- Email: [email protected]
S.05.03 Early intervention
S.05. TEM symposium − Vulnerability and resilience in the development of anxiety on a prospective-longitudinal design − to generate insights into vulnerability and resilience in the development of anxiety disorders. It has been consistently shown that anxiety disorders are frequent, early emerging and persistent conditions that constitute a significant risk constellation for subsequent psychopathological complications such as depression [1]. As the core incidence period for anxiety disorders is in childhood and adolescence, factors promoting or preventing first onset take effect early in life. Various familial risk factors such as parental anxiety disorders and adverse parental rearing styles (e.g. overprotection) have been identified as have various environmental factors such as early adverse events or conditions (e.g. separation from parents) [2]. Behavioral inhibition, a consistent restraint in response to both social and nonsocial situations, has been reliably seen as temperamental antecedent of various forms of anxiety disorders, measurable as early as in infancy before disorder onset occurs. Nevertheless, not all children or adolescents develop anxiety conditions in the face of vulnerability and risk. Protective factors such as positive coping expectations may contribute to resiliency to anxiety disorders. Thus, advancing our understanding of both (a) the core vulnerability and risk factors as well as their interactions, and (b) the resiliency mechanisms allows to improve intervention programs to prevent the onset of anxiety and a cascade of secondary complications [3]. References [1] Beesdo, K., Knappe, S. and Pine, D.S. (2009). Anxiety and anxiety disorders in children and adolescents: Developmental issues and implications for DSM-V. Psychiatric Clinics of North America 32, 483– 524. [2] Beesdo, K., Pine, D.S., Lieb, R. and Wittchen, H.U. (2010). Incidence and risk patterns of anxiety and depressive disorders and categorization of Generalized Anxiety Disorder. Archives of General Psychiatry 67, 47−57. [3] Shear, M.K., Bjelland, I., Beesdo, K., Gloster, A.T. and Wittchen, H.-U. (2007). Supplementary dimensional assessment in anxiety disorders. International Journal of Methods in Psychiatric Research 16, S52-S64.
S.05.02 Neurobiology G. Fl¨ugge1 ° 1 German Primate Center Leibniz Institute for Primate Research, Clinical Neurobiology Laboratory, G¨ottingen, Germany Anxiety is a natural emotional state, and the neuroanatomical and neurochemical entities that generate this state have been shaped by evolutionary selection. Normal anxiety disposes the individual to recognize danger and enables a subject to deal with an unknown internal or external threat. As such, anxiety has lifesaving qualities since it warns of bodily damage, of pain or of dangerous perturbation in the social environment. Pathological anxiety is conceptualized to be related to hyperexcitability of the neuronal circuits that generate this emotional state. These circuits include the amygdala, the extended amygdala and the prefrontal cortex. Pathological anxiety may develop early in life. In children and adolescents, factors such as a stressful environment or traumatic experiences may induce central nervous or bodily changes that overburden the adaptive capacities of a subject. These factors, together with a genetic predisposition, may generate a high vulnerability for pathological anxiety or another psychiatric disorder later in life. At all ages, anxiety patients require neuropsychiatric assessments and individually tailored treatments, possibly cognitive behavioral, psychological or psychopharmacological therapy.
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Animal models have helped to elucidate aspects of the neurobiological basis of anxiety, from neuroanatomy, neurochemistry to behavior. Especially ‘developmental models’ (e.g. prenatal or juvenile stress) provided evidence that early life-insults may persistently impair an individual’s mental health. The presentation will summarize key issues from the current literature on the neurobiology of fear and anxiety and on central nervous deficits related to pathological anxiety. New findings in preclinical models will be shortly reviewed putting emphasis on possible translational aspects. References [1] Yee N, Ribic A, de Roo CC, Fuchs E, 2011. Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: no evidence for the “double-hit hypothesis”. Behav Brain Res 224, 180–188.
