eu Monday ECNP Daily News 15 October 2012 5

Live from ECNP A warm introduction to the 25th ECNP congress

he Keynote Session of Zohar highlighted all ECNP portunity, in light of the different Awards, Poster Awards and of maintaining cross-industry the 25th ECNP congress initiatives that are working to economic situations in the broad Seminar Awards.” relationships, saying: “We are an T was opened by its presi- achieve a borderless network range of European countries, is President Zohar went on to organisation busy in facilitating dent, Joseph Zohar (Chaim She- of scientific communication the reduction of membership note the important reasons for dialogue. We are doing this in ba Medical Center, Department throughout Europe. fees for young scientists in devel- supporting multi-centre Euro- the form of Consultation Meet- of Psychiatry, Tel Hashomer, The focus upon interaction is oping economies. He said: “Its pean collaborations, which are ings every year in March. This is Israel) with a description of the a key element in the knowledge- purpose is to make sure that the designed to “standardise vari- an open dialogue between the exciting events marking out its sharing process at ECNP, dem- membership fee is not an obsta- ables collected from different scientific community, regulatory 25th anniversary. Describing the onstrated by the workshops for cle for individuals that would like studies, and to build a platform authorities, and the pharmaco- workshops, educational events, young scientists held every March to join the college. And we also to enable the network to sup- logical industry, and the output is national interactive seminars, in Nice. Another step that ECNP give grants and awards, including port a joint grant proposal.” published in the journal European and other sessions, Professor has taken in ensuring equal op- six Fellowship Awards, fifty Travel He also noted the importance Neuropsychopharmacology.”

The immune–brain axis: a concept gaining momentum Monday October 15 14:30 Hall IK

transmitter metabolism, neuroendocrine involved in the development of psychi- disorder or the dynamic course of the this may be limited to early-onset cases. function, synaptic plasticity, and the atric symptoms, there are also immune disease. Moreover, 30 to 60 percent of While these findings point to the need neurocircuits that regulate mood, motor models of schizophrenia in animals that patients do not or only partially recover for greater understanding of such im- activity, motivation, anxiety and alarm.” focus on possible early mother-child in- from depressive or psychotic symptoms mune interactions, there is a parallel On the possible outcomes of such fection during pregnancy as a risk factor after treatment with currently available necessity for aligning them with the disequilibrium, Professor Schäfer noted: for later developing psychosis.” drugs that primarily influence dopamine diagnosis of disorder subtypes. Professor “Behavioural consequences of these Citing a well-known immune-brain or serotonin neurotransmission.” Schäfer added: “TNF-alpha or IL-2 recep- effects of the immune system on the interaction, the hypothalamic-pituitary- However, there is encouraging tor antagonists have also been discussed brain include depression, anxiety, fatigue, adrenal axis, he remarked: “Stress is evidence that further pursuit of immune as possible targets for a psycho-immuno- psychomotor slowing, anorexia, cogni- clearly associated with an increased risk therapies will bear fruit: “Antidepres- logical treatment. However, although the tive dysfunction and sleep impairment; for affective disorders or other psychiatric sants (SSRIs) have been shown to be current available antidepressants, mood- symptoms that overlap with those that symptoms. Stress is linked to changes effective in the treatment and preven- stabilisers and antipsychotics have some characterise neuropsychiatric disorders, in the hormonal axis and the immune tion of depression caused by cytokine effect on the immune system, it remains especially depression.” system and finally also with neurotrans- treatment with interferon-alpha. COX-2 unknown if such an effect is involved in These immune changes seem to mitters.” inhibitors are known to influence the the clinical stabilisation of patients.” plug an aetiological gap in our under- Translating this fascinating knowl- immune system, and recently the COX-2 standing of CNS disorders, as Professor edge into valuable clinical therapy is a inhibitor, celecoxib, has been tested as a Professor Schäfer will co-chair the Schäfer explained: “Although many challenge for research. Professor Schäfer possible adjunctive therapeutic approach symposium ‘The immune–brain axis: a things remain unclear, immune changes illustrated that the present state of in the treatment of depression and concept gaining momentum’ at 14:30 this have been shown in patients with acute therapy leaves much room for improve- schizophrenia,” he said. afternoon in Hall IK. The session will be or chronic schizophrenic, unipolar and ment, saying: “Up to now, genetic Although the first trial of COX-2 in immediately followed by a scientific café bipolar affective disorders. Beside acute research could not really explain the schizophrenia yielded positive results, on psychoneuroimmunology at 16:10 in immunological changes possibly being individual vulnerability to a psychiatric additional studies have indicated that foyer IK. 6 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Plenary lecture: Disruptive innovations in clinical neuroscience Monday 15 October 13:30 Hall D Blossoming future perspectives for mental health More consideration of the whole gamut of therapeutic, diagnostic and cultural aspects in clinical neuroscience would offer significant benefits in the treatment of mental disorders, Thomas R Insel (Director of the National Institute of Mental Health in Bethesda, USA) will communicate to delegates in his plenary lecture this afternoon at the congress.

