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S.08.04 The nitric oxide pathway in anxiety and stress-related disorders
S.08 The nitric oxide pathway in psychiatric disease: avenues and perspectives G¨oteborg, Sweden; 2 National University of Ireland, Department of Chemistry, Maynooth, Ireland Cognitive dysfunction is considered a core deficit of schizophrenia and predicts social and long-term outcome in patients. This cognitive dysfunctionality currently lacks effective pharmacological treatment. In order to identify novel drug targets, translational experimental animal models of cognitive dysfunction are required. We have established a behavioural test battery in rodents, ranging from pre-attentive information processing to cognitive flexibility. Using this test battery, we have demonstrated that nitric oxide (NO) synthase inhibitors can ameliorate impairments induced by the schizophrenomimetic drug phencyclidine (PCP), across several levels of cognitive complexity. In addition, a recent study by our research group has shown that preventing the access of NO synthase substrate can attenuate the disruptive effect of PCP on pre-attentive information processing. This suggests an important role of NO signalling in PCP-induced deficits on a number of cognitive domains. Recent findings from our laboratory indicate that PCP induces a NO-dependent increase in the second messenger molecule cGMP in the prefrontal cortex, a brain region closely linked to cognition. Furthermore, inhibition of NO-mediated cGMP production in this brain region attenuates the disruptive effect of PCP on preattentive information processing. These data indicate that cGMP signaling in the prefrontal cortex may play an important role in the some of the cognitive deficits induced by PCP. Preliminary data using a NO sensitive microsensor show that systemic administration of PCP increases NO levels in the prefrontal cortex. Targeting this system may thus provide a novel pharmacological treatment rationale for the cognitive dysfunctionality associated with schizophrenia. References [1] Klamer D, P˚alsson E, Revesz A, Engel JA, Svensson L, 2004 Nov, Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms. Psychopharmacology 176(3−4), 440−50. [2] Klamer D, Palsson E, Wass C, Archer T, Engel JA, Svensson L, 2005 June 3, Antagonism of the nitric oxide synthase inhibitor, L-NAME, of the effects of phencyclidine on latent inhibition in taste aversion conditioning. Behav Brain Res 161(1), 60−8. [3] P˚alsson E, Fejgin K, Wass C, Engel JA, Svensson L, Klamer D, 2007 Jan 19, The amino acid, L-lysine, blocks the disruptive effect of phencyclidine on prepulse inhibition in mice. Psychopharmacology.
S.08.03 Nitric oxide synthase promoter polymorphisms and psychiatric disease states A. Reif1 ° , C.P. Jacob1 , S. Herterich2 , W. Retz3 , C.F. Freitag4 , A. Dempfle5 , M. Heine1 , A. Boreatti-H¨ummer1 , M. R¨osler3 , K.P. Lesch1 . 1 University of W¨urzburg, Dept. of Psychiatry & Psychotherapy Section of Clinical and Molecular Psychobiology, W¨urzburg, Germany; 2 University of W¨urzburg, Central Laboratory Department of Clinical Biochemistry and Pathobiochemistry, W¨urzburg, Germany; 3 University of the Saarland, Institute for Forensic Psychology and Psychiatry, Homburg, Germany; 4 University of the Saarland, Department of Child and Adolescent Psychiatry, Homburg, Germany; 5 University of Marburg, Institute of Medical Biometry and Epidemiology, Marburg, Germany Nitric oxide (NO) has been suggested to play a role in behavioral control (Snyder and Ferris, 2000), while little is known about
S189
the function of NO in humans. We thus investigated a functional NOS1 promoter polymorphism for an association with psychiatric disease and behavioral traits. Five different samples have been ascertained for this study: a sample of patients with adult ADHD (n = 383), a sample of subjects with Cluster B and Cluster C personality disorder (n = 403), a sample of prison inmates stratified for violent and non-violent criminality (n = 233), 195 patients suffering from schizophrenia and, finally, a control sample of 469 subjects (total n = 1683). Short NOS1 exon 1f alleles were significantly associated with disease severity and prefrontal functioning in schizophrenia, while an association with disease per se was only found for a NOS1 exon1c promoter SNP (Reif et al., 2006). However, short NOS1 exon 1f alleles were significantly associated with Cluster B personality disorder, especially histrionic personality disorder. With regards to personality dimensions, an association was observed with NEO “Openness”. Likewise, short alleles were found significantly more in patients suffering from adult ADHD. Finally, short allele carriers were more prone to commit violent crime. Collectively, these data argue for a role of NOS-I in human behaviour and it appears that especially interpersonal, disruptive, outward bound behaviours are influenced by NOS1 genotype. Its association with adult ADHD however might well be due to the high presence of histrionic personality disorder in the investigated sample, as no association with childhood ADHD was found. References [1] Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP, Wienker T, T¨opner T, Fritzen S, Walter U, Schmitt A, Fallgatter AJ, Lesch KP, 2006, Mol Psychiatry 286–300. [2] Snyder SH, Ferris CD, 2000, Am J Psychiatry 157, 1738–1751.