S.05.03 Early intervention E.M.W.J. Utens1 ° 1 ErasmusMC-Sophia Children’s Hospital, Child and Adolescent Psychiatry/Psychology, Rotterdam, The Netherlands Randomized controlled trials have demonstrated the efficacy of cognitive behaviour therapy (CBT) for childhood anxiety disorders. However, over a third of children do not respond to CBT and still show an anxiety disorder post-treatment. This lecture addresses predictors/moderators of CBT treatment success for childhood anxiety disorders, based on the first published clinical trial, using a stepped care approach [1]. Clinically anxious children (8−12 years, n = 133) and their parents participated in evidence based CBT (FRIENDS protocol, 10 sessions). If assessments indicated additional treatment was necessary, a second and third − manual based − CBT phase followed (each 5 sessions), in which parental involvement was intensified. After the first, second and third treatment phase respectively 45%, 52% and finally 74% of the Intention-To-Treat sample was free of any anxiety disorder [1]. These results indicate that stepped care offers a structured, additional treatment, specifically attuned to needs of children who do not respond to the initial CBT. After phase 1, no significant difference was found between individual versus group treatment (absence of any anxiety disorder). For adolescents, maternal lifetime anxiety disorders were positively associated with favourable treatment outcomes. Responders to phase 1 and 2 showed a reduction in attentional bias [2]. Nonresponders did not show any changes in selective attention. Anxiety-disordered children employed significantly more maladaptive cognitive coping strategies than healthy controls [3], suggesting that cognitive coping seems a valuable target for prevention. A new development is prevention and CBT treatment of anxiety and building emotional resilience in pre-schoolers (FUNFRIENDS). References [1] van der Leeden, A.J., van Widenfelt, B.M., van der Leeden, R., Liber, J.M., Utens, E.M., Treffers, P, D. 2011. Stepped care cognitive behavioural therapy for children with anxiety disorders: a new treatment approach. Behav Cogn Psychother 39, 55−75. [2] Legerstee, J.S., Tulen, J.H., Dierckx, B., Treffers, P.D., Verhulst, F.C., Utens, E.M. 2010. CBT for childhood anxiety disorders: differential
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S.07. Young Scientists symposium − New insights into major and bipolar depression: mood, cognition and pain
changes in selective attention between treatment responders and nonresponders. J Child Psychol Psychiatry. 51, 162−72. [3] Legerstee JS, Garnefski N, Jellesma FC, Verhulst FC, Utens EM. 2010. Cognitive coping and childhood anxiety disorders. Eur Child Adolesc Psychiatry. 19, 143−50. Disclosure statement: The Department of Child and Adolescent Psychiatry/Psychology at Erasmus Medical Centre is publisher of the Dutch ‘FRIENDS for Life’ protocol, from which Dr. E. Utens receives remuneration.
S.06. Are there relevant biomarkers of bipolar disorder? S.06.01 Multi-omics profiling approaches to biomarker discovery in bipolar disorder S. Bahn1 ° , M. Alsaif1 , H. Rahmoune1 1 University of Cambridge, Institute of Biotechnology, Cambridge, United Kingdom Major depressive disorder (MDD) and bipolar disorder (BD) are debilitating mental diseases. Currently the diagnosis of these disorders is only based on subjective clinical assessments and the identification of molecular biomarkers could contribute to improved understanding of the underlying pathophysiological pathways. In turn, this could lead to more accurate empirical diagnoses and improved treatment strategies. Recently we carried out central (post mortem) and peripheral (blood) molecular profiling on MDD and BD patients. Shotgun proteomic analysis of dorsolateral prefrontal cortex samples from MDD patients (+/− psychosis) revealed alterations associated with energy metabolism and synaptic function. Interestingly, the psychosis proteomics changes showed a marked overlap with brain proteome profiles of schizophrenia patients. Separate analysis of post mortem pituitary and hippocampal proteome profiles of BD patients showed disruption of hormones, core histones and mitochondrial pathways. Proteome analysis by multiplexed immunoassay analysis of plasma from 25 BD mania patients showed hormonal dysregulation and disturbances in energy and lipid metabolism. Mass spectrometry analysis of plasma from 17 BD mania patients identified changes in inflammatory and coagulation proteins. We then followed up 13 patients after they experienced a manic episode and this revealed marked suppression of plasma pro-inflammatory markers. Ultimately, further molecular and functional investigations could lead to increased understanding of these disorders and help to distinguish different subtypes these broad psychiatric classifications. In turn, this could lead to novel approaches for drug target identification and discovery strategies. Disclosure statement: Psynova Neurotech and Myriad RBM Inc. Thank you to the Stanley Medical Research Institute for Centre support.