ore consideration of the whole next generation of therapeutics could gamut of therapeutic, diag- come from; where are the opportuni- M nostic and cultural aspects in ties.” clinical neuroscience would offer signifi- Moving on to discuss the second cant benefits in the treatment of mental point he would like to communicate to disorders, Thomas R Insel (Director of those in attendance, Dr Insel stressed the National Institute of Mental Health that we must rethink the way in which in Bethesda, USA) will communicate we even talk about these disorders, as to delegates in his plenary lecture this he believes one of the reasons that we afternoon at the congress. haven’t reached our full potential is Speaking to ECNP Daily News, Dr because we are somewhat hindered by Insel began by noting that there is simply the language that we use, particularly in an enormous public health burden the realms of diagnostics. stemming from mental disorders: “The He explained: “The diagnostic cate- needs here are really very striking, very gories we have are not biologically valid. profound and very urgent,” he said. “As They largely come about from consensus an example, in the Unites States, the of subjective observations. And increas- mortality defined here by suicide is really ingly, when you look at the biological ob- unchanged over the last two or three servations that are accumulating – both decades.” from genetics and from clinical neurosci- He added: “There’s a suicide every ence – it’s becoming apparent that these 15 minutes in the United Sates, about are fictive categories that don’t really 36,000 per year, so the actual suicide help us to either identify the mechanisms rate is higher than the rate of homicide of disease or identify the most effective and the rate of traffic fatalities.” treatments for the subgroups of people.” However, this very significant mortal- As such, Dr Insel highlighted that ity rate is only part of the puzzle in the while the labelling of depression or Thomas R Insel poor prognosis for those suffering from autism (for example) as a single disorder serious mental health disorders. There has now been moved away from, diag- and the lack of cognitive markers, and standardisation in the way that data are is also a marked increase in the number nostically it is still often the case that we frankly the lack of insight we have about collected. The integration of data across of complicated medical problems that assign one antidepressant or one class of e disorders, and the way that we still talk multiple platforms, and the importance manifest alongside mental illness. “So drug to cover a syndrome that is highly about them precludes the progress that of sharing. And I’ll talk about how this on both scores we have problems with heterogeneous. we need in many ways. culture – which is beginning to develop mortality,” said Dr Insel. “So point number two in other areas of medicine – needs to be “We also have evidence would be the importance of quickly implemented in the space that that the morbidities from these “In the new era the focus needs transforming our approach to we call neuropsychopharmacology.” disorders have actually not gone prognosis using what we call In summation, Dr Insel added that down, as far as we can tell from to be on understanding these the research domain criteria, we should be pulling together these any of the measures that we disorders mechanistically. So not and I’ll talk about what those therapeutic, diagnostic and cultural have (measured either as diag- by thinking that the problem is are and how we’ll develop a considerations with improved language nosis or prevalence, or measures new approach to nosology or and attribution. Explicitly, he believes we such as employment or comple- chemical imbalance, or that the diagnosis.” should now foster an era in which the tion of education).” problem is a lack of Thorazine, If Dr Insel’s first and second terms ‘psychiatry’ and ‘neuropharma- This, he added, was despite points could be boiled down to cology’ are better placed in the grand the incredible journey made in but by understanding them the need for new therapeutics scheme of clinical neuroscience. the field of neuropharmacol- the way we understand other and new diagnostics, respec- What’s more, this should sit alongside ogy, with an “extraordinary” tively, his third point could be a better diagnostic and therapeutic three-decade growth in the diseases in medicine: at the concisely described as relating framework, as he described: “In the new medications now available. But level of molecular, cellular and to the need for a change in the era the focus needs to be on under- these improvements, even when system pathophysiology.” culture of how we operate. “It’s standing these disorders mechanistically. coupled to the increased number not so much what we do but So not by thinking that the problem is of patients now being exposed Thomas R Insel (National Institute of Mental how we do it,” he said. chemical imbalance, or that the problem to them, has made too little Health, Bethesda, USA) Specifically, he stressed that is a lack of Thorazine, but by under- impact in Dr Insel’s opinion: “The we need to form better part- standing them the way we understand reality is that the public health nerships, i.e. nurturing patient other diseases in medicine: at the level of outcomes don’t seem to be much bet- “We don’t do this any longer for advocacy groups and other organisations molecular, cellular and system patho- ter,” he said. hypertension. We don’t do it even for which will ultimately benefit in the quest physiology.” “And that tells me – and this is my most forms of cancers, where we now for new cures, and in the resolution of first point – that we need a new genera- understand much more precisely how unmet public need. Plenary lecture: ‘Disruptive innovations in tion of therapeutics, and what I will talk to diagnose the subtypes,” he added. Dr Insel continued: “So what I’m clinical neuroscience’; Monday 15 October, about is the likelihood of where those “But because of the lack of biomarkers, going to talk about is the importance of 13:30, Hall D. www.ecnp.eu Monday ECNP Daily News 15 October 2012 7

Social anxiety disorder (SAD): from the clinic to the laboratory and backwards Monday 15 October 14:30 Hall E The unmet needs of social phobia

ocial anxiety disorder explains the damaging effects He continued on the topic of still an enduring issue in the (SAD) will take centre on academic performance, rela- combinational therapies, saying: provision of effective treatment, S stage this afternoon in tionships and employment. Left “Combining medication and with debilitating consequences a session that will see experts untreated, affected individuals psychological interventions is for social phobia sufferers, as discuss a range of related is- can develop depression, and common in clinical practice, but Professor Baldwin explained: sues all the way from clinic to alcohol and other drug abuse, the trial evidence suggesting “Many individuals with social laboratory. To that end, session and have an increased risk of this is more effective than drug phobia are probably unaware presenter David Baldwin (Profes- attempted suicide.” treatment or psychotherapy they have a potentially treatable sor of Psychiatry, University of Clues from neuroimaging alone is rather inconsistent.” condition, and that treatment Southampton, UK) spoke to and psychological studies can Whether this is due to inconsist- could see improvements across ECNP Daily News ahead of the offer targets for psychological encies in psychological treatment many domains of their life.” congress to introduce the topic intervention, and neurobiologi- methods, disorder heterogeneity Speaking of unmet needs, of social phobia, as well as de- cal evidence has an equal place or external factors is clearly an Professor Baldwin concluded: scribing the limits of our current David Baldwin in developing drug therapies. important avenue of future study. “The existing treatments for knowledge and the problems Professor Baldwin summarised Professor Baldwin looked patients with social phobia can- that must be addressed. individuals have a fear and the state of our knowledge, back over the past few decades not be considered ideal. Many Beginning with the distinction avoidance of most social and saying: “The neurobiology of of development in our under- patients do not respond, others between social phobia and shy- performance situations, and social phobia is likely to be standing of social phobia. He relapse despite continuing treat- ness, Professor Baldwin explained could be markedly disabled ment, and others soldier that although shyness may be a by these symptoms. In the “Many individuals with social phobia are probably on with distressing side feature of social phobia, they are non-generalised form, indi- effects, so there is much far from similar, noting: “Social viduals may fear just a few unaware they have a potentially treatable room for improvement in phobia is an anxiety disorder – in situations, and so typically condition, and that treatment could see developing novel interven- which shyness is admittedly a are less affected.” tions which are more effec- prominent symptom – charac- Early diagnosis and improvements across many domains of their life” tive and more acceptable terised by the fear and avoid- treatment is a target for than those which are David Baldwin (Professor of Psychiatry, University of Southampton, UK) ance of social encounters and many psychiatric disorders; currently available.” performance situations, in which however, perhaps because people think they will humiliate social phobia often has an early complex, with some involvement said: “Even 25 years ago, social Professor Baldwin will or embarrass themselves or ap- onset (in late childhood and ear- of serotonergic, noradrenergic phobia could still be called ‘the discuss the efficacy, acceptability pear ridiculous to others.” ly adolescence), evidence for the and dopaminergic systems, neglected anxiety disorder’ and unmet needs of a pharmaco- Further defining social phobia efficacy of earlier intervention is and possibly contributions from and indeed it was, but the last logical approach to social phobia subtypes, Professor Baldwin limited. This certainly does not neuropeptides such as oxytocin. few decades have seen great in the session ‘Social anxiety dis- continued: “There are two main negate the benefit of treatment, The principal pharmacological advances in understanding of types of social phobia: gener- however, as Professor Baldwin treatments are the selective sero- the epidemiology, aetiology and order (SAD): from the clinic to the alised and non-generalised. In explained: “Social phobia tends tonin reuptake inhibitors and treatment of social phobia.” laboratory and backwards’ held the generalised form, affected to run a chronic course, which monoamine oxidase inhibitors.” That being said, there is this afternoon at 14:30 in Hall E.

