- Email: [email protected]
S.14.02 Update of neuroimaging in social anxiety disorder
S.14. Social anxiety disorder (SAD): from the clinic to the laboratory and backwards References [1] Gourdain, P., Gr´egoire, S., Iken, S., Bachy, V., Dorban, G., Chaigneau, T., Debiec, H., Bergot, A-S., Renault, I., Aucouturier, P., Carnaud, C., 2009. Adoptive transfer of T lymphocytes sensitized against the prion protein attenuates prion invasion in scrapie-infected mice. J Immunol 183, 6619–6628. [2] Bachy, V., Ballerini, C., Gourdain, P., Prignon, A., Iken, S., Antoine, N., Rosset, M., Carnaud, C., 2010. Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie. J Gen Virol 91, 809–820. [3] Iken, S., Bachy, V., Gourdain, P., Lim, A., Gr´egoire, S., Chaigneau, T., Aucouturier, P., Carnaud, C., 2011. Th2-polarised PrP-specific transgenic T-cells confer partial protection against murine scrapie. PLoS Pathog. 7 Epub Sep 1.
S.13.04 Immunotherapy in amyotrophic lateral sclerosis J.P. Julien1 ° , P. Patel1 , J. Kriz1 , C. Gravel2 1 Universit´e Laval, Centre de Recherche du Centre Hospitalier de Qu´ebec Pavillon CHUL T2−41, Qu´ebec, Canada; 2 Universit´e Laval, Centre de Recherche de l’Institut universitaire en sant´e mentale de Qu´ebec, Qu´ebec, Canada Mutations in superoxide dismutase (SOD1) is one of the causes of familial amyotrophic lateral sclerosis (ALS). Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of secretory pathways for SOD1 [1] led us to propose that immunization strategies should be considered as potential approaches for ALS treatment. Active immunization with metal-free SOD1 delayed onset and mortality in mice expressing SOD1G37R mutant [2]. In order to develop passive immunization strategies for ALS, we generated a collection of monoclonal antibodies that recognize misfolded SOD1 species but not the intact wildtype (WT) SOD1 [3]. We discovered that intracerebroventricular (ICV) infusion of such monoclonal antibodies and their Fabderived fragment can delay mortality of ALS mice in proportion to the duration of treatment. From hybridomas, we generated recombinant single-chain variable fragments (scFv) which are able to bind misfolded SOD1. Recombinant scFV antibodies present many advantages. They are small in size resulting in higher tissue penetration and they are less immunogenic. We have tested in SOD1G93A mice a gene therapy approach based on adenoassociated virus (AAV) encoding scFv antibodies against SOD1. A single intrathecal injection of AAV-scFv at 40 days of age in SOD1G93A mice conferred remarkable protection with increased survival by up to 30% depending on scFv antibody titer in the spinal cord. The main advantage of the AAV-delivery approach is that it can achieve high level and sustained expression of secreted scFv antibodies in situ without repeated administration of antibodies. References [1] Urushitani, M., Sik A., Sakurai T., Nukina N., Takahashi, R., Julien, J.P., 2006 Chromogranin-mediated Secretion of mutant Superoxide Dismutase proteins linked to ALS, Nature Neuroscience 9, 108–118. [2] Urushitani, M., Abou Ezzi S., Julien, J.-P., 2007 Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci, 104, 2495–2500. [3] Gros-Louis, F., Larivi`ere R., Julien, J.-P, 2010 Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS, J. Neurochem., 113, 1188–1199.