S.06.04 Staging and biomarkers in bipolar disorders F. Kapczinski1 ° 1 Hospital de Cl´ınicas de Porto Alegre, Molecular Psychiatry Laboratory and INCT Translational Medicine, Porto Alegre, Brazil The concept of a clinical staging model of disease progression is widely used in clinical medicine; however, only recently it was proposed as a useful framework in psychiatry. Current understanding of Bipolar Disorder (BD) recognizes it as a progressive
disorder leading to significant cognitive and functional impairment. We present a clinical model of staging for BD defined as: Stage I, patients who have the diagnose of BD and return to a baseline clinical condition whenever episodes are resolved; Stage II, symptoms in the inter-episodic periods are subclinical or confined to comorbidities; Stage III includes symptoms in the inter-episodic period due to subsyndromal BD symptoms and/or cognitive impairment or functioning decline; and stage IV includes unremitting symptoms and/or severe functioning impairment − patients are unable to live independently and need daily care of specialized centers or family. The present model focus on clinical presentation and emphasizes the inter-episodic period as the most adequate window to perform staging assessment. However, recent data suggest that peripheral biomarkers, including BDNF, inflammatory cytokines and oxidative stress parameters, may work as adjunctive tools for staging, since they are differently expressed in early and late stages of the disorder. Current treatment guidelines and randomized clinical trials do not take into account this deteriorating course of illness. Prospective studies are underway that will validate the consistency of the present staging construct and its ability to improve treatment decisions by clinicians and to inform patients and their families about what to expect from their treatment and prognosis. Disclosure statement: Fl´avio Kapczinski is a NARSAD Independent Investigator and is supported by the Stanley Medical Research Institute, CNPq, INCT-TM, CAPES, FIPE-HCPA. Additionally, Kapczinski is a speaker and/or advisor and/or receives research support from Lilly, Lundbeck, AstraZeneca, Servier and Janssen.
S.07. Young Scientists symposium − New insights into major and bipolar depression: mood, cognition and pain S.07.01 Alterations in nociceptive responding and prefrontal chemokine expression in a rat model of depression: effects of chronic amitriptyline N.N. Burke1 ° , R. Henry2 , S. Chiu2 , D.P. Finn3 , M. Roche1 University of Ireland Galway, Physiology and Centre for Pain Research and NCBES Neuroscience Cluster, Galway, Ireland; 2 National University of Ireland Galway, Physiology, Galway, Ireland; 3 National University of Ireland Galway, Pharmacology and Therapeutics and Centre for Pain Research and NCBES Neuroscience Cluster, Galway, Ireland 1 National
Chemokines modulate neurotransmission and inflammation, and have been implicated in the pathogenesis of both depression and chronic pain. However, their role in depression–pain comorbidity has not been examined. This study investigated the effect of chronic amitriptyline (AMI) administration on nociceptive responding in a model of depression, and associated alterations in chemokine expression in the prefrontal cortex (PFC). Rats underwent olfactory bulbectomy (OB) or Sham surgery and were administered AMI (10 mg/kg i.p.) or vehicle (Veh) daily. Nociceptive responding to mechanical and thermal stimuli were assessed 2 weeks post OB/Sham surgery and following L5-L6 Spinal Nerve Ligation (SNL). The expression of chemokines CCL2, CCL5 and CXCL10 was determined in PFC 24 hrs following behavioural testing. OB rats exhibited mechanical allodynia,
S.05.02 Neurobiology G. Fl¨ugge1 ° 1 German Primate Center Leibniz Institute for Primate Research, Clinical Neurobiology Laboratory, G¨ottingen, Germany Anxiety is a natural emotional state, and the neuroanatomical and neurochemical entities that generate this state have been shaped by evolutionary selection. Normal anxiety disposes the individual to recognize danger and enables a subject to deal with an unknown internal or external threat. As such, anxiety has lifesaving qualities since it warns of bodily damage, of pain or of dangerous perturbation in the social environment. Pathological anxiety is conceptualized to be related to hyperexcitability of the neuronal circuits that generate this emotional state. These circuits include the amygdala, the extended amygdala and the prefrontal cortex. Pathological anxiety may develop early in life. In children and adolescents, factors such as a stressful environment or traumatic experiences may induce central nervous or bodily changes that overburden the adaptive capacities of a subject. These factors, together with a genetic predisposition, may generate a high vulnerability for pathological anxiety or another psychiatric disorder later in life. At all ages, anxiety patients require neuropsychiatric assessments and individually tailored treatments, possibly cognitive behavioral, psychological or psychopharmacological therapy.
