Psychotic disorders
neurobiology
Jiří Horáček
Psychiatrické centrum Praha
3. LF UK Praha
Centrum neuropsychiatrických studií
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) delusions
3) both
The Tragedy of Schizophrenia
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A catastrophic illness
Tends to persist chronically
10% suicide rate
Very common -- 0.5-1% of population
The “cancer of mental illness”
Subdivision of Symptoms into
Three Dimensions
• Psychotic
Positive
Delusions
Hallucinations
• Disorganized
Disorganized speech
Disorganized behavior
Inappropriate affect
• Negative
Poverty of speech
Avolition
Affective Blunting
Anhedonia
Social
withdrawal
The Importance of
Negative Symptoms
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Impair ability to function in daily life
Holding a job
Attending school
Forming friendships
Having intimate family relationships
Schizofrenia: course
Attack
(positive symptoms)
Defect
(negative symptoms)
Disease Genes
Viral Infection
Environmental Toxins
Peri-natal/Birth
Complications
TRIGGERS: Environmental Stress
Biological Factors
Drug Use
Biological Vulnerability
Structure
Biochem
Function
Age
0
Neurol +
Cognitive
Deficits
5
Premorbid
Early
Negative
Symptoms
Weak
Positive
Symptoms
12
15
Early
Prodrome
Emerging
Psychotic
Symptoms
18
Late
Prodrome
21
Neuropathology
and structural imaging
“Schizophrenia is the
graveyard of
neuropathology”
Comment by neurologist Fred
Plum at an International Congress
of Neuropathology
Twin Studies
Španiel, Hájek, et al. 2002
Our sample
MR Images of Brain, Ventricles,
and Hippocampus
Control
Schizophrenia
VBM (voxel-based morphometry)
Decrease
GM in SCH
increase
GM in
SCH
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.
Brain Regions Showing Replicable
Neuropathological Abnormalities
• Temporolimbic regions
• Thalamus
• Prefrontal cortex
the brains of schizophrenics are 6 % lighter and 4 %
smaller than normal controls
Neuropil in Frontal Cortex
Schizophrenia
Glantz 2006
Neurodevelopmental or
neurodegenerative??
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
But neurodegeneration, as well
Sporn,
2003
Thompson, 2008
Functional neuroinaging
Ingvar and Lassen
Normals
Patients
(Hypofrontality)
Weinberger and Berman
Normals
Patients
Number
WCS
Frontal Functions
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Fluency of thought and speech
Emotional attachments
Social and moral judgment
Volition and drive
Planning and identifying goals
Formulating abstract concepts
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
Hypermetabolismus v
mediotemporálním ctx
Copyright © 2004 Allyn and Bacon
PFC
ACC
18FDG
Amygdala
PET: schizofrenie (N=48) vs. zdravé kontroly (N=17)
Hippocampus
(Horáček, Kopeček, PCP, CNS,2002)
18FDG
PET: schizofrenie (N=48) vs. zdravé kontroly (N=17)
p=0.05 s Bohnferonniho korekcí
Genetics
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%
Dissecting Genetic Vs
Environmental Effects
• Identical twins have identical DNA, while
dizygotic twins share 50% of their DNA
• Monozygotic twins should be identical
Etiology of schizophrenia
Amfetamin
Obstetric compl.
22 qDS
Combination
Genes
Environment
Nongenetic
Factors
Birth Injuries
Viral Infections
Nutrition
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
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.
Introduction
Why is the immunity response
altered in schizophrenia?
Immunology of SCH
Infection:
1957 pandemic of
A2 influenza
1) maternal
(Mednick 1988,
O’Callaghan, 1991)
Which infections?
2) postnatal
Toxoplasma gondii and
gray matter
Uusimaa
Illness
OR (RR)
Influenza
3,0
Gynecol.(pregnancy)* 5,0
Attributable How
proportion
T. gondii affects
brain?
14%
6%
*endometritis, cervicitis, pelvic infection, HSV 2 (OR=3), vaginitis, syphilis, condylomata,
gonorrhea….
(Brown, 2010)
Conclusions and
implications
Copyright © 2004 Allyn and Bacon
Why is the immunity response
altered in schizophrenia?
Introduction
Immunology of SCH
Infection:
Which infections?
1) maternal
2) postnatal
Toxoplasma gondii and
gray matter
How T. gondii affects
brain?
Toxopasma
gondii
Conclusions and
implications
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.
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.
Social factors
• The effect of social class
General 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.
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.
Gene-environment interaction model
genetic vulnerability
 morphological
+ environment  damage
?
  risk of SCH
Cytokines:
proteins involved in regulation of
immunologic and inflammatory
responses
Kuncová, Horáček, 2009
Neurotransmitters
Drugs That May Induce
Psychosis
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Amphetamines
Marijuana
Hallucinogens
Cocaine
NMDA antagonists
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
1.
Dopamine
Theory:
the
golden
triad
Drugs that increase dopamine, such as amphetamine
2.
3.
and cocaine, can cause psychosis.
Antidopaminergic drugs can improve psychosis.
Identified mechanism: overactivity in the mesolimbic
dopamine pathway could be the mediator of positive
symptoms of schizophrenia such as delusions and
hallucinations.
47
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.
01.07.2010
49
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”.
01.07.2010
50
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
01.07.2010
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The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms
01.07.2010
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Glutamate Hypofunctioning Theory:
golden triad
1. Antiglutamatergic drugs e.g. PCP and
Ketamine > NMDA receptors hypofunctional >
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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.
Glutamatergic teory of schizofrenia
GABA
Glut
NMDA/GlyB
GABA
GABA
Psychosis
Glut
Cortex
GABA
Glut
PFC
GABA
Glut
NMDA/GlyB
GABA
GABA
Glut
Thalamus
STR
NMDA/GlyB
GABA
PFC
GABA
DA
D2/D3
Non-NMDA
NACC, STR
VTA/PC-SN
Psychosis
(Millan, 2005, Konradi 2003 )
The Glutamate Excitotoxicity as part of the
Neurodevelopmental Theory of Schizophrenia:
The excessive pruning theory
More than 40% loss  SCH
The Glutamate Excitotoxicity as part of the
Neurodedegenarative Model of Schizophrenia:
Neurotoxicity and the excessive apoptosis theory
Conclusions
Disease Genes
Viral Infection
Environmental Toxins
Peri-natal/Birth
Complications
TRIGGERS: Environmental Stress
Biological Factors
Drug Use
Biological Vulnerability
Structure
Biochem
Function
Age
0
Neurol +
Cognitive
Deficits
5
Premorbid
Early
Negative
Symptoms
Weak
Positive
Symptoms
12
15
Early
Prodrome
Emerging
Psychotic
Symptoms
18
Late
Prodrome
21