A clinician’s perspective on the amygdala story

peaking to ECNP Daily News ahead of this af- opposed to a small overall brain volume. ternoon’s session dedicated to the latest clinical “There is another disorder called Urbach–Wiethe S and research insights in social anxiety disorder Disorder, which exhibits calcification of the amygdala. (SAD), psychiatrist Iulian Iancu (Director of the Yavne In this disorder, there is probably a problem in fear Community Clinic, Beer Yaakov Hospital, Tel Aviv Uni- response and evaluation of untrustworthy people that versity, Israel) described his great interest in the disorder arises directly or indirectly from calcifications in the and his intrigue at the role of the amygdala in fear and amygdala.” anxiety modulation. Illustrating the current understand- The over-activation of the amygdala that SAD ing of SAD and citing interesting clinical examples, he patients experience has naturally led to therapies that suggests areas of research that could lead to the most work to reduce activation, as Dr Iancu described: “SS- promising novel targets. RIs, CBT and mindfulness-based interventions reduce Functional imaging studies have uncovered a great blood flow to the amygdala, among other regions. This deal with regards to attenuation is as- SAD emotional pro- “SSRIs, CBT and mindfulness-based sociated with clinical cessing and behaviour, improvements at the as Dr Iancu explained: interventions reduce blood flow to the one-year follow-up “Individuals with SAD amygdala, among other regions. This stage.” showed higher activa- The role of the tion of the amygdala attenuation is associated with clinical neuromodulatory when they were shown improvements at the one-year follow- hormone oxytocin angry or fearful faces, up stage.” in pair bonding and and they have also social recognition has been shown to have a Iulian Iancu (Yavne Community Clinic, Beer Yaakov Hospital, prompted its study in smaller amygdala. In Tel Aviv University, Israel) SAD as well as other normal people the size disorders, such as of the amygdala cor- depression and PTSD. Iulian Iancu relates with the size of social networks; this is logically Dr Iancu described its action, saying: “Acute oxytocin correct with respect to SAD behavioural traits.” treatment reduces amygdala activity in generalised “I cannot say that SAD is a primary problem in the Citing the rare genetic disorder, William’s syndrome, social anxiety disorder, which is very interesting. When amygdala, but I will suggest that oxytocin may prove in which the amygdala is hypoactive, Dr Iancu contin- patients see negative faces when they are on oxytocin, to be a good agent for SAD in the long term. It will be ued: “I will talk in my speech about the lack of stranger the amygdala shows reduced activation when com- interesting to see if oxytocin helps in social problems anxiety in William’s syndrome. It seems that these pared to placebo.” and also in amygdala hyperarousal.” individuals fail to recruit the amygdala, which may Although there are certainly other brain regions in- explain their disinhibited social behaviour and unusual volved in SAD mechanisms, there are clearly therapeutic ‘Social anxiety disorder (SAD): from the clinic to the labo- friendliness. These individuals have large amygdalas, as benefits in targeting the amygdala. Dr Iancu concluded: ratory and backwards’; Monday 15 October, 14:30, Hall E 8 15 October 2012 ECNP Daily News Monday www.ecnp.eu

The immune–brain axis: a concept gaining momentum Monday 15 October 14:30 Hall IK Bridging the gap between gut and brain

hile the process of reduction helps to W understand psychi- atric disorders in terms of their constituent aspects, it is nev- ertheless important to bear in mind that the brain is connected to and continually affected by the goings on in the rest of the body. Bridging this gap is one of the principle interests of Peter Holzer (Professor of Neurogas- troenterology, Medical University of Graz, Austria), and he spoke to ECNP Daily News ahead of the congress to divulge a little about the gut-brain axis and the various ways in which the body and brain and intertwined. Speaking of their specific mechanisms of communication, Professor Holzer said: “There is an important information channel between the gut and the brain, and this is not only fa- cilitated via sensory neurons or gut hormones, but also via the immune system.” The interactions between the gut lining and the immune system are well established, and the effects on the brain are simi- larly intuitive as well as being evidenced by various clinical and Peter Holzer microbiological observations. Professor Holzer explained: and depression-like behaviours (Department of Psychology, The research.” the neurochemical changes that “At the ECNP conference in can be changed if you perturb Hebrew University of Jerusalem, The symposium will be could explain these effects and Amsterdam two years ago to the intestinal immune system Israel ), who will be talking addressing basic research ques- found that the GABA system there was a symposium which balance,” he said. about the interaction of the tions relating to gut-brain in- was altered by the probiotic.” in part covered similar areas. Citing his own research immune system with emotion teractions, as well as proposing Changes in microbiota were not Michael Maes presented find- in this field that serves to and cognition. Professor Holzer psychiatric treatment strategies measured in this experiment, ings pertaining to some patients strengthen this hypothesis, he highlighted Professor Yirmiya’s that could be used as adjuncts but documenting these changes who apparently had a leaky gut, continued: “We also have data contribution to the field, say- to more conventional thera- would surely be a useful topic of with antibodies circulating in showing that if you change the ing: “He was one of the first pies, particularly in depression study in order to understand the the blood in an elevated manner gut-hormone situation you may researchers to show that if you and anxiety. Professor Holzer causal factors that emerge from against bacterial components also end up with some mood stimulate the peripheral immune described the work of John F the gut to affect the immune such as LDS. He thinks leaky disturbances in mice deficient in system – not just the gut, but Cryan (Department of Anatomy system and brain. gut activation of the immune the hormone PYY. This peptide the entire thing – by giving & Neuroscience, University Professor Holzer also sum- system, the flooding of the body is really only present in the animals LPS, which activates College Cork, Ireland) whose marised other methods that with microbial chemicals, could gut. The mice that lacked this toll-like receptors (receptors of focus is stress-related disorders, may be applied to disrupt the somehow reach the brain and peptide appeared to be some- the innate immune system), saying: “He had very interesting microbiota-immune equilib- initiate processes that eventu- what depressed. So this rium, which could ally lead to depression or other system, and especially “There is an important information form a foundation psychiatric conditions.” the PYY in the intestinal of knowledge upon The development in under- epithelium, probably channel between the gut and the brain, which human studies standing of the psychological does respond in some could be based. He effects of immune disruption on way to the changes in and this is not only facilitated via sensory said: “You can disturb the brain demands a broaden- microbiota.” the microbiota with ing of concepts of psychiatric Professor Holzer neurons or gut hormones, but also via antibiotic treatment, treatment, and many data went on to reason as to or use germ-free mice, already support the notion of the underlying mecha- the immune system” which show differences psychiatric risk due to birth nisms that may explain in several phenotypes complications and maternal these mood changes, Peter Holzer (Professor of Neurogastroenterology, Medical from normal mice. I illness during gestation. Citing saying: “Microbiota University of Graz, Austria) am not really aware a well known example of this usually helps to digest of studies in humans phenomenon, Professor Holzer indigestible carbohy- that the relationship described how negative psychi- drates, producing short chain then you do cause changes in data published recently showing between gut microbiota and atric effects might be amelio- fatty acids that act on PYY cells behaviour.” that if the microbiota is changed the brain, but experimental rated with immune therapy: and release PYY. This gets into Analogous studies in hu- – in this case using lactobacil- studies really suggest that there “In schizophrenia the idea has the circulation and reaches the mans since then have shown lus probiotics for a few weeks is a relationship, which could been around for some time that brain, changing appetite and similar effects in inducing mood in mice – very surprising effects have great use in psychiatric infection early in life or during food intake but may also have changes. Professor Holzer con- are seen in behaviour: these disorders.” gestation could be a risk factor an effect on other processes in cluded: “So this is one of the probiotics reduced anxiety, re- in developing schizophrenia the brain such as those that are ideas, the concept of cytokine- duced depression-like behaviour Professor Holzer will co-chair the later. However, I think the data, relevant to depression.” induced depression; this is still a and seemed to increase stress session ‘The immune–brain axis: although mostly from animal One of the speakers of hypothesis, but it has been used resilience. a concept gaining momentum’; studies, suggest that anxiety the symposium is Raz Yirmiya for some time in depression “He also looked at some of Monday 15 October, 14:30, Hall IK.