S119
Animal models have helped to elucidate aspects of the neurobiological basis of anxiety, from neuroanatomy, neurochemistry to behavior. Especially ‘developmental models’ (e.g. prenatal or juvenile stress) provided evidence that early life-insults may persistently impair an individual’s mental health. The presentation will summarize key issues from the current literature on the neurobiology of fear and anxiety and on central nervous deficits related to pathological anxiety. New findings in preclinical models will be shortly reviewed putting emphasis on possible translational aspects. References [1] Yee N, Ribic A, de Roo CC, Fuchs E, 2011. Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: no evidence for the “double-hit hypothesis”. Behav Brain Res 224, 180–188.
S.05.03 Early intervention E.M.W.J. Utens1 ° 1 ErasmusMC-Sophia Children’s Hospital, Child and Adolescent Psychiatry/Psychology, Rotterdam, The Netherlands Randomized controlled trials have demonstrated the efficacy of cognitive behaviour therapy (CBT) for childhood anxiety disorders. However, over a third of children do not respond to CBT and still show an anxiety disorder post-treatment. This lecture addresses predictors/moderators of CBT treatment success for childhood anxiety disorders, based on the first published clinical trial, using a stepped care approach [1]. Clinically anxious children (8−12 years, n = 133) and their parents participated in evidence based CBT (FRIENDS protocol, 10 sessions). If assessments indicated additional treatment was necessary, a second and third − manual based − CBT phase followed (each 5 sessions), in which parental involvement was intensified. After the first, second and third treatment phase respectively 45%, 52% and finally 74% of the Intention-To-Treat sample was free of any anxiety disorder [1]. These results indicate that stepped care offers a structured, additional treatment, specifically attuned to needs of children who do not respond to the initial CBT. After phase 1, no significant difference was found between individual versus group treatment (absence of any anxiety disorder). For adolescents, maternal lifetime anxiety disorders were positively associated with favourable treatment outcomes. Responders to phase 1 and 2 showed a reduction in attentional bias [2]. Nonresponders did not show any changes in selective attention. Anxiety-disordered children employed significantly more maladaptive cognitive coping strategies than healthy controls [3], suggesting that cognitive coping seems a valuable target for prevention. A new development is prevention and CBT treatment of anxiety and building emotional resilience in pre-schoolers (FUNFRIENDS). References [1] van der Leeden, A.J., van Widenfelt, B.M., van der Leeden, R., Liber, J.M., Utens, E.M., Treffers, P, D. 2011. Stepped care cognitive behavioural therapy for children with anxiety disorders: a new treatment approach. Behav Cogn Psychother 39, 55−75. [2] Legerstee, J.S., Tulen, J.H., Dierckx, B., Treffers, P.D., Verhulst, F.C., Utens, E.M. 2010. CBT for childhood anxiety disorders: differential
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S.07. Young Scientists symposium − New insights into major and bipolar depression: mood, cognition and pain
changes in selective attention between treatment responders and nonresponders. J Child Psychol Psychiatry. 51, 162−72. [3] Legerstee JS, Garnefski N, Jellesma FC, Verhulst FC, Utens EM. 2010. Cognitive coping and childhood anxiety disorders. Eur Child Adolesc Psychiatry. 19, 143−50. Disclosure statement: The Department of Child and Adolescent Psychiatry/Psychology at Erasmus Medical Centre is publisher of the Dutch ‘FRIENDS for Life’ protocol, from which Dr. E. Utens receives remuneration.
