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S.06.02 Can we explain the epidemiology of schizophrenia in terms of the pathology of striatal dopamine?
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S.06. Gene–environment in psychoses: new developments in clinical and basic research
[3] Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U, et al. Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5585−90.
S.06. Gene–environment in psychoses: new developments in clinical and basic research
S.05.05 D-cycloserine and exposure therapy
S.06.02 Can we explain the epidemiology of schizophrenia in terms of the pathology of striatal dopamine?
Rothbaum1 ° ,
Davis1 ,
Ressler1 .
1 Emory
M. K. University B. School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, USA Exposure therapy is recommended for most of the anxiety disorders and involves confrontation with feared stimuli in a therapeutic manner and is based on extinction training from the animal literature. By presenting the feared stimuli repeatedly with no aversive consequences, the fear decreases until ideally, the stimuli no longer engender fear. In a novel model for combining pharmacotherapy and psychotherapy, pharmacotherapy is aimed at improving the learning that takes place during exposure-based therapy and not at treating the symptoms of anxiety [1]. The glutamatergic NMDA receptor has been found to be critically involved in learning and memory, and this learning may be augmented by the NMDA partial agonist, d-cycloserine. d-Cycloserine has been shown in animal studies to facilitate the extinction of learned fear [1]. The first clinical test of a treatment for anxiety in humans combined d-cycloserine with exposure therapy [2] and indicated greater improvement on all measures in the patients who received d-cycloserine than the placebo group. D-cycloserine has now been shown to facilitate exposure therapy in the treatment of obsessive compulsive disorder, panic disorder, and social phobia whereas adding “traditional” medications (e.g., alprazolam, imipramine, fluvoxamine) to exposure therapy has shown no advantage over CBT alone for these anxiety disorders. A recent meta-analysis confirmed that d-cycloserine is effective in animals and humans [3]. Lower and less frequent doses seem to be more effective than higher doses. Too frequent dosing (daily) seems to be ineffective. Disclosure statement: Dr. Rothbaum is a consultant to and owns equity in Virtually Better, Inc., which is developing products related to the virtual reality research described in this paper. Drs. Davis and Ressler have applied for a patent for the use of D-cycloserine as an adjunct to CBT and are entitled to royalties and milestone payments from Extinction Pharmaceuticals should this technology be commercialized. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. References [1] Davis M, Ressler K, Rothbaum BO, Richardson R: Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006; 60:369–375. [2] Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M: Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004; 61:1136–1144. [3] Norberg MN, Krystal JH, Tolin DF: A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 2008; 63:1118–1126.
R. Murray1 ° . 1 Institute of Psychiatry, Professor of Psychiatric ResearchPO Box 63, London, United Kingdom The relationship between epidemiology and pathogenesis has been established for many medical disorders; for example, coronary artery disease. This is as it should be. However, in contrast, epidemiological and pathogenetic research have remained stubbornly separate in schizophrenia. This presentation will make the case that it is now time to integrate these two lines of research. Positive psychotic symptoms are thought to arise from the inappropriate attribution of excessive salience to insignificant events, and, although GABA and glutamatergic abnormalities may well play a role, the final common pathway to this excessive salience appears to be striatal dopamine dysregulation. Prodromal subjects and some of the relatives of schizophrenic patients show similar abnormalities of striatal dopamine to schizophrenic patients, and certain genes regulating the dopamine system have been implicated as popular candidates. The risk-increasing effect of obstetric complications is well known, and human and animal studies suggest that these are associated with an over-responsive dopamine system. The excessive use of stimulant drugs which induce striatal dopamine release can also induce psychosis. Furthermore, young males, the group which show the highest incidence of schizophrenia, show the largest behavioural response to amphetamines. Finally, exposure to adverse social factors including migration, urbanisation, and childhood maltreatment have been implicated in the aetiology of schizophrenia; and it has been proposed that such factors may have in common the experience of social defeat which in animals can be shown to influence striatal dopamine. In short, all risk roads lead to dopamine! S.06.04 NGF and BDNF as neuroendocrine factors involved in the response to early life stress and susceptibility to psychopathology: evidence from animal models F. Cirulli1 ° , L. Aloe2 , N. Francia3 , A. Berry3 , E. Alleva3 , 1 Istituto Superiore di Sanit` a, Section of S.J. Suomi4 . Behavioural Neuroscience Department of Cell Biology, Rome, Italy; 2 CNR/EBRI, Institute of Neurobiology and Molecular Medicine, Rome, Italy; 3 Istituto Superiore di Sanit`a, Section of Behavioural Neuroscience Department of Cell Biology and Neuroscience, Rome, Italy; 4 NICHD, Laboratory of Comparative Ethology, Poolesville, USA Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing the rearing environment into stable changes in brain and behavioral plasticity are currently being investigated [1,2]. Here we tested the hypothesis that peripheral levels of Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF), which are involved in the response to stress and in the pathophysiology of anxiety and depression, might be affected in a non-human primate model of adverse rearing. Males and females rhesus macaques reared with
S.06. Gene–environment in psychoses: new developments in clinical and basic research
[3] Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U, et al. Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5585−90.