S.08.04 The nitric oxide pathway in anxiety and stress-related disorders G. Wegener1 ° , A.K. Vistisen1 , S.R. Nielsen1 , V. Volke2 , B.H. Harvey3 . 1 University of Aarhus, Centre for Psychiatric Research, Risskov, Denmark; 2 University of Tartu, Department of Physiology, Tartu, Estonia; 3 University of North West, Department of Pharmacology, Potchefstroom, South Africa Affective disorders are widely distributed disorders with severe social and economic effects. Strong evidence underlines that effective treatment helps to restore function and quality of life. Unfortunately, patients with major affective disorders respond variably and unpredictably to different treatments, which underline the need of alternative approaches. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology. However, recent evidence strongly suggests involvement of neurodegenerative pathology in the disease. Since there is accumulating evidence that the novel neurotransmitter NO acts as a neuromodulator, and participate in several sub-cellular processes, such as cellular memory and neuronal toxicity, nitrergic pathways may have an important role in hippocampal degenerative pathology and cognitive deficits seen in patients with affective disorders. A few clinical and several pre-clinical studies, strongly suggests involvement of the nitric oxide (NO) signalling pathway in these disorders (Harvey 1996). Several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO (Wegener et al. 2000). Interestingly, distinct classes of antidepressants (Imipramine, Tianeptine, Citalopram and Paroxetine) have been found to modulate the NO level in
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S.09 Bipolar affective disorders: therapeutic options beyond current guidelines
the living rat hippocampus in clinically relevant doses (Wegener et al., 2003). Moreover, our recent work, using selective inhibitors of phosphodiesterase 5, indicate that the whole NO signalling pathway may play a major role in the behavioural and neurochemical effects observed. The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis. References [1] Harvey BH, 1996, Affective disorders and nitric oxide: a role in pathways to relapse and refractoriness? Hum Psychopharmacol 11, 309–319. [2] Wegener G, Volke V, Harvey BH, Rosenberg R, 2003, Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 959(1), 128–134. [3] Wegener G, Volke V, Rosenberg R, 2000, Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol 130(3), 575–580.
S.08.05 Metabolic parameters of the NO pathway in relationship to psychiatric disorders O. Akyol ° , H. Alacam. Hacettepe University Medical School, Department of Biochemistry, Ankara, Turkey Nitric oxide has been known as a endogenous molecule that functions as a hormone, reactive oxygen species, neurotransmitter, constitutive and inducible mediator, cytoprotective and cytotoxic molecule. It has been implicated in a number of physiological functions such as noradrenaline and dopamine release, memory and learning, regulation of the cerebrovascular system, and certain pathologies such as schizophrenia (Yilmaz et al. 2007), bipolar disorders, major depression (Herken et al. 2007), Alzheimer’s disease, autism, alcohol and substance abuse-related disorders and cerebral ischemia. NO can interact with neuromodulators in order to modify them and thereby change their regulatory action on synaptic transmission. NO may also react with thiol groups of amino acids and proteins and form relatively stable nitroso-thiols. After interaction with heme-containing protein, such as cytochromes, NO may lead to impairment of oxidative phosphorylation. Peroxynitrite, a harmful compound for cellular structures produced by the reaction of NO with molecular oxygen, has been linked to several interactions which may contribute to cellular injury, including lipid peroxidation, nitrosylation of some molecules, inactivation of sodium channels and interactions with metals whic have redox potential such as iron and copper (Akyol et al. 2004). The importance of NO as an intermediary in cell communication in the brain is highlighted by the fact that the excitatory amino acid glutamate is an initiator of the reaction that forms NO. The generation of NO following NMDA or norepinephrine receptor activation seems to be important in the context of central nervous system pathologies. References [1] Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A, 2004, Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo 18, 377–390. [2] Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M, Kap O, Yumru M, Savas HA, Akyol O, 2007, Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Arch Med Res 38, 247–252. [3] Yilmaz N, Herken H, Cicek HK, Celik A, Yurekli M, Akyol O, 2007, Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med Princ Pract 16, 137–141.
