psychotic disorders neurobiology jiří horáček psychiatrické centrum praha 3. lf uk praha...
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Psychotic disorders neurobiology
Jiří Horáček
Psychiatrické centrum Praha3. LF UK Praha
Centrum neuropsychiatrických studií
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What is psychosis?
Psychosis - a mental state involving a "loss of contact with reality".
Psychosis is given to the more severe forms of psychiatric disorder with:
1) hallucinations 2) delusions3) both
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The Tragedy of Schizophrenia
• A catastrophic illness
• Tends to persist chronically
• 10% suicide rate
• Very common -- 0.5-1% of population
• The “cancer of mental illness”
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Subdivision of Symptoms into Three Dimensions
• PsychoticDelusionsHallucinations
• DisorganizedDisorganized speechDisorganized behaviorInappropriate affect
• NegativePoverty of speechAvolitionAffective BluntingAnhedonia
Positive
Social withdrawal
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The Importance of Negative Symptoms
• Impair ability to function in daily life• Holding a job• Attending school• Forming friendships• Having intimate family relationships
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Schizofrenia: course
Attack (positive symptoms)
Defect (negative symptoms)
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Environmental StressBiological FactorsDrug Use
StructureBiochemFunction
Neurol +CognitiveDeficits
EarlyNegativeSymptoms
WeakPositiveSymptoms
EmergingPsychoticSymptoms
B i o l o g i c a l V u l n e r a b i l i t y
Age5 12 15 180 21
Premorbid EarlyProdrome
LateProdrome
Disease GenesViral InfectionEnvironmental Toxins
Peri-natal/BirthComplications
TRIGGERS:
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Neuropathologyand structural imaging
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“Schizophrenia is the graveyard of
neuropathology”
Comment by neurologist Fred Plum at an International Congress
of Neuropathology
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Twin Studies
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Our sample
Španie
l, H
áje
k, e
t al. 2
00
2
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MR Images of Brain, Ventricles, and Hippocampus
Schizophrenia
Control
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VBM (voxel-based morphometry)
52 = SCH, 44 = Controls:
Optimized VBM: 1.5 3T Siemens, MP-RAGE, 1 mm isovoxels, SPM5, modulated, normalized 10 mm, p < 0.001 FDR (false discovery rate correction)
Horáček, Španiel, 2007.
Decrease GM in SCH
increase GM in SCH
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Brain Regions Showing Replicable
Neuropathological Abnormalities
• Temporolimbic regions
• Thalamus
• Prefrontal cortex
the brains of schizophrenics are 6 % lighter and 4 % smaller than normal controls
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Neuropil in Frontal Cortex
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Schizophrenia
Glantz 2006
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Neurodevelopmental or neurodegenerative??
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A Neurodevelopmental Disorder: Supporting Evidence from
Neuropathology• Absence of gliosis
• Abnormal cytoarchitecture
• Visible markers of neurodevelopmental abnormalities such as cavum septi pellucidi
• Most brain abnormalities are present at onset: e.g., decrease in total brain tissue
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Thompson, 2008
But neurodegeneration, as well
Sporn, 2003
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Functional neuroinaging
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Ingvar and Lassen
Normals
Patients (Hypofrontality)
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Weinberger and Berman
Normals
Patients
Number WCS
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Frontal Functions• Fluency of thought and speech• Emotional attachments• Social and moral judgment• Volition and drive• Planning and identifying goals• Formulating abstract concepts
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Hypermetabolismus v mediotemporálním ctx
Evidence for neurological abnormalities in schizophrenia
Schizophrenics with negative symptoms have similar symptoms as those with frontal lobe damage.
• Frontal lobe size• Ventricle size • Cerebral gray matter decreases
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Copyright © 2004 Allyn and Bacon
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PFC
Amygdala
ACC
Hippocampus
18FDG PET: schizofrenie (N=48) vs. zdravé kontroly (N=17)
(Horáček, Kopeček, PCP, CNS,2002)
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18FDG PET: schizofrenie (N=48) vs. zdravé kontroly (N=17)
p=0.05 s Bohnferonniho korekcí
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Genetics
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Family History and Family Studies
• Provide evidence for a modest level of familial transmission
• Morbid risk for parents: 5.6%
• Morbid risk for siblings: 10.1%
• Morbid risk for offspring: 12.8%
• Second degree relatives: 2.4-4.2%
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Dissecting Genetic Vs Environmental Effects
• Identical twins have identical DNA, while dizygotic twins share 50% of their DNA
• Monozygotic twins should be identical
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22 qDS22 qDS AmfetaminObstetric compl.
AmfetaminObstetric compl.
CombinationCombination
Genes Environment
Etiology of schizophrenia
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Nongenetic Factors
Birth Injuries
Viral Infections
Nutrition
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Nutritional Factors
• Studies of children born to pregnant mothers who survived the “Dutch Hunger Winter” of World War II
• Offspring have an increased risk for schizophrenia
• Implicates nutrition as another potential contributor to the pathophysiology of schizophrenia
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Biological factors- NEUROLOGICAL
•The cause of such brain damage could be a viral disease although there is no direct evidence for this. Alternatively, it could be caused by obstetrical problems.
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Why is the immunity response altered in schizophrenia?
Introduction
Immunology of SCH
Which infections?
Toxoplasma gondii and gray matter
How T. gondii affects brain?
Conclusions and implications
Infection:
1) maternal
2) postnatal
Illness OR (RR) Attributable proportion
Influenza 3,0 14%
Gynecol.(pregnancy)* 5,0 6%
*endometritis, cervicitis, pelvic infection, HSV 2 (OR=3), vaginitis, syphilis, condylomata,
gonorrhea….
