Psychotic disorders neurobiology

Jiří Horáček

Psychiatrické centrum Praha3. 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) delusions3) both

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”

Subdivision of Symptoms into Three Dimensions

• PsychoticDelusionsHallucinations

• DisorganizedDisorganized speechDisorganized behaviorInappropriate affect

• NegativePoverty of speechAvolitionAffective BluntingAnhedonia

Positive

Social withdrawal

The Importance of Negative Symptoms

• 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)

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:

Neuropathologyand structural imaging

“Schizophrenia is the graveyard of

neuropathology”

Comment by neurologist Fred Plum at an International Congress

of Neuropathology

Twin Studies

Our sample

Španie

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k, e

t al. 2

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2

MR Images of Brain, Ventricles, and Hippocampus

Schizophrenia

Control

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

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

Thompson, 2008

But neurodegeneration, as well

Sporn, 2003

Functional neuroinaging

Ingvar and Lassen

Normals

Patients (Hypofrontality)

Weinberger and Berman

Normals

Patients

Number WCS

Frontal Functions• Fluency of thought and speech• Emotional attachments• Social and moral judgment• Volition and drive• Planning and identifying goals• Formulating abstract concepts

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

Copyright © 2004 Allyn and Bacon

PFC

Amygdala

ACC

Hippocampus

18FDG PET: schizofrenie (N=48) vs. zdravé kontroly (N=17)

(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

22 qDS22 qDS AmfetaminObstetric compl.

AmfetaminObstetric compl.

CombinationCombination

Genes Environment

Etiology of schizophrenia

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.

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

Copyright © 2004 Allyn and Bacon

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

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 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.

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 + environment morphological damage

risk of SCH

?

Cytokines: proteins involved in regulation of

immunologic and inflammatory responses

Kuncová, Horáček, 2009

Neurotransmitters

Drugs That May Induce Psychosis

• 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

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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

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.

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 )

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

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