- Email: [email protected]
S.08.05 Parkin: from genetics to physiopathology
S.09 Phenotypic heterogeneity of anxiety disorders
$328
~ T h e
rotenone model
R. Betarbet 1 *, J.T. Greenamyre 2. lEmo/y University, Center for Neurodegenerative Disease, Atlanta, USA," 2Emoty University, Center for Neurodegenerative Disease, Neurology, USA Parkinson's disease is a complex disorder, probably caused by a combination of environmental and genetic factors. Mitochondrial impairment (especially at complex I), oxidative stress, dysfunctional protein degradation and 0t-synuclein aggregation have each been implicated in Parkinson's disease pathogenesis, but how they are related to each other is unclear. Using both its vivo and its vitro models of chronic low-grade complex I inhibition with the pesticide rotenone we demonstrate that chronic rotenone exposure its vivo caused oxidative modification of D J-l, accumulation and aggregation of 0t-synuclein, and proteasomal impairment, all of which were selective for the ventral midbrain region. DJ-1 translocation, 0t-synuclein accumulation and proteasomal dysfunction were also seen in vitro and these effects could be prevented with 0t-tocopherol. Thus, chronic exposure to a pesticide and mitochondrial toxin brings into play three systems, DJ-1, 0t-synuclein, and the ubiquitin-proteasome system, which have been implicated in pathogenesis of genetic forms of the disease. Moreover, its vivo the effects become more regionally restricted such that systemic complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. It is suggested that mitochondrial dysfunction and oxidative stress link environmental and genetic forms of the disease and raises the possibility that antioxidants may have a broad applicability in the treatment of the disease.
•
Parkin: from genetics to physiopathology
A. Brice*. Hospital Piti~-Salpdtri~re, INSERM Unit 679, Paris
Cedex, France Parkin represents the first identified and the most frequent autosomal recessive form of parkinsonism. Although initially described in Japan, Parkin carriers are found worldwide. Over 100 different mutations have been described in this gene, which contains 12 coding exons, with a size of 2.35Mb. There are many different point mutations as well as rearrangements (deletions or multiplications), both of which must be taken into account in molecular testing. Parkin mutations are very frequent in patients with early onset parkinsonism (age at onset <45 years), accounting for approximately 50% of the familial forms and up to 15% of isolated cases. However, Parkin is much more rare in patients with late onset. The phenotype is that of typical dopa-responsive parkinsonism, often with dystonia at onset and very slow progression. Interestingly, in most pathological cases, there is severe neurodegeneration in the substantia nigra pars compacta and in the locus ceruleus, but without Lewy bodies. Parkin is an E3 ubiquitin-ligase involved in the ubiquitin proteasome pathway, which has many different substrates. It is thought that mutations leading to a loss of function result in the accumulation of Parkin substrates, leading to toxicity in dopaminergic neurons. The normal function of Parkin remains unknown. It has been shown, however, to be protective against various stresses in different cell compartments. Since mice in w h i c h the Parkin gene was invalidated have no overt degeneration in the substantia nigra, it is not yet known why loss of its function in humans results in neurodegeneration.
uniform treatments?
S.09 Phenotypic heterogeneity of anxiety disorders - uniform treatments? ~
Treatment of panic disorder with and without agoraphobia
D.S. Baldwin*. University of Southampton, Division of Clinical Neurosciences, Southampton, United Kingdom Systematic reviews demonstrate that a range of pharmacological, psychological and combination interventions are effective in acute treatment of panic disorder. Randomised double-blind placebo-controlled trials of antidepressants indicate that all SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline); some TCAs (clomipramine, imipramine); and some benzodiazepines (alprazolam, clonazepam, diazepam and lorazepam) are efficacious in acute treatment. Other antidepressants with proven efficacy include the MAOI brofaromine; the SNRI venlafaxine; and the selective noradrenaline reuptake inhibitor reboxetine. Comparator-controlled studies provide some evidence for efficacy of mirtazapine and moclobemide; suggest that escitalopram is superior to citalopram; and indicate some SSRIs (paroxetine, fluvoxamine) are superior to some noradrenaline reuptake inhibitors (reboxetine, maprotiline). Double-blind studies indicate that continuing SSRI treatment from 12 weeks to 52 weeks is associated with an increase in overall treatment response rates. Placebo-controlled and other relapse-prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (fluoxetine, paroxetine, sertraline, imipramine), compared to switching to placebo for up to six months. Overall, it is uncertain whether combining drug and psychological treatments is associated with greater overall efficacy than with either treatment, given alone. However combination treatment with paroxetine was superior to psychological treatment alone, in studies of bibliotherapy, 'very brief' CBT and basic CBT; and buspirone may enhance the short term efficacy of CBT.
References [1] Bandelow B, Zohar J, Hollander E, et al (2002). World Federation of Societies of Biological PsychiatL2¢(WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171 189. [2] National Institute for Clinical Excellence (2004). The management of panic disorder and generalised anxiety disorder in primaL2¢ and secondary care. National Collaborating Centre for Mental Health, London. December 2004.