10 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Live from ECNP ECNP Neuropsychopharmacology Award 2012

Continued from page 3 Meyer-Lindenberg (Director of the Central Institute has now set up independently in this part of the world in post-mortem brains to see whether one can model of Mental Health, Mannheim, Germany), Professor and is doing fantastic work, related partly to initiatives those kinds of abnormalities in animals and to link that to Goodwin said:”His work has been groundbreaking in – one of the key ways in which we see collaboration the potential for drugs and treatments to modify those linking genetic variation with variation in brain structure between academia and industry being pushed forward problems. So he very much plays in the areas which is and in function. in Europe. dear to the hearts of all of us in this society, which is to “This is work that he originally conducted with Dan- “And he has been at the cutting edge of develop- look for the science that can improve treatment, in this iel Weinberger in the United States, and mercifully his ments again as to how we translate the new science case particularly in schizophrenia and psychosis.” brain was not permanently drawn to that part of the that informs our understanding of psychosis and Continuing to introduce the next recipient, Andreas world, and he returned to Europe some years ago. He schizophrenia into new treatments.

Paul Harrison Andreas Meyer-Lindenberg

Department of Director of the Central Psychiatry, University Institute of Mental of Oxford, UK Health, Mannheim, “Thank you very much Germany indeed Guy, and it is an “Thank you very much, honour to get this award. Guy, and thank you very I mean that very sincerely much to the committee – it is a particular pleasure for giving me this award. of course to receive it from I’m very honoured and I Guy, though I’m glad to can give right back what hear he was conflicted Paul said: It’s an enormous with the decision! Guy honour and pleasure to be actually appointed me sandwiched between Paul to my present post and I Harrison and Jules Angst have had the pleasure of – scientists who I very greatly admire. That’s a bit humbling but is working in his department also a great pleasure to give thanks to many people who are really for many years since beyond the work that you mentioned. then.” “There is a conceptual debt to my colleagues at the National He added: “It’s also a real honour to share it with Andreas Meyer- Institute of Mental Health especially Danny Weinberg and Karen Lindenberg. I’ve always thought he was an absolutely outstanding Berman for their work on genetic variation, and there is a debt to scientist, so I’m very grateful to the committee that they consider my outstanding colleagues at the Central Institute of Mental Health me inseparable from Andreas. It’s a great honour. who have made it a great pleasure to continue and extend that “Lastly, and most importantly I’d just like to thank all of the work here in Europe. And I would like to specially mention my group members of my research group past and present, as well as our leaders in the imaging genetics work, Peter Kirsch and Heike Tost collaborators in Oxford and beyond. The person receiving this award who have been supporting that work greatly. And finally of course is really just a figurehead of a team effort, and this really has been all of that wouldn’t be possible if you didn’t have understanding exceptional in my case for a number of years so I am very, very families so I am very pleased that my wife is here to witness this grateful to all of those members who’ve had the ideas and done the award. hard work for the experimental data that allowed me to receive this “So thank you to all of these people who are really the ones to award. Thank you very much to them, and thank you to the ECNP.” whom the honour goes. Thank you very much to the committee and thank you to ECNP.”

ECNP Lifetime Achievement Award ules Angst trained under one’s lifetime’s work. And in the committee especially for giving the auspicious wing of case of our recipient this evening, me this honour. It is a wonder- J Manfred Bleuler, son that has been a particular prob- ful and unexpected honour to of Eugen Bleuler, in Zurich, lem because he has not stopped receive this lifetime achievement Switzerland, where he now producing fantastic work!” award after my 60 years of ac- resides as Emeritus Professor of Offering his gratitude for the tivity in research in psychiatry.” Psychiatry at Zurich University. honour, Professor Angst said: Referring to how he has His six-decade span of work “I’d like to thank you for these witnessed the field develop in in the field earned him the wonderful words, and to the his lifetime, Professor Angst Lifetime Achievement added: “Progress Award on this special was, and still is 25th anniversary ECNP “The ECNP Lifetime Achievement dramatic, and we Congress. Award will encourage and help me have the pleasure Professor Angst to see our knowl- was introduced by Guy to continue work to follow these edge of the Goodwin (Department scientific developments as long as I complexity and of Psychiatry, University dynamics of our of Oxford, UK) during possibly can, and I thank you once human nature the Keynote Session on more immensely for this great expanded every Saturday evening, who honour.” day; the keynote Jules Angst said: “Lifetime achieve- lecture illustrated ment awards pose a Jules Angst (Emeritus Professor of Psychiatry at that again. The Award will encourage and help as long as I possibly can, and I delicate problem as to Zurich University, Switzerland). ECNP Lifetime me to continue work to follow thank you once more immensely when one has achieved Achievement these scientific developments for this great honour.” www.ecnp.eu Monday ECNP Daily News 15 October 2012 11