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S.14. Social anxiety disorder (SAD): from the clinic to the laboratory and backwards S.14.01 The amygdala story in social anxiety disorder I. Iancu1 ° , M. Kotler1 1 Tel Aviv University, Beer Yaakov Hospital, Beer Yaakov, Israel Objective: This review will summarize the current knowledge about the role of the amygdala in the neurobiological basis of Social Anxiety Disorder (SAD). Methods and Results: In patients with SAD studies using functional neuroimaging techniques have demonstrated hyperactivation in the amygdala during symptom provocation. Blair and colleagues [1] used fMRI to compare the neural response to facial expressions in SAD patients and showed that SAD patients had increased activation to fearful relative to neutral expressions in several regions including the amygdala. Symptom severity in SAD correlated with the amygdala response to fearful expressions. It also has been hypothesized that SSRIs may inhibit the postsynaptic neuronal excitability in the amygdala. In support of this theory, controlled studies have demonstrated the efficacy of SSRIs in SAD. Several studies on the effect of pregabalin and oxytocin on the amygdala activation in SAD will be described. Additionally, Furmark et al. [2] used PET and compared the effects of short and long-term citalopram and CBT on regional cerebral blood flow (rCBF) in SAD. rCBF was assessed during an anxiogenic speaking task at baseline and after 9 weeks. Among responders in all groups, improvement was correlated with a decreased rCBF to public speaking bilaterally in the amygdala. The degree of amygdalar attenuation was associated with clinical improvement a year later suggesting that brain changes associated with treatment response persist. Conclusions: Neurobiological studies support the view that SAD involves an exaggerated fear response which may be mediated by amygdalar dysfunction. References [1] Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, et al. Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders. Am. J. Psychiatry. 2008; 165: 1193–202. [2] Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A, et al. Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch. Gen. Psychiatry. 2002; 59: 425−33.
S.14.02 Update of neuroimaging in social anxiety disorder A.B. Br¨uhl1 ° , M. Rufer2 , U. Herwig1 1 University Hospital of Psychiatry, Clinic for General and Social Psychiatry, Z¨urich, Switzerland; 2 University Hospital of Zurich, Department of Psychiatry, Z¨urich, Switzerland Specific anxiety disorders as social anxiety disorder (SAD) are characterized by alterations of emotion processing and regulation when confronted with anxiety evoking situations, which has also been shown on the neurobiological level. This is also reflected in the psychotherapy of SAD, which adresses in the first line cognitions, emotions and behavior in social situations. Nearly
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S.14. Social anxiety disorder (SAD): from the clinic to the laboratory and backwards
all research in SAD has focused on neurocircuits involved in anxiety and fear activated by social stimuli. However, recent studies in SAD provide evidence for additional disturbances in the processing of general emotional stimuli [1,2]. Both studies found increased activations in SAD compared to healthy subjects in brain regions typically involved in fear and anxiety processing such as the amygdala when anticipating [1] and perceiving [2] stimuli of negative emotional valence. These increased brain activations were in both studies correlated with the severity of social anxiety. These results point to disturbances not only in the processing of specific fear evoking stimuli in SAD as a specific anxiety disorder but also to alterations in the processing of general emotional stimuli on the neurobiological level. In the field of emotion regulation, deficits have been detected in SAD during the confrontation with negative social stimuli [3]. However, we have also detected disturbed emotion regulation circuits in SAD when anticipating and perceiving general negative, but not social stimuli. Altogether, there is more and more evidence for biased processing of not only social, but general emotional stimuli in SAD as an example for a specific anxiety disorder. References [1] Br¨uhl, A.B., Rufer, M., Delsignore, A., Kaffenberger, T., J¨ancke, L., Herwig, U., 2011. Neural correlates of altered general emotion processing in social anxiety disorder. Brain Res 1378, 72−83. [2] Shah, S.G., Klumpp, H., Angstadt, M., Nathan, P.J., Phan, K.L., 2009. Amygdala and insula response to emotional images in patients with generalized social anxiety disorder. J Psychiatry Neurosci 34, 296– 302. [3] Goldin, P.R., Manber, T., Hakimi, S., Canli, T., Gross, J.J., 2009. Neural bases of social anxiety disorder: emotional reactivity and cognitive regulation during social and physical threat. Arch Gen Psychiatry 66, 170–180.