S.09 Bipolar affective disorders: therapeutic options beyond current guidelines S.09.01 Bipolar disorder treatment guidelines: right answers to the wrong questions or vice versa? G. Goodwin ° . University of Oxford, Department of Psychiatry, Headington Oxford, United Kingdom Current guidelines specify the scope and target of treatment for bipolar disorder. They are usually based on the available evidence and presented as recommendations for practitioners. They may serve as a source of information for patients and carers. The main tension in all guidelines is between those that seek to give correct answers to general questions and those that seek to be more specific and prescriptive. The latter risk giving the wrong answers to the right questions, either by stepping beyond the evidence or having the evidence itself change rapidly. The difficulties can be illustrated by where guidelines generally agree – in the treatment of mania – and where they do not – in the treatment of bipolar depression. Methodology is also important. The basis for most recommendations is a consensus meeting: experts in bipolar disorder review key areas and consider the strength of evidence and clinical implications. The guidelines are usually drawn up after extensive feedback from interested parties. The split between the general and the specific may also occur in this synthesis. If one includes only what everyone fully agrees, the guideline will be shorter but less specific. If everyone’s view is included – a different kind of consensus – the result may be very strange. Finally, what sort of evidence?: it could be clinical science, patient opinion or economic imperative. Understanding these factors illuminates how we have developed the diagnosis of bipolar disorder, its clinical management, and strategies for the use of medicines in short term treatment of episodes, and relapse prevention. References [1] Goodwin GM, 2003, Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology. J Psychopharmacology 17, 149–173.
S.09.02 Lithium and traditional anticonvulsants: still useful? J. Rybakowski ° . University of Medical Sciences, Department of Adult Psychiatry, Poznan, Poland Lithium and traditional anticonvulsants (valproate and carbamazepine) can be named the first generation mood stabilizers, preceding the introduction of other substances showing mood stabilizing properties by more then two decades. Lithium, introduced for the treatment of mania in 1949 and for prophylaxis of affective recurrences in early 1960s, has still been regarded as a prototype of mood stabilizer, showing therapeutic and prophylactic action in both psychopathological poles of bipolar illness. The efficacy of lithium in prevention of affective recurrences has been observed in patients receiving this drug for more than 30 years. A subgroup of excellent lithium responders has been delineated as an endophenotype for molecular genetic studies of bipolar illness. Antisuicidal action of lithium demonstrated during longterm administration adds to its clinical usefulness. Antidepressant
S.08.03 Nitric oxide synthase promoter polymorphisms and psychiatric disease states A. Reif1 ° , C.P. Jacob1 , S. Herterich2 , W. Retz3 , C.F. Freitag4 , A. Dempfle5 , M. Heine1 , A. Boreatti-H¨ummer1 , M. R¨osler3 , K.P. Lesch1 . 1 University of W¨urzburg, Dept. of Psychiatry & Psychotherapy Section of Clinical and Molecular Psychobiology, W¨urzburg, Germany; 2 University of W¨urzburg, Central Laboratory Department of Clinical Biochemistry and Pathobiochemistry, W¨urzburg, Germany; 3 University of the Saarland, Institute for Forensic Psychology and Psychiatry, Homburg, Germany; 4 University of the Saarland, Department of Child and Adolescent Psychiatry, Homburg, Germany; 5 University of Marburg, Institute of Medical Biometry and Epidemiology, Marburg, Germany Nitric oxide (NO) has been suggested to play a role in behavioral control (Snyder and Ferris, 2000), while little is known about
S189