Live from ECNP

Sunday brainstorming

he first Brainstorming Sessions support its role in learning and memory ment where rats were put on a treadmill effects of ketamine on depression, which yesterday morning at the 25th as well as in spatial orientation). Studying to look at how increased physical activity is distinct from the effects of conventional T ECNP Congress were packed to the condition presents familiar practical would increase neurogenesis, there were antidepressants, which require around full capacity as delegates joined each problems in this discipline, as Professor rats that were running voluntarily, really three weeks to take effect. Providing an other for the chance to discuss, query Fuchs described: “In humans, the field enjoying it, and their neurogenesis in- explanation for this phenomenon, Dr and – of course – brainstorm issues in suffers from a major limitation in that it’s creased significantly. There was another Couillard-Despres said: “It was observed the field. difficult to detect neurogenesis. We are cohort that didn’t enjoy it at all however. in the clinic that you do need a week to a In the ‘Neurogenesis, major depres- limited in markers of proliferation per se, They were trying to force them to run by month to increase neurogenesis for those sion and antidepressive action: a relevant and it’s hard to get antibodies that work bumping them in the back when they cells to be integrated in the system. You link?’ session, Eberhard Fuchs (Germany) in human tissue. On top of that, it’s quite stopped running. These animals went had a very strong secretion of functional was joined by Sebastien Couillard- hard to get these tissues of course.” through the experiment in a very stress- BDNF associated with these acute effects, Despres (Austria) and Paul John which was linked to post- Lucassen (the Netherlands) to transcriptional maturation of discuss with participants the the peptide.” obstacles and questions regard- “In humans, the field suffers from a major limitation in This rapid onset of ing the effects of antidepres- antidepressant action is sants on neurogenesis, and that it’s difficult to detect neurogenesis. We are limited certain useful clinically, but what we have learned that converting this to long-term could be significant for the in markers of proliferation per se, and it’s hard to get antidepressant action is a treatment of depression. Recent antibodies that work in human tissue. On top of that, it’s key concern of clinicians. Dr findings regarding exercise and Couillard-Despres said: “I neurogeneration in rats, as well quite hard to get these tissues of course.” definitely think this is a very as the interesting effects of good means of increasing ketamine, suggest interesting Eberhard Fuchs, (University of München, Germany) BDNF for the synaptic plastic- directions for future research. ity that you need to kick-start Decreasing hippocampal the system, to stabilise it and volume is a factor of many psy- improve the activation level. I chiatric disorders, including depression, Experiments in rats have shown ful way because they didn’t enjoy it at think we should keep that in mind in the and studies have shown the increases of that exercise can increase hippocampal all, and in that experiment, neurogenesis future, to develop a sequence of events neurogenesis by antidepressant admin- neurogenesis. During the brainstorming actually decreased.” Clearly, whether in the future, to first kick start the system istration in rats. But the relationship is segment, Dr Couillard-Despres addressed or not the stimulus is enjoyable plays in an acute way, and then try to build up not clear as of yet, and the significance the variability of the stress response, say- a significant role in the animals’ stress the system as a whole network by long of hippocampal neurogenesis unspeci- ing: “One point that is very interesting is response, a finding that is surely relevant term antidepressant action, to give the fied, especially with regard to glial cells the individual reaction to stress, the indi- for studying the human population. opportunity to change these connections (although there is some evidence to vidual response to running. In the experi- Another participant noted the acute in a long term fashion.” 12 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Poster and travel awards @ ECNP congress

Congratulations to all of the recipients of the poster award and travel award on Sunday. Poster Award winners: Pablo Leon-Ortiz, Mexico Poster number: P.3.c.008

Anthony Vernon, United Kingdom Poster number: P.3.d.007

Sinead E. Shortall, United Kingdom Poster number: P.6.d.001

Laura Pina-Camacho, Spain Poster number: P.7.a.009 Travel Award winners: P.3.a.014 Marta Bosia, Italy P.3.b.001 Suzanne Gage, United Kingdom P.6.a.005 Daniele Stavros Hatzigiakoumis, Italy P.6.b.005 Erika Comasco, Sweden P.6.b.006 Magdalena Sikora, Poland P.6.b.007 Francisco Navarrete Rueda, Spain P.6.c.007 Tom Freeman, United Kingdom P.6.c.011 Michael Bloomfield, United Kingdom P.6.d.001 Sinead Shortall, United Kingdom P.6.d.004 Jana Merhautová, Czech Republic P.7.a.001 Marta Tyszkiewicz, Poland P.7.a.009 Laura Pina-Camacho, Spain P.7.a.014 Sara Carucci, Italy P.7.c.005 Dragan Dronjak, Serbia P.7.c.007 Covadonga Díaz-Caneja, Spain

14 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Live from ECNP The neural mechanisms of pathological gambling A presentation that delved deeper into our understanding of brain activation associated with pathological gambling – and offered a comparison to other addictive and dependent disorders – took place on Sunday morning at ECNP congress.

eginning her lecture, Anna of alcohol or drug dependence when E. Goudriaan (Department of compared to those who are pathological. B Psychiatry, Academic Medical To that end, within the new DSM-5 Center, University of Amsterdam, The classification, pathological gambling Netherlands) recalled Nancy Petry and has been moved from the ‘impulsive Marc Potenza’s 2005/2006 work that control disorder’ group to the ‘addic- discusssed whether pathological gam- tion and related disorders’ group, based bling should be classed as an addictive upon similarities and core symptoms, disorder. co-morbidity patterns, shared heritability “They started lots of research on the or genetics and functional imaging and topic of whether gambling would actu- neurocognitive profiles. ally be similar to substance dependence, Offering her results in functional or dissimilar,” said Dr Goudriaan. “When imaging and neurocognitive profiles you look at the diagnostic criteria for specifically, Dr Goudriaan first posed symptoms, the DSM-4 defines pathologi- the question of why people gamble, i.e. cal gambling as ‘persistent and recurrent where does the “fun” come from?: “Is maladaptive gambling behaviour’.” it the winning?” she said. “Or maybe Pre-occupation with gambling; loss it’s not the winning but the excitement. of control... unable to stop gambling; You don’t win as of yet, but there is a gambling with increasing amounts to moment of anticipation or arousal where achieve the desired excitement (similar to you don’t know what is coming. Or tolerance). maybe it is the rewarding effect.” As such, she added that almost all of She continued: ”We know from brain the criteria resembled those of substance studies that the reward circuitry gets dependence. That is, apart from the activated when you win money. And also persistence to keep gambling in order when you anticipate winning money. In to regain lost money – a concept which substance dependence there is lots of cannot be analogous in areas such as evidence showing diminished activation alcohol dependence. of the reward circuitry... Is this similar in Moving on to show co-morbidity pathological gambling or not? Do these data of gamblers who also have alcohol people also have diminished reward or drug use disorders, Dr Goudriaan sensitivity?” based upon the established ‘impaired (2002/2006) in which people who have demonstrated that non-pathological To try and answer this question, Dr response inhibition salience attribu- substance dependence exhibit a dimin- gamblers have a significantly lower rate Goudriaan designed a test paradigm tion model’ by Goldstein & Volkow ished reward sensitivity.