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Social anxiety disorder: subtypes and spectrums
D.J. Stein*. University of Stellenbosch, Department of Psychiatty,
Cape Town, South Africa Social anxiety disorder (SAD) is uniformly characterized by fear of social or performance situations. However, SAD entail a good deal of phenomenological and psychobiological heterogeneity. This paper explores SAD subtypes and spectrums, with a focus on treatment implications. Current nomenclatures emphasize distinguish generalized and non-generalized SAD. Generalized SAD is more severe and disabling, and characterized by earlier onset, greater comorbidity, and increased heritability. Recent trials of antidepressants focus on generalized SAD; whether these agents
$328
~ T h e
rotenone model
R. Betarbet 1 *, J.T. Greenamyre 2. lEmo/y University, Center for Neurodegenerative Disease, Atlanta, USA," 2Emoty University, Center for Neurodegenerative Disease, Neurology, USA Parkinson's disease is a complex disorder, probably caused by a combination of environmental and genetic factors. Mitochondrial impairment (especially at complex I), oxidative stress, dysfunctional protein degradation and 0t-synuclein aggregation have each been implicated in Parkinson's disease pathogenesis, but how they are related to each other is unclear. Using both its vivo and its vitro models of chronic low-grade complex I inhibition with the pesticide rotenone we demonstrate that chronic rotenone exposure its vivo caused oxidative modification of D J-l, accumulation and aggregation of 0t-synuclein, and proteasomal impairment, all of which were selective for the ventral midbrain region. DJ-1 translocation, 0t-synuclein accumulation and proteasomal dysfunction were also seen in vitro and these effects could be prevented with 0t-tocopherol. Thus, chronic exposure to a pesticide and mitochondrial toxin brings into play three systems, DJ-1, 0t-synuclein, and the ubiquitin-proteasome system, which have been implicated in pathogenesis of genetic forms of the disease. Moreover, its vivo the effects become more regionally restricted such that systemic complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. It is suggested that mitochondrial dysfunction and oxidative stress link environmental and genetic forms of the disease and raises the possibility that antioxidants may have a broad applicability in the treatment of the disease.
•
Parkin: from genetics to physiopathology
A. Brice*. Hospital Piti~-Salpdtri~re, INSERM Unit 679, Paris
Cedex, France Parkin represents the first identified and the most frequent autosomal recessive form of parkinsonism. Although initially described in Japan, Parkin carriers are found worldwide. Over 100 different mutations have been described in this gene, which contains 12 coding exons, with a size of 2.35Mb. There are many different point mutations as well as rearrangements (deletions or multiplications), both of which must be taken into account in molecular testing. Parkin mutations are very frequent in patients with early onset parkinsonism (age at onset <45 years), accounting for approximately 50% of the familial forms and up to 15% of isolated cases. However, Parkin is much more rare in patients with late onset. The phenotype is that of typical dopa-responsive parkinsonism, often with dystonia at onset and very slow progression. Interestingly, in most pathological cases, there is severe neurodegeneration in the substantia nigra pars compacta and in the locus ceruleus, but without Lewy bodies. Parkin is an E3 ubiquitin-ligase involved in the ubiquitin proteasome pathway, which has many different substrates. It is thought that mutations leading to a loss of function result in the accumulation of Parkin substrates, leading to toxicity in dopaminergic neurons. The normal function of Parkin remains unknown. It has been shown, however, to be protective against various stresses in different cell compartments. Since mice in w h i c h the Parkin gene was invalidated have no overt degeneration in the substantia nigra, it is not yet known why loss of its function in humans results in neurodegeneration.
uniform treatments?
S.09 Phenotypic heterogeneity of anxiety disorders - uniform treatments? ~
Treatment of panic disorder with and without agoraphobia
D.S. Baldwin*. University of Southampton, Division of Clinical Neurosciences, Southampton, United Kingdom Systematic reviews demonstrate that a range of pharmacological, psychological and combination interventions are effective in acute treatment of panic disorder. Randomised double-blind placebo-controlled trials of antidepressants indicate that all SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline); some TCAs (clomipramine, imipramine); and some benzodiazepines (alprazolam, clonazepam, diazepam and lorazepam) are efficacious in acute treatment. Other antidepressants with proven efficacy include the MAOI brofaromine; the SNRI venlafaxine; and the selective noradrenaline reuptake inhibitor reboxetine. Comparator-controlled studies provide some evidence for efficacy of mirtazapine and moclobemide; suggest that escitalopram is superior to citalopram; and indicate some SSRIs (paroxetine, fluvoxamine) are superior to some noradrenaline reuptake inhibitors (reboxetine, maprotiline). Double-blind studies indicate that continuing SSRI treatment from 12 weeks to 52 weeks is associated with an increase in overall treatment response rates. Placebo-controlled and other relapse-prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (fluoxetine, paroxetine, sertraline, imipramine), compared to switching to placebo for up to six months. Overall, it is uncertain whether combining drug and psychological treatments is associated with greater overall efficacy than with either treatment, given alone. However combination treatment with paroxetine was superior to psychological treatment alone, in studies of bibliotherapy, 'very brief' CBT and basic CBT; and buspirone may enhance the short term efficacy of CBT.
References [1] Bandelow B, Zohar J, Hollander E, et al (2002). World Federation of Societies of Biological PsychiatL2¢(WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171 189. [2] National Institute for Clinical Excellence (2004). The management of panic disorder and generalised anxiety disorder in primaL2¢ and secondary care. National Collaborating Centre for Mental Health, London. December 2004.
•
Social anxiety disorder: subtypes and spectrums
D.J. Stein*. University of Stellenbosch, Department of Psychiatty,
Cape Town, South Africa Social anxiety disorder (SAD) is uniformly characterized by fear of social or performance situations. However, SAD entail a good deal of phenomenological and psychobiological heterogeneity. This paper explores SAD subtypes and spectrums, with a focus on treatment implications. Current nomenclatures emphasize distinguish generalized and non-generalized SAD. Generalized SAD is more severe and disabling, and characterized by earlier onset, greater comorbidity, and increased heritability. Recent trials of antidepressants focus on generalized SAD; whether these agents