S.14.03 Brain SPECT studies in social anxiety disorder J. Warwick1 ° 1 University of Stellenbosch, Faculty of Health Sciences & MRC Unit for Stress and Anxiety Disorders, Cape Town, South Africa Brain SPECT is a relatively cost-effective and widely available modality which can provide a sensitive measure of different aspects of brain function. Specifically tracers can provide information on brain perfusion and neuroreceptor binding. Early work examining resting cerebral blood flow (CBF) showed no difference between SAD patients and controls in a number of preselected regions of interest. A later whole brain voxelwise study showed increased frontal function in SAD consistent with modulation of excessive limbic activity, and altered posterior cortical function suggesting an altered perception of self and others [1]. A study of a number of preselected regions of interest showed reduced CBF activity in a number of cortical areas after treatment with citalopram. A subsequent whole brain voxelwise study in a larger group of patients showed decreased resting CBF in the insula following treatment with both citalopram and moclobemide [2]. This may suggest that these therapies may have a common pathway targeting altered insular activity in SAD. SPECT studies also suggest altered dopaminergic function in SAD. A number of studies comparing striatal dopamine transporter (DAT) binding in SAD and controls have given conflicting results, possibly due to differences in methodology. There is also SPECT evidence for lower striatal D2 receptor binding. Recently
published work reveals increased striatal DAT binding following escitalopram therapy in SAD which may reflect that at least some therapeutic effects may operate via indirect activation of dopaminergic function [3]. References [1] Warwick JM, Carey P, Jordaan GP, Dupont P, Stein D, 2008. Resting Brain Perfusion in Social Anxiety Disorder: a Voxel-wise whole brain comparison with healthy control subjects. Progress in Neuropsychopharmacology & Biological Psychiatry 32: 1251–1256. [2] Warwick JM, Carey P, Van der Linden G, Prinsloo C, Niehaus D, Seedat S, Dupont P, Stein DJ, 2006. A Comparison of the effects of citalopram and moclobemide on resting brain perfusion in Social Anxiety Disorder. Metabolic Brain Disease 21: 241–252. [3] Warwick JM, Carey PD, Cassimjee N, Lochner C, Hemmings S, Moolman-Smook H, Beetge E, Dupont P, Stein DJ, 2012. Dopamine Transporter Binding in Social Anxiety Disorder: the effect of Treatment with Escitalopram. Metabolic Brain Disease Feb 16.
S.14.04 Pharmacological treatment of social phobia: efficacy, acceptability and unmet needs D.S. Baldwin1 ° 1 University of Southampton, Faculty of Medicine, Southampton, United Kingdom Social phobia can no longer be described as ‘a neglected anxiety disorder’, but there are many areas of persisting uncertainty regarding optimal management, and many patients have unsatisfactory outcomes with current treatment approaches. A recent systematic review of randomised controlled trials of the acute treatment of patients with social phobia (social anxiety disorder) has highlighted the efficacy of ‘second-generation’ antidepressant drugs, when compared to placebo [1]: good evidence for efficacy is also seen for monoamine oxidase inhibitors. However the superiority of one form of medication over another has not been established satisfactorily. Cognitive behaviour therapy (CBT) and pharmacological treatments have broadly similar efficacy in acute treatment, but randomised controlled trials of the combination of medication with cognitive behaviour therapy versus either treatment given alone have produced inconsistent findings. Although a recent systematic review suggests CBT is a reasonable next step, when patients have not responded to initial pharmacological treatment [2] − and an accumulating evidence base for antipsychotic drugs in monotherapy − there is at present no convincing evidence to recommend one type of second-line approach over another. Most evidence-based guidelines recommend long-term treatment, following early symptom reduction, but there have been comparatively few randomised placebo-controlled relapse prevention studies and the optimal duration of continuation treatment is uncertain [3]. The strengths and weaknesses of the current evidence base will be highlighted, with additional reference to recent studies with cannabidiol, cortisol, d-cycloserine, oxytocin and vasopressin, which suggest novel targets for pharmacological treatment. References [1] de Menezes., G.B., Coutinho, E.S.F., Fontenelle, L.F., Vigne, P., Figueira, I., Versiani, M., 2011. Second-generation antidepressants in social anxiety disorder: meta-analysis of controlled clinical trials. Psychopharmacology; 215: 1−11. [2] Rodrigues, H., Figueira, I., Gon¸calves, R., Mendlowicz, M., Macedo, T., Ventura, P., 2011. CBT for pharmacotherapy nonremitters − a systematic review of a next-step strategy. Journal of Affective Disorders 129: 219–228.