Genetic and functional dissection of dopaminergic pathway functions Wednesday 17 October 09:00 Hall IK Analysing individual neuronal roles in motor control and addiction

n overview of cutting- Kerchove d’ Exaerde (Laboratory ambulation seen with ablation implicated in motor control and in motor learning, as observed edge research that has of Neurophysiology, University of striatonigral neurons.1 As the learning of habits and skills2, during models in which mice A been illuminating the of Brussels, Belgium) told ECNP such, the data provided direct thus there was great interest in were observed attempting roles of the medium-sized spiny Daily News. experimental evidence that building on the rather limited a set task. “When they lost neurons (MSN) in locomotion, To begin to understand more striatopallidal and striatonigral knowledge in this arena: “We striatopallidal neurons in the learning and dopaminergenic about the individual roles of neurons inhibit and stimulate tried to understand the respec- whole striatum we saw an early drug response will be delivered each neuron in this setting, Dr motor activity, respectively. tive role of these two popula- impairment of the task, but with to delegates on Wednesday de Kerchove d’ Exaerde and his In the second part of his tions in these two different parts progressive improvement of morning. colleagues developed transgenic work, Dr de Kerchove d’ of the dorsal striatum because learning of the task,” said Dr de The MSN population is sub- mice in which they were able to Exaerde investigated both of nothing was really known when Kerchove d’ Exaerde. “When we divided into striatonigral neu- ablate each of these populations these neuronal populations in we began our study,” said Dr de completely ablate striatonigral rons and striatopallidal neurons, specifically. Expanding upon the dorsomedial striatum (DMS) Kerchove d’ Exaerde. neurons the mice were abso- but to date the individual roles models of basal ganglia where and dorsolateral striatum (DLS). In these tests, the neurons lutely unable to learn the task.” of each of the sub-populations striatopallidal neurons had an The dorsal striatum is primarily were found to be fundamental As such, these results in motor control and addic- inhibitory action on locomo- suggest that striatonigral tion has been under-exposed, tion – and striatonigral neurons are necessary for leading to the genesis of new neurons had an activating “These results highlight the reliance of the undertaking of these investigation : “One of the main effect – they first investi- striatopallidal neurons in the dorsomedial types of motor-learning points is the fact that these gated the effect that ablating tasks, whereas striatopalli- two populations are completely each of these neurons had on striatum for amphetamine sensitisation. This dal neurons appear to be mixed in the striatum, and locomotion in mice. result was not predicted by models.” unnecessary once a task is when we began this study there In their results, full abla- already learnt. didn’t exist a model or way to tion of striatopallidal neurons Alban de Kerchove d’ Exaerde (Laboratory of Neurophysiology, Moving on to describe specifically target one of these led to hyperlocomotion, in University of Brussels, Belgium) similar work exploring the two populations,” Alban de contrast to the reduction of reaction of the mice to www.ecnp.eu Monday ECNP Daily News 15 October 2012 15

Live from ECNP

The neural mechanisms of pathological gambling “Problem gamblers have heightened The test utilised visual cues of people diminished effect of losing activity in their reward system during the data, there was no drinking beer, for example, which in in pathological gamblers as expectation of winning, and this is significant difference in turn increase the action of the reward well. Their results showed the how often healthy system owing to the memory of pleasant that problem gamblers had dissimilar from substance dependence, controls or gamblers experience of having had an alcoholic lower reactivity compared where there is a lower reward anticipation. over-estimated their drink before. This increased drive when to healthy controls. Smok- There is this imbalance between control chances of winning. confronted with cues diminishes cogni- ers also showed this trait. However, when using tive function and lowers the ability to “This shows that and motivation which can be crucial for functional magnetic control behaviour. pathological gamblers are continuation of problematic gambling.” resonance imaging to “Dorsolateral prefrontal cortex func- less sensitive to losses... delve deeper, results tion and anterior singlet functioning is less sensitive to negative Anna E. Goudriaan (Department of Psychiatry, Academic showed there was higher related to a higher chance of a relapse consequences of addic- Medical Center, University of Amsterdam, The Netherlands) activation in the bilateral in substance dependence,” said Dr tive behaviour,” said Dr ventral striatum, bilateral Goudriaan. “So how does this cognitive Goudriaan. ventromedial prefrontal control centre function in pathological Probing another aspect, cortex and left insula in gamblers?” her team then investigated the cue reac- users to press a button corresponding gamblers versus control patients. These To answer this question, she began tivity patterns of this gambling behaviour to the appropriate direction they saw. differences were not apparent when by showing an example of the pioneer- and compared it to that seen in cocaine Crucially, a number of images ap- subjects were confronted with losing. ing work by Reuter et al. (Nat Nuerosci, and alcohol dependence. Specifically, peared intermittently that subjects were Offering a summary of her work, Dr 2005) who designed a simple card game they imaged the brains of subjects when instructed not to respond to. Goudriaan said: “Gamblers showed: in which gamblers and controls lost exposed to pictorial cues of drugs, “Everyone made errors in the task less reactivity in reward areas during money or gained money. In the study, alcohol, gambling or, conversely, neutral because it is designed that way,” said Dr monetary gain outcomes... and when the activity from both winning and losing picture controls. Goudriaan. “Normally what happens is they experience losses; higher reactivity was compared. “We saw an increased pattern of that you activate your cognitive control to gambling cues compared to healthy “What they found was that in reactivity in the reward circuitry of patho- circuit in order to adapt your behaviour. controls (and also this was related to healthy controls, you see an activation of logical gamblers... so higher activation in So, in healthy controls we see that hap- gambling cravings); and diminished the reward system after winning when the dorsal and ventral attentional routes, pens very well. Smokers we see there is activity of the cognitive control network compared to losing money, as you would showing that pathological gamblers also less activity and gamblers even less.” during response inhibition.” expect, but in problem gamblers there process these stimuli with more atten- She added that while similarities She continued: “The addiction is also is diminished activation of the reward tion,” said Dr Goudriaan. clearly exist between gambling and in the anticipation: problem gamblers circuitry,” she said. She added that there was still higher substance dependence, when purchasing have heightened activity in their reward “That could mean two things: One, activity in controls observing gambling alcohol or drugs, the user has a given system during expectation of winning, that they developed this diminished cues when compared to neutral cues. expectation of the effect they will feel, and this is dissimilar from substance reward because they are gambling with She postulated a reason, referencing the whereas gamblers do not know if they dependence, where there is a lower increasing amounts of money. Or, they use of colours and lights etc found in will win or lose. Thus the anticipation reward anticipation. There is this imbal- could have diminished reward system ac- gambling environments: “The gambling may be a large factor. ance between control and motivation tivity in the first place, before developing industry does a good job of attracting “Does over-estimation of winning which can be crucial for continuation of gambling problems which would make the attention of even healthy controls,” play a role?” Dr Goudriaan questioned, problematic gambling. them prone.” she said. suggesting that gamblers have difficulty “There is diminished ability for them In later studies, Dr Goudriaan incor- Responsiveness was also examined in assessing just how often they will win, to control their higher motivational drive porated a ‘probabilistic reversal learning closely, tested with the aid of simple left and just how much they have done so to gamble.” task’ to investigate if there was a and right-facing drawings that required already. In the initial interpretation of