S.06. Gene–environment in psychoses: new developments in clinical and basic research
S.05.05 D-cycloserine and exposure therapy
S.06.02 Can we explain the epidemiology of schizophrenia in terms of the pathology of striatal dopamine?
Rothbaum1 ° ,
Davis1 ,
Ressler1 .
1 Emory
M. K. University B. School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, USA Exposure therapy is recommended for most of the anxiety disorders and involves confrontation with feared stimuli in a therapeutic manner and is based on extinction training from the animal literature. By presenting the feared stimuli repeatedly with no aversive consequences, the fear decreases until ideally, the stimuli no longer engender fear. In a novel model for combining pharmacotherapy and psychotherapy, pharmacotherapy is aimed at improving the learning that takes place during exposure-based therapy and not at treating the symptoms of anxiety [1]. The glutamatergic NMDA receptor has been found to be critically involved in learning and memory, and this learning may be augmented by the NMDA partial agonist, d-cycloserine. d-Cycloserine has been shown in animal studies to facilitate the extinction of learned fear [1]. The first clinical test of a treatment for anxiety in humans combined d-cycloserine with exposure therapy [2] and indicated greater improvement on all measures in the patients who received d-cycloserine than the placebo group. D-cycloserine has now been shown to facilitate exposure therapy in the treatment of obsessive compulsive disorder, panic disorder, and social phobia whereas adding “traditional” medications (e.g., alprazolam, imipramine, fluvoxamine) to exposure therapy has shown no advantage over CBT alone for these anxiety disorders. A recent meta-analysis confirmed that d-cycloserine is effective in animals and humans [3]. Lower and less frequent doses seem to be more effective than higher doses. Too frequent dosing (daily) seems to be ineffective. Disclosure statement: Dr. Rothbaum is a consultant to and owns equity in Virtually Better, Inc., which is developing products related to the virtual reality research described in this paper. Drs. Davis and Ressler have applied for a patent for the use of D-cycloserine as an adjunct to CBT and are entitled to royalties and milestone payments from Extinction Pharmaceuticals should this technology be commercialized. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. References [1] Davis M, Ressler K, Rothbaum BO, Richardson R: Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006; 60:369–375. [2] Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M: Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004; 61:1136–1144. [3] Norberg MN, Krystal JH, Tolin DF: A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 2008; 63:1118–1126.
R. Murray1 ° . 1 Institute of Psychiatry, Professor of Psychiatric ResearchPO Box 63, London, United Kingdom The relationship between epidemiology and pathogenesis has been established for many medical disorders; for example, coronary artery disease. This is as it should be. However, in contrast, epidemiological and pathogenetic research have remained stubbornly separate in schizophrenia. This presentation will make the case that it is now time to integrate these two lines of research. Positive psychotic symptoms are thought to arise from the inappropriate attribution of excessive salience to insignificant events, and, although GABA and glutamatergic abnormalities may well play a role, the final common pathway to this excessive salience appears to be striatal dopamine dysregulation. Prodromal subjects and some of the relatives of schizophrenic patients show similar abnormalities of striatal dopamine to schizophrenic patients, and certain genes regulating the dopamine system have been implicated as popular candidates. The risk-increasing effect of obstetric complications is well known, and human and animal studies suggest that these are associated with an over-responsive dopamine system. The excessive use of stimulant drugs which induce striatal dopamine release can also induce psychosis. Furthermore, young males, the group which show the highest incidence of schizophrenia, show the largest behavioural response to amphetamines. Finally, exposure to adverse social factors including migration, urbanisation, and childhood maltreatment have been implicated in the aetiology of schizophrenia; and it has been proposed that such factors may have in common the experience of social defeat which in animals can be shown to influence striatal dopamine. In short, all risk roads lead to dopamine! S.06.04 NGF and BDNF as neuroendocrine factors involved in the response to early life stress and susceptibility to psychopathology: evidence from animal models F. Cirulli1 ° , L. Aloe2 , N. Francia3 , A. Berry3 , E. Alleva3 , 1 Istituto Superiore di Sanit` a, Section of S.J. Suomi4 . Behavioural Neuroscience Department of Cell Biology, Rome, Italy; 2 CNR/EBRI, Institute of Neurobiology and Molecular Medicine, Rome, Italy; 3 Istituto Superiore di Sanit`a, Section of Behavioural Neuroscience Department of Cell Biology and Neuroscience, Rome, Italy; 4 NICHD, Laboratory of Comparative Ethology, Poolesville, USA Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing the rearing environment into stable changes in brain and behavioral plasticity are currently being investigated [1,2]. Here we tested the hypothesis that peripheral levels of Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF), which are involved in the response to stress and in the pathophysiology of anxiety and depression, might be affected in a non-human primate model of adverse rearing. Males and females rhesus macaques reared with