S.13.04 Immunotherapy in amyotrophic lateral sclerosis J.P. Julien1 ° , P. Patel1 , J. Kriz1 , C. Gravel2 1 Universit´e Laval, Centre de Recherche du Centre Hospitalier de Qu´ebec Pavillon CHUL T2−41, Qu´ebec, Canada; 2 Universit´e Laval, Centre de Recherche de l’Institut universitaire en sant´e mentale de Qu´ebec, Qu´ebec, Canada Mutations in superoxide dismutase (SOD1) is one of the causes of familial amyotrophic lateral sclerosis (ALS). Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of secretory pathways for SOD1 [1] led us to propose that immunization strategies should be considered as potential approaches for ALS treatment. Active immunization with metal-free SOD1 delayed onset and mortality in mice expressing SOD1G37R mutant [2]. In order to develop passive immunization strategies for ALS, we generated a collection of monoclonal antibodies that recognize misfolded SOD1 species but not the intact wildtype (WT) SOD1 [3]. We discovered that intracerebroventricular (ICV) infusion of such monoclonal antibodies and their Fabderived fragment can delay mortality of ALS mice in proportion to the duration of treatment. From hybridomas, we generated recombinant single-chain variable fragments (scFv) which are able to bind misfolded SOD1. Recombinant scFV antibodies present many advantages. They are small in size resulting in higher tissue penetration and they are less immunogenic. We have tested in SOD1G93A mice a gene therapy approach based on adenoassociated virus (AAV) encoding scFv antibodies against SOD1. A single intrathecal injection of AAV-scFv at 40 days of age in SOD1G93A mice conferred remarkable protection with increased survival by up to 30% depending on scFv antibody titer in the spinal cord. The main advantage of the AAV-delivery approach is that it can achieve high level and sustained expression of secreted scFv antibodies in situ without repeated administration of antibodies. References [1] Urushitani, M., Sik A., Sakurai T., Nukina N., Takahashi, R., Julien, J.P., 2006 Chromogranin-mediated Secretion of mutant Superoxide Dismutase proteins linked to ALS, Nature Neuroscience 9, 108–118. [2] Urushitani, M., Abou Ezzi S., Julien, J.-P., 2007 Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci, 104, 2495–2500. [3] Gros-Louis, F., Larivi`ere R., Julien, J.-P, 2010 Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS, J. Neurochem., 113, 1188–1199.
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S.14. Social anxiety disorder (SAD): from the clinic to the laboratory and backwards S.14.01 The amygdala story in social anxiety disorder I. Iancu1 ° , M. Kotler1 1 Tel Aviv University, Beer Yaakov Hospital, Beer Yaakov, Israel Objective: This review will summarize the current knowledge about the role of the amygdala in the neurobiological basis of Social Anxiety Disorder (SAD). Methods and Results: In patients with SAD studies using functional neuroimaging techniques have demonstrated hyperactivation in the amygdala during symptom provocation. Blair and colleagues [1] used fMRI to compare the neural response to facial expressions in SAD patients and showed that SAD patients had increased activation to fearful relative to neutral expressions in several regions including the amygdala. Symptom severity in SAD correlated with the amygdala response to fearful expressions. It also has been hypothesized that SSRIs may inhibit the postsynaptic neuronal excitability in the amygdala. In support of this theory, controlled studies have demonstrated the efficacy of SSRIs in SAD. Several studies on the effect of pregabalin and oxytocin on the amygdala activation in SAD will be described. Additionally, Furmark et al. [2] used PET and compared the effects of short and long-term citalopram and CBT on regional cerebral blood flow (rCBF) in SAD. rCBF was assessed during an anxiogenic speaking task at baseline and after 9 weeks. Among responders in all groups, improvement was correlated with a decreased rCBF to public speaking bilaterally in the amygdala. The degree of amygdalar attenuation was associated with clinical improvement a year later suggesting that brain changes associated with treatment response persist. Conclusions: Neurobiological studies support the view that SAD involves an exaggerated fear response which may be mediated by amygdalar dysfunction. References [1] Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, et al. Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders. Am. J. Psychiatry. 2008; 165: 1193–202. [2] Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A, et al. Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch. Gen. Psychiatry. 2002; 59: 425−33.