the function of NO in humans. We thus investigated a functional NOS1 promoter polymorphism for an association with psychiatric disease and behavioral traits. Five different samples have been ascertained for this study: a sample of patients with adult ADHD (n = 383), a sample of subjects with Cluster B and Cluster C personality disorder (n = 403), a sample of prison inmates stratified for violent and non-violent criminality (n = 233), 195 patients suffering from schizophrenia and, finally, a control sample of 469 subjects (total n = 1683). Short NOS1 exon 1f alleles were significantly associated with disease severity and prefrontal functioning in schizophrenia, while an association with disease per se was only found for a NOS1 exon1c promoter SNP (Reif et al., 2006). However, short NOS1 exon 1f alleles were significantly associated with Cluster B personality disorder, especially histrionic personality disorder. With regards to personality dimensions, an association was observed with NEO “Openness”. Likewise, short alleles were found significantly more in patients suffering from adult ADHD. Finally, short allele carriers were more prone to commit violent crime. Collectively, these data argue for a role of NOS-I in human behaviour and it appears that especially interpersonal, disruptive, outward bound behaviours are influenced by NOS1 genotype. Its association with adult ADHD however might well be due to the high presence of histrionic personality disorder in the investigated sample, as no association with childhood ADHD was found. References [1] Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP, Wienker T, T¨opner T, Fritzen S, Walter U, Schmitt A, Fallgatter AJ, Lesch KP, 2006, Mol Psychiatry 286–300. [2] Snyder SH, Ferris CD, 2000, Am J Psychiatry 157, 1738–1751.
S.08.04 The nitric oxide pathway in anxiety and stress-related disorders G. Wegener1 ° , A.K. Vistisen1 , S.R. Nielsen1 , V. Volke2 , B.H. Harvey3 . 1 University of Aarhus, Centre for Psychiatric Research, Risskov, Denmark; 2 University of Tartu, Department of Physiology, Tartu, Estonia; 3 University of North West, Department of Pharmacology, Potchefstroom, South Africa Affective disorders are widely distributed disorders with severe social and economic effects. Strong evidence underlines that effective treatment helps to restore function and quality of life. Unfortunately, patients with major affective disorders respond variably and unpredictably to different treatments, which underline the need of alternative approaches. Due to the action of most modern antidepressant drugs, serotonergic mechanisms have traditionally been suggested to play major roles in the pathophysiology. However, recent evidence strongly suggests involvement of neurodegenerative pathology in the disease. Since there is accumulating evidence that the novel neurotransmitter NO acts as a neuromodulator, and participate in several sub-cellular processes, such as cellular memory and neuronal toxicity, nitrergic pathways may have an important role in hippocampal degenerative pathology and cognitive deficits seen in patients with affective disorders. A few clinical and several pre-clinical studies, strongly suggests involvement of the nitric oxide (NO) signalling pathway in these disorders (Harvey 1996). Several of the conventional neurotransmitters, including serotonin, glutamate and GABA, are intimately regulated by NO (Wegener et al. 2000). Interestingly, distinct classes of antidepressants (Imipramine, Tianeptine, Citalopram and Paroxetine) have been found to modulate the NO level in
S190
S.09 Bipolar affective disorders: therapeutic options beyond current guidelines
the living rat hippocampus in clinically relevant doses (Wegener et al., 2003). Moreover, our recent work, using selective inhibitors of phosphodiesterase 5, indicate that the whole NO signalling pathway may play a major role in the behavioural and neurochemical effects observed. The NO system is therefore a potential target for antidepressant and anxiolytic drug action in acute therapy as well as in prophylaxis. References [1] Harvey BH, 1996, Affective disorders and nitric oxide: a role in pathways to relapse and refractoriness? Hum Psychopharmacol 11, 309–319. [2] Wegener G, Volke V, Harvey BH, Rosenberg R, 2003, Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 959(1), 128–134. [3] Wegener G, Volke V, Rosenberg R, 2000, Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. Br J Pharmacol 130(3), 575–580.