(Brown, 2010)
1957 pandemic of A2 influenza (Mednick 1988, O’Callaghan, 1991)
Uusimaa
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Copyright © 2004 Allyn and Bacon
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Why is the immunity response altered in schizophrenia?
Introduction
Immunology of SCH
Which infections?
Toxoplasma gondii and gray matter
How T. gondii affects brain?
Conclusions and implications
Infection:
1) maternal
2) postnatal
Toxopasma gondii
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The regional gray matter volume reduction in schizophrenia for the whole sample, T. gondii positive and T. gondii negative subjects. Significant results (p ≤ 0.05, FWE, cluster 50 voxels) are displayed on study specific 3D template and mean image slices. Legend: L or R, left or right hemisphere; sch or con, schizophrenia or control subjects, the bar in the lower left corner represents T value for slices.
Horacek et al., WJBP, 2011.
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Social factors
– Labelling theory
Individuals are labelled as having schizophrenia and then fulfil the role.
Without the diagnoses, the inappropriate behaviour would be more likely to have been temporary.
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Social factors
• The effect of social classGeneral life stresses might cause schizophrenia
Sociogenic hypothesis – stress from a low level of education, with poor rewards and opportunities, can lead to schizophrenia.
Social selection theory – suggest its not class that cause schizophrenia but those with the illness drift downwards in terms of social class.
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Psychological factors
• The schizophrenogenic mother –the double-bind theory
Schizophrenic son could result from an overprotective, rigid, rejecting mother who gives out 2 messages when making a statement.
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Gene-environment interaction model
genetic vulnerability + environment morphological damage
risk of SCH
?
Cytokines: proteins involved in regulation of
immunologic and inflammatory responses
Kuncová, Horáček, 2009
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Neurotransmitters
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Drugs That May Induce Psychosis
• Amphetamines
• Marijuana
• Hallucinogens
• Cocaine
• NMDA antagonists
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Schizophrenia integration
– Hypofrontality (caused by a reduction in cell volume in the dorsolateral frontal cortices) is associated with negative symptoms of schizophrenia.
– Hypofrontality also results in an increase in dopamine activity in the mesolimbic system which is associated with positive symptoms.
– Dopamine hypothesis suggests that hypofrontality results in a disruption of normal glutamate activity from the frontal cortex to the mesolimbic system.
– NMDA agonists cannot be used because they would cause seizures, but glycine may be effective in treating schizophrenics since it is also an NMDA agonist. Several studies have shown good results with negative symptoms
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Dopamine Theory: the golden triad
1. Drugs that increase dopamine, such as amphetamine and cocaine, can cause psychosis.
2. Antidopaminergic drugs can improve psychosis.
3. Identified mechanism: overactivity in the mesolimbic dopamine pathway could be the mediator of positive symptoms of schizophrenia such as delusions and
hallucinations.
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Dopamine Theory: problems• It explains only part of schizophrenia
(positive symptoms not negative symptoms)
• Anti-dopamenergic drugs usually – make negative symptoms worse in patients– induce negative symptoms in healthy people.
• Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better anti-schizophrenic drugs.
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Dopamine Theory: problems• Under activity in the meso-cortical
dopamine pathway is hypothesized to be the mediator of negative symptoms of schizophrenia: this indicates that reduced dopamine activity is the problem rather than dopamine overactivity.
• DA theory is a “psychosis theory” more than it is a “schizophrenia theory”.
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Key DA Pathways
(a) The nigrostriatal pathway. (b) The mesolimbic pathway. (c) The mesocortical pathway (dorsolateral prefrontal cortex & ventromedial cortex). (d) The tuberoinfundibular pathway. (e) The thalamic DA pathway
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The DA Hypothesis of Schizophrenia: Positive Symptoms
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The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms
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Glutamate Hypofunctioning Theory: golden triad
1. Antiglutamatergic drugs e.g. PCP and Ketamine > NMDA receptors hypofunctional >
• positive symptoms such as delusions and hallucinations
• Affective, negative and cognitive symptoms • Physiological symptoms of schizophrenia
2. Glutamate linked drugs seems, so far, to improve both positive and negative symptoms of schizophrenia
3. Neurophysiological studies also suggest that hypofunction of NMDA receptors could better explain the negative, cognitive and affective symptoms of schizophrenia.
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Glutamatergic teory of schizofrenia
GABA
NMDA/GlyB
Glut
GABA
GABA
NMDA/GlyB GABA
PFC STR Thalamus
Glut
GABA
Glut
Psychosis
Psychosis
Cortex
Glut
GABA
GABA
Non-NMDA
VTA/PC-SN
GABA
NMDA/GlyB
DAGlut
GABA
PFC D2/D3
NACC, STR
(Millan, 2005, Konradi 2003 )
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The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of Schizophrenia:
The excessive pruning theory
More than 40% loss SCH
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The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of Schizophrenia:
Neurotoxicity and the excessive apoptosis theory
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Environmental StressBiological FactorsDrug Use
StructureBiochemFunction
Neurol +CognitiveDeficits
EarlyNegativeSymptoms
WeakPositiveSymptoms
EmergingPsychoticSymptoms
B i o l o g i c a l V u l n e r a b i l i t y
Age5 12 15 180 21
Premorbid EarlyProdrome
LateProdrome
Disease GenesViral InfectionEnvironmental Toxins
Peri-natal/BirthComplications
TRIGGERS:
Conclusions