S.14.02 Update of neuroimaging in social anxiety disorder A.B. Br¨uhl1 ° , M. Rufer2 , U. Herwig1 1 University Hospital of Psychiatry, Clinic for General and Social Psychiatry, Z¨urich, Switzerland; 2 University Hospital of Zurich, Department of Psychiatry, Z¨urich, Switzerland Specific anxiety disorders as social anxiety disorder (SAD) are characterized by alterations of emotion processing and regulation when confronted with anxiety evoking situations, which has also been shown on the neurobiological level. This is also reflected in the psychotherapy of SAD, which adresses in the first line cognitions, emotions and behavior in social situations. Nearly
S132
S.14. Social anxiety disorder (SAD): from the clinic to the laboratory and backwards
all research in SAD has focused on neurocircuits involved in anxiety and fear activated by social stimuli. However, recent studies in SAD provide evidence for additional disturbances in the processing of general emotional stimuli [1,2]. Both studies found increased activations in SAD compared to healthy subjects in brain regions typically involved in fear and anxiety processing such as the amygdala when anticipating [1] and perceiving [2] stimuli of negative emotional valence. These increased brain activations were in both studies correlated with the severity of social anxiety. These results point to disturbances not only in the processing of specific fear evoking stimuli in SAD as a specific anxiety disorder but also to alterations in the processing of general emotional stimuli on the neurobiological level. In the field of emotion regulation, deficits have been detected in SAD during the confrontation with negative social stimuli [3]. However, we have also detected disturbed emotion regulation circuits in SAD when anticipating and perceiving general negative, but not social stimuli. Altogether, there is more and more evidence for biased processing of not only social, but general emotional stimuli in SAD as an example for a specific anxiety disorder. References [1] Br¨uhl, A.B., Rufer, M., Delsignore, A., Kaffenberger, T., J¨ancke, L., Herwig, U., 2011. Neural correlates of altered general emotion processing in social anxiety disorder. Brain Res 1378, 72−83. [2] Shah, S.G., Klumpp, H., Angstadt, M., Nathan, P.J., Phan, K.L., 2009. Amygdala and insula response to emotional images in patients with generalized social anxiety disorder. J Psychiatry Neurosci 34, 296– 302. [3] Goldin, P.R., Manber, T., Hakimi, S., Canli, T., Gross, J.J., 2009. Neural bases of social anxiety disorder: emotional reactivity and cognitive regulation during social and physical threat. Arch Gen Psychiatry 66, 170–180.