S.08.05 Metabolic parameters of the NO pathway in relationship to psychiatric disorders O. Akyol ° , H. Alacam. Hacettepe University Medical School, Department of Biochemistry, Ankara, Turkey Nitric oxide has been known as a endogenous molecule that functions as a hormone, reactive oxygen species, neurotransmitter, constitutive and inducible mediator, cytoprotective and cytotoxic molecule. It has been implicated in a number of physiological functions such as noradrenaline and dopamine release, memory and learning, regulation of the cerebrovascular system, and certain pathologies such as schizophrenia (Yilmaz et al. 2007), bipolar disorders, major depression (Herken et al. 2007), Alzheimer’s disease, autism, alcohol and substance abuse-related disorders and cerebral ischemia. NO can interact with neuromodulators in order to modify them and thereby change their regulatory action on synaptic transmission. NO may also react with thiol groups of amino acids and proteins and form relatively stable nitroso-thiols. After interaction with heme-containing protein, such as cytochromes, NO may lead to impairment of oxidative phosphorylation. Peroxynitrite, a harmful compound for cellular structures produced by the reaction of NO with molecular oxygen, has been linked to several interactions which may contribute to cellular injury, including lipid peroxidation, nitrosylation of some molecules, inactivation of sodium channels and interactions with metals whic have redox potential such as iron and copper (Akyol et al. 2004). The importance of NO as an intermediary in cell communication in the brain is highlighted by the fact that the excitatory amino acid glutamate is an initiator of the reaction that forms NO. The generation of NO following NMDA or norepinephrine receptor activation seems to be important in the context of central nervous system pathologies. References [1] Akyol O, Zoroglu SS, Armutcu F, Sahin S, Gurel A, 2004, Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo 18, 377–390. [2] Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M, Kap O, Yumru M, Savas HA, Akyol O, 2007, Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Arch Med Res 38, 247–252. [3] Yilmaz N, Herken H, Cicek HK, Celik A, Yurekli M, Akyol O, 2007, Increased levels of nitric oxide, cortisol and adrenomedullin in patients with chronic schizophrenia. Med Princ Pract 16, 137–141.
S.09 Bipolar affective disorders: therapeutic options beyond current guidelines S.09.01 Bipolar disorder treatment guidelines: right answers to the wrong questions or vice versa? G. Goodwin ° . University of Oxford, Department of Psychiatry, Headington Oxford, United Kingdom Current guidelines specify the scope and target of treatment for bipolar disorder. They are usually based on the available evidence and presented as recommendations for practitioners. They may serve as a source of information for patients and carers. The main tension in all guidelines is between those that seek to give correct answers to general questions and those that seek to be more specific and prescriptive. The latter risk giving the wrong answers to the right questions, either by stepping beyond the evidence or having the evidence itself change rapidly. The difficulties can be illustrated by where guidelines generally agree – in the treatment of mania – and where they do not – in the treatment of bipolar depression. Methodology is also important. The basis for most recommendations is a consensus meeting: experts in bipolar disorder review key areas and consider the strength of evidence and clinical implications. The guidelines are usually drawn up after extensive feedback from interested parties. The split between the general and the specific may also occur in this synthesis. If one includes only what everyone fully agrees, the guideline will be shorter but less specific. If everyone’s view is included – a different kind of consensus – the result may be very strange. Finally, what sort of evidence?: it could be clinical science, patient opinion or economic imperative. Understanding these factors illuminates how we have developed the diagnosis of bipolar disorder, its clinical management, and strategies for the use of medicines in short term treatment of episodes, and relapse prevention. References [1] Goodwin GM, 2003, Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology. J Psychopharmacology 17, 149–173.
S.09.02 Lithium and traditional anticonvulsants: still useful? J. Rybakowski ° . University of Medical Sciences, Department of Adult Psychiatry, Poznan, Poland Lithium and traditional anticonvulsants (valproate and carbamazepine) can be named the first generation mood stabilizers, preceding the introduction of other substances showing mood stabilizing properties by more then two decades. Lithium, introduced for the treatment of mania in 1949 and for prophylaxis of affective recurrences in early 1960s, has still been regarded as a prototype of mood stabilizer, showing therapeutic and prophylactic action in both psychopathological poles of bipolar illness. The efficacy of lithium in prevention of affective recurrences has been observed in patients receiving this drug for more than 30 years. A subgroup of excellent lithium responders has been delineated as an endophenotype for molecular genetic studies of bipolar illness. Antisuicidal action of lithium demonstrated during longterm administration adds to its clinical usefulness. Antidepressant