S.06. Are there relevant biomarkers of bipolar disorder? S.06.01 Multi-omics profiling approaches to biomarker discovery in bipolar disorder S. Bahn1 ° , M. Alsaif1 , H. Rahmoune1 1 University of Cambridge, Institute of Biotechnology, Cambridge, United Kingdom Major depressive disorder (MDD) and bipolar disorder (BD) are debilitating mental diseases. Currently the diagnosis of these disorders is only based on subjective clinical assessments and the identification of molecular biomarkers could contribute to improved understanding of the underlying pathophysiological pathways. In turn, this could lead to more accurate empirical diagnoses and improved treatment strategies. Recently we carried out central (post mortem) and peripheral (blood) molecular profiling on MDD and BD patients. Shotgun proteomic analysis of dorsolateral prefrontal cortex samples from MDD patients (+/− psychosis) revealed alterations associated with energy metabolism and synaptic function. Interestingly, the psychosis proteomics changes showed a marked overlap with brain proteome profiles of schizophrenia patients. Separate analysis of post mortem pituitary and hippocampal proteome profiles of BD patients showed disruption of hormones, core histones and mitochondrial pathways. Proteome analysis by multiplexed immunoassay analysis of plasma from 25 BD mania patients showed hormonal dysregulation and disturbances in energy and lipid metabolism. Mass spectrometry analysis of plasma from 17 BD mania patients identified changes in inflammatory and coagulation proteins. We then followed up 13 patients after they experienced a manic episode and this revealed marked suppression of plasma pro-inflammatory markers. Ultimately, further molecular and functional investigations could lead to increased understanding of these disorders and help to distinguish different subtypes these broad psychiatric classifications. In turn, this could lead to novel approaches for drug target identification and discovery strategies. Disclosure statement: Psynova Neurotech and Myriad RBM Inc. Thank you to the Stanley Medical Research Institute for Centre support.
S.06.04 Staging and biomarkers in bipolar disorders F. Kapczinski1 ° 1 Hospital de Cl´ınicas de Porto Alegre, Molecular Psychiatry Laboratory and INCT Translational Medicine, Porto Alegre, Brazil The concept of a clinical staging model of disease progression is widely used in clinical medicine; however, only recently it was proposed as a useful framework in psychiatry. Current understanding of Bipolar Disorder (BD) recognizes it as a progressive
disorder leading to significant cognitive and functional impairment. We present a clinical model of staging for BD defined as: Stage I, patients who have the diagnose of BD and return to a baseline clinical condition whenever episodes are resolved; Stage II, symptoms in the inter-episodic periods are subclinical or confined to comorbidities; Stage III includes symptoms in the inter-episodic period due to subsyndromal BD symptoms and/or cognitive impairment or functioning decline; and stage IV includes unremitting symptoms and/or severe functioning impairment − patients are unable to live independently and need daily care of specialized centers or family. The present model focus on clinical presentation and emphasizes the inter-episodic period as the most adequate window to perform staging assessment. However, recent data suggest that peripheral biomarkers, including BDNF, inflammatory cytokines and oxidative stress parameters, may work as adjunctive tools for staging, since they are differently expressed in early and late stages of the disorder. Current treatment guidelines and randomized clinical trials do not take into account this deteriorating course of illness. Prospective studies are underway that will validate the consistency of the present staging construct and its ability to improve treatment decisions by clinicians and to inform patients and their families about what to expect from their treatment and prognosis. Disclosure statement: Fl´avio Kapczinski is a NARSAD Independent Investigator and is supported by the Stanley Medical Research Institute, CNPq, INCT-TM, CAPES, FIPE-HCPA. Additionally, Kapczinski is a speaker and/or advisor and/or receives research support from Lilly, Lundbeck, AstraZeneca, Servier and Janssen.
S.07. Young Scientists symposium − New insights into major and bipolar depression: mood, cognition and pain S.07.01 Alterations in nociceptive responding and prefrontal chemokine expression in a rat model of depression: effects of chronic amitriptyline N.N. Burke1 ° , R. Henry2 , S. Chiu2 , D.P. Finn3 , M. Roche1 University of Ireland Galway, Physiology and Centre for Pain Research and NCBES Neuroscience Cluster, Galway, Ireland; 2 National University of Ireland Galway, Physiology, Galway, Ireland; 3 National University of Ireland Galway, Pharmacology and Therapeutics and Centre for Pain Research and NCBES Neuroscience Cluster, Galway, Ireland 1 National
Chemokines modulate neurotransmission and inflammation, and have been implicated in the pathogenesis of both depression and chronic pain. However, their role in depression–pain comorbidity has not been examined. This study investigated the effect of chronic amitriptyline (AMI) administration on nociceptive responding in a model of depression, and associated alterations in chemokine expression in the prefrontal cortex (PFC). Rats underwent olfactory bulbectomy (OB) or Sham surgery and were administered AMI (10 mg/kg i.p.) or vehicle (Veh) daily. Nociceptive responding to mechanical and thermal stimuli were assessed 2 weeks post OB/Sham surgery and following L5-L6 Spinal Nerve Ligation (SNL). The expression of chemokines CCL2, CCL5 and CXCL10 was determined in PFC 24 hrs following behavioural testing. OB rats exhibited mechanical allodynia,