S.14.03 Brain SPECT studies in social anxiety disorder J. Warwick1 ° 1 University of Stellenbosch, Faculty of Health Sciences & MRC Unit for Stress and Anxiety Disorders, Cape Town, South Africa Brain SPECT is a relatively cost-effective and widely available modality which can provide a sensitive measure of different aspects of brain function. Specifically tracers can provide information on brain perfusion and neuroreceptor binding. Early work examining resting cerebral blood flow (CBF) showed no difference between SAD patients and controls in a number of preselected regions of interest. A later whole brain voxelwise study showed increased frontal function in SAD consistent with modulation of excessive limbic activity, and altered posterior cortical function suggesting an altered perception of self and others [1]. A study of a number of preselected regions of interest showed reduced CBF activity in a number of cortical areas after treatment with citalopram. A subsequent whole brain voxelwise study in a larger group of patients showed decreased resting CBF in the insula following treatment with both citalopram and moclobemide [2]. This may suggest that these therapies may have a common pathway targeting altered insular activity in SAD. SPECT studies also suggest altered dopaminergic function in SAD. A number of studies comparing striatal dopamine transporter (DAT) binding in SAD and controls have given conflicting results, possibly due to differences in methodology. There is also SPECT evidence for lower striatal D2 receptor binding. Recently
published work reveals increased striatal DAT binding following escitalopram therapy in SAD which may reflect that at least some therapeutic effects may operate via indirect activation of dopaminergic function [3]. References [1] Warwick JM, Carey P, Jordaan GP, Dupont P, Stein D, 2008. Resting Brain Perfusion in Social Anxiety Disorder: a Voxel-wise whole brain comparison with healthy control subjects. Progress in Neuropsychopharmacology & Biological Psychiatry 32: 1251–1256. [2] Warwick JM, Carey P, Van der Linden G, Prinsloo C, Niehaus D, Seedat S, Dupont P, Stein DJ, 2006. A Comparison of the effects of citalopram and moclobemide on resting brain perfusion in Social Anxiety Disorder. Metabolic Brain Disease 21: 241–252. [3] Warwick JM, Carey PD, Cassimjee N, Lochner C, Hemmings S, Moolman-Smook H, Beetge E, Dupont P, Stein DJ, 2012. Dopamine Transporter Binding in Social Anxiety Disorder: the effect of Treatment with Escitalopram. Metabolic Brain Disease Feb 16.
S.14.04 Pharmacological treatment of social phobia: efficacy, acceptability and unmet needs D.S. Baldwin1 ° 1 University of Southampton, Faculty of Medicine, Southampton, United Kingdom Social phobia can no longer be described as ‘a neglected anxiety disorder’, but there are many areas of persisting uncertainty regarding optimal management, and many patients have unsatisfactory outcomes with current treatment approaches. A recent systematic review of randomised controlled trials of the acute treatment of patients with social phobia (social anxiety disorder) has highlighted the efficacy of ‘second-generation’ antidepressant drugs, when compared to placebo [1]: good evidence for efficacy is also seen for monoamine oxidase inhibitors. However the superiority of one form of medication over another has not been established satisfactorily. Cognitive behaviour therapy (CBT) and pharmacological treatments have broadly similar efficacy in acute treatment, but randomised controlled trials of the combination of medication with cognitive behaviour therapy versus either treatment given alone have produced inconsistent findings. Although a recent systematic review suggests CBT is a reasonable next step, when patients have not responded to initial pharmacological treatment [2] − and an accumulating evidence base for antipsychotic drugs in monotherapy − there is at present no convincing evidence to recommend one type of second-line approach over another. Most evidence-based guidelines recommend long-term treatment, following early symptom reduction, but there have been comparatively few randomised placebo-controlled relapse prevention studies and the optimal duration of continuation treatment is uncertain [3]. The strengths and weaknesses of the current evidence base will be highlighted, with additional reference to recent studies with cannabidiol, cortisol, d-cycloserine, oxytocin and vasopressin, which suggest novel targets for pharmacological treatment. References [1] de Menezes., G.B., Coutinho, E.S.F., Fontenelle, L.F., Vigne, P., Figueira, I., Versiani, M., 2011. Second-generation antidepressants in social anxiety disorder: meta-analysis of controlled clinical trials. Psychopharmacology; 215: 1−11. [2] Rodrigues, H., Figueira, I., Gon¸calves, R., Mendlowicz, M., Macedo, T., Ventura, P., 2011. CBT for pharmacotherapy nonremitters − a systematic review of a next-step strategy. Journal of Affective Disorders 129: 219–228.