Genetic and functional dissection of dopaminergic pathway functions Wednesday 17 October 09:00 Hall IK

of striatonigral neurons did not have an effect on amphetamine Analysing individual neuronal roles in motor control and addiction 1 sensitisation. “Thus these results highlight novel objects, Dr de Kerchove d’ Exaerde. the reliance of striatopallidal d’ Exaerde first explained the In addition to motor control neurons in the dorsomedial test methodology: decoupled and learning, the dorsal striatum striatum for amphetamine sen- delayed spontaneous object rec- is also critically involved in the sitisation. This result was not ognition. “It’s not an automatic motor response to pscyhostimu- predicted by models,” he said task – the mice have to recog- lants and neuroleptic drugs.1 As in closing. nise an object put in the middle such, when one considers the of an open field,” he said. cataleptic side effects of many Co-chair Dr de Kerchove d’ Ex- “Mice without striatopalli- neuroleptic drugs used to treat aerde give his presentation ‘The dal neurons on the DMS had schizophrenia (haloperidol, for roles of specific neuronal popula- a dramatic increase of the example), understanding more tions of the striatum in addiction exploration of the novel object, about the roles of these neurons mice, and finally discovered that tion to include the psycho- and motor control: a molecular and mice without striatonigral in this setting in crucial. only in the ablation of the stri- stimulant amphetamine – an and transgenic approach’ in the neurons have a decrease of this “These [drugs] are often atopallidal neurons of the DMS agent associated with a potent session ‘Genetic and functional exploration. Moreover, mice antagonists for dopamine D2 re- would we completely lose this increase in dopamine concentra- dissection of dopaminergic path- without striatopallidal neurons ceptors,” said Dr de Kerchove d’ haloperidol-induced immobility tion – with particular focus on way functions’; Wednesday 17 October, 09:00, Hall IK. in the DMS are also unable Exaerde, adding that the direct catalepsy,” he said. observing changes in sensitisa- to decrease this exploration neuronal interaction involved in “Thus we have demon- tion after ablation of either References when an object is frequently these side effects had previously strated that the dopamine D2 striatopallidal or striatonigral 1) PF Durieux, SN Schiffmann and A de Kerchove d’Exaerde. Differential regula- presented.” remained elusive. antagonism in the striatopallidal neurons. tion of motor control and response to As such, these results point To that end, Dr de Kerchove neurons of the DMS are respon- “If we ablate striatopallidal dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum sub- to the importance of the DMS in d’ Exaerde set out to investigate sible for the locomotory side neurons in the DMS we com- regions. The EMBO Journal, 2011; 1–14 mediating novel reactivity: “This the individual striatal neuron effects of neuroleptics.” pletely disrupt this ampheta- 2) P F Durieux et al. D2R striatopallidal neu- rons inhibit both locomotor and drug was not known before this ex- roles in mediation of these side Logically, Dr de Kerchove d’ mine locomotor sensitisation,” reward processes. Nature Neuroscience, periment,” said Dr de Kerchove effects: “We tested four ablated Exaerde expanded this investiga- he said. In contrast, ablation 2009; 12 (4): 393-395 16 15 October 2012 ECNP Daily News Monday www.ecnp.eu

Glutamate co-transmission in brain: where, when, how and what for? Monday 15 October 09:00 Hall IK Discussing the main messages in neuronal co-transmission

ew understanding of the types another subtype of neurons in the brain: of neuronal messengers at work the neurons that use serotonin and ace- N in the dopamine, serotonin and tylcholine as chemical messengers. other associated systems could have “In the case of serotonin, this is also significant implications for combating a another transmitter that people are variety of brain diseases, delegates will interested in because it is associated with hear this morning in a pre-clinical track diseases like depression and anxiety. And symposium. so, for example, the mechanism of action “In Parkinson’s disease there are of anti-depressant drugs is to enhance many dopamine-containing neurons the amount of serotonin in the brain that in the brain that degenerate and die, can activate some cells. And now with and in diseases such as drug abuse and the same concept of co-transmission, we schizophrenia, there are some known realised that the serotonin neurons also perturbations of dopamine signalling in have this capacity to use glutamate as a the brain,” session co-chair Louis-Eric second neurotransmitter.” Trudeau (Department of pharmacology, To that end, while the serotonin sys- University of Montreal, Canada) told tem can be identified as dysfunctional ECNP Daily News. in some patients with depression and As such, there is a lot of interest in anxiety, this realisation means that it is understanding how these neurons func- unclear whether it is a direct problem tion, and Professor Trudeau underlined with serotonin or a perturbation of the that, in the last few years, much work second neurotransmitter that is at the has been carried out by both his centre, helm. and others worldwide, to garner new “At this point there is no direct link perspectives. “Now we know they don’t that has been established, but this is only use dopamine as a chemical mes- really in the works, and I think this is senger, they also use glutamate as an why this is interesting for the people additional messenger,” said Professor that will attend this meeting because it Trudeau. is alerting them to a new phenomenon This ‘co-transmission’ – describing that maybe will change the way that we Louis-Eric Trudeau neurons with more than one chemical think about these brain circuits,” said messenger – has changed previous think- Professor Trudeau. two chemical messengers, especially as GABA or excitatory signalling depending ing of a ‘main language’ in the mes- The fourth presentation in the session these chemical messengers use different on therapeutic application, new drugs saging mechanisms of neurons. “Now will be delivered by Gudrun Ahnert- types of receptors. that can take full advantage of new un- essentially what we have to do is under- Hilger who will discuss the co-existence “But in the case of glutamate and derstanding are “simply not there yet”. stand why they do this and whether this of GABA (gamma-aminobutyric acid) and GABA, they use completely opposite “It may be a question of, eventually, has some relevance for brain diseases,” glutamate in defined neurons: an issue types of receptors in the brain. Gluta- gene therapy rather than drugs,” he he added. mate typically has said, adding that one problem is that With an already intricate excitatory effects, drugs to increase GABA, for example, network of synaptic trans- “At this point there is no direct link that has and GABA typically do so everywhere in the brain, not just mission to comprehend, and been established, but this is really in the works, has some inhibitory specific targets. the many, many neurons and I think this is why this is interesting for the effects. And what “This is a big problem obviously and circuits to consider, the they are linking because it leads to sedation for example, concept of co-transmission people that will attend this meeting because this with function- and it is very difficult to reduce the adds a layer of complex- it is alerting them to a new phenomenon that ally – and it’s quite drug doses so that people do not have ity: not only do cells have interesting – is they too many side effects. If in this case multiple connections to their maybe will change the way that we think suggest that in we know that there is specific circuit in neighbours, but they also about these brain circuits.” epilepsy perhaps the brain that is over excited maybe we release different transmitters some neurons that can actually modify these over-excited depending on the interact- Louis-Eric Trudeau (Department of pharmacology, University of typically use gluta- neurons and make them release more ing cell. Montreal, Canada) mate as a neuro- GABA instead. Referring to the specific transmitter will start “This could be a eventual therapeutic presentations within the gradually releasing strategy, but I would see this as a more ECNP session, Professor Trudeau contin- that adds another level of complexity, as more and more GABA, and this may be as a gene therapy approach rather than ued: “Myself and Dr Wallén-Mackenzie Professor Trudeau explained: “When we an attempt of the brain to compensate a pharmacological approach.” will speak about this concept of co-trans- think about dopamine and glutamate or for the over-excitation.” mission in the dopamine system, and serotonin and glutamate, it’s complicated Despite all of these observations, ‘Glutamate co-transmission in brain: there will be Dr El Mestikawy who will be but it’s not that difficult to understand Professor Trudeau stressed that, while where, when, how and what for?’; Mon- talking about the same concept but in why one neuron could signal through we have existing therapies that modulate day 15 October, 09:00, Hall IK.

Delegates enjoying a spot of lunch and browsing the posters.

18 15 October 2012 ECNP Daily News Monday www.ecnp.eu

GABA modulation of dopamine mesolimbic system in addiction Monday 15 October 14:30 Hall F1 The impulsivity of addiction

A ‘bench to bedside’ approach in and in attention deficit-hyperac- tivity disorder (ADHD). understanding the gamma-aminobutyric “The work I am doing is acid (GABA) modulation of the dopamine primarily pre-clinical work, and system, including a detailed look at inhibitory it looks like these different fields are now merging, and there is a pathways and the role of impulsivity lot of consistency between the in addiction will take centre stage this pre-clinical – laboratory animal afternoon at ECNP congress. work – and clinical observa- tions... there is a lot of cross oncentrating on the Dr Pattij added that, given talk now between the different interplay between im- we know that dopamine eleva- fields,” he said. C pulsivity and addiction tion increases impulsive behav- This unison of clinical and during the session will be Tom- iour, it follows that compounds pre-clinical work mirrors a trend my Pattij (VU University Medical that potently elevate dopamine emerging in many different Center, Amsterdam, The Nether- levels, such as amphetamine, areas of research, but Dr Pattij lands). “The main topic that I’m also have implications in impul- was still keen to stress that going to talk about is, first, that sivity: “There is a clear overlap there was much to be done in impulsivity might be a vulner- between the role of dopamine order to establish solid clinical ability trait or predictor, if you in impulsive behaviour and drug support for this kind of work: “I will, of drug dependence,” he addiction,” he said. think that is still a little bit soon told ECNP Daily News. “The pathways I am going to tell – as far as I am aware During his presentation, to talk about are primarily the I don’t know if there is solid Dr Pattij hopes to clinical support for this,” he said discuss the evidence in closing. for this idea, while “Impulsivity might be a vulnerability trait or focussing on the predictor, if you will, of drug dependence.” Dr Pattij will delve into the topic neurobiology of Tommy Pattij of impulsivity in addiction in impulsive behaviour Tommy Pattij (VU University Medical Center, Amsterdam, The Netherlands) more detail during his presenta- as a way to perhaps addiction, Dr Pattij emphasised tion ‘Role of impulsivity in ad- intervene, prevent or that, clinically, we are now able diction: dopamine and inhibitory help those suffering from drug opioid pathway and the cannab- Therefore they indirectly act on to better understand the role of pathways’ during the session dependence. “Not by targeting inoid pathway, and these are in- the dopaminergic system.” dopamine in impulsive behav- ‘GABA modulation of dopamine drug dependence itself, but by hibitory pathways that are able Moving on to discuss how iour, and there is a huge amount mesolimbic system in addiction: targeting impulsivity as a pos- to modulate dopamine action or impulsivity is now linking psy- of data emerging on the role of from bench to bedside’; Monday sible predictor,” he clarified. dopamine function in the brain. chiatric disorders such as drug dopamine both in drug addiction 15 October, 14:30, Hall F1.

Fiona Fox and Claire Bithell recieve the ECNP Media Award for the Science Media Centre, United Kingdom

Musical entertainment in the Keynote Session on Saturday evening www.ecnp.eu Monday ECNP Daily News 15 October 2012 19

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Councillors: Anton Bespalov, Russia Contributors to Celso Arango, Spain Eero Castrén, Finland th Jaanus Harro, Estonia Roberto Cavallaro, Italy the 25 ECNP Gitte M Knudsen, Denmark Andreas Heinz, Germany Mark J Millan, France Iris Manor, Israel Wim van den Brink, The Netherlands Luisa Minghetti, Italy Congress: Eduard Vieta, Spain Florence Noble, France Chair Scientific Programme Committee Andrzej Pilc, Poland Michel Hamon, France Nicolas Singewald, Austria Executive Committee (2010-2013) Editor-in-Chief Daniel Souery, Belgium Joseph Zohar, Israel, president European Neuropsychopharmacology Wim van den Brink, The Netherlands Hans-Ulrich Wittchen, Germany, vice-president Michael Davidson, Israel Ove Wiborg, Denmark Guy Goodwin, UnitedKingdom, president-elect Executive Director Celso Arango, Spain, chair Educational Committee David Nutt, UnitedKingdom, past-president Alexander Schubert, The Netherlands Local Advisor Sven Ove Ögren, Sweden, secretary Scientific Programme Committee Siegfried Kasper, Austria Nicoletta Brunello, Italy, treasurer Michel Hamon, France, chair

Issue 3 of ECNP Daily News Available Tuesday