Schizophrenia Etiology

1. Schizophrenia
Introduction & etiology

2. History
 Emil Kraepelin: This illness develops
relatively early in life, and its course is likely
deteriorating and chronic; deterioration
reminded dementia (Dementia praecox), but
was not followed by any organic changes of the
brain, detectable at that time.
 Eugen Bleuler: He renamed Kraepelin’s
praecox as schizophrenia (1911); he recognized
the cognitive impairment in this illness, which
he named as a “splitting” of mind.
 Kurt Schneider: He emphasized the role
psychotic symptoms, as hallucinations,
delusions and gave them the privilege of “the
first rank symptoms” even in the concept of the
diagnosis of schizophrenia.

3. Introduction
 Schizophrenia is a chronic, severe, and disabling brain disorder arising from
the adverse interaction of predisposing biological, psychological, social
factors and environmental factors.
 The psychopathology is characterized by a wide array of disturbing
cognitive, emotional, and behavioral symptoms that interfere with the
individual's capacity to function in society.

4. Aetiological factors and theories in
Schizophrenia
Category Genes Neurochemical Environment Social Structural Functional imaging Neurophysiology Psychological Hypothesis
Examples ZNF804A
Neureglin 1
Dopamine
Glutamate
Prenatal infections
Birth complications
Early cannabis use
Paternal age
Migration
Urban birth &
upbringing
Recent life events
Similar brain size
Reduced synaptic
markers
Hypofrontality Abnormal eye
tracking
Abnormal sensory
evoked potentials
Cognitive impairment
Personality factors
Theory of mind
Family dynamics &
communication
Neurodevelopmental
Aberrant connectivity
Stress vulnerability

5. The Biological Model

6. Genetics
 According to the genetic hypothesis, the more closely
related the family member to the schizophrenic, the
greater their chance of developing the disorder.
 80% of the risk of Schizophrenia is being inherited.
 Increased likelihood of disorder with closeness of
relationship status (1-degree or 2nd degree relative)
 It was also observed that there’s a higher rate of
schizophrenia & schizophrenia-related disorders
(Schizoid personality, paranoid personality etc)
amongst those with biological relations.

7. Genetic Studies
Mode of inheritance is complex or non-Mendelian
pattern.
Twin Studies
 Concordance rate amongst
MZ twins- 50%
DZ twins- 10%
 Adoption studies
 Circumstances varied- rate higher in biological adoptees than control group.

8. Schizophrenia susceptibility loci & genes:
Whole genome linkage
1q,2p,5q,6p,6q,8p,10p,11q,13q,15q,22q
Finer mapping
SNP association
dysbindin (6p) (seven)*
neuregulin (8p) (six)*
G72 (13q) (three)*
MRDS1 (6p) (four)*
Functional candidates
COMT (22q) (eight)*
GRM3 (7q) (four)*
GAD 1 (2q) (four)*
CNRNA7 (15q) (two)*
PPP3CC (8p) (two)*
Akt1 (two)
Chromosomal
translocation
DISC1 (1q)
(three)*
PRODH (22q) (two)
Expression profiling
RGS4 (1q) (four)*
* Number of positive samples
worldwide

9. Neurobiology
Structural changes
 Brain Imaging
 Decreased brain volume
 Enlarged Lateral ventricles
 Enlarged third ventricles
 Smaller medial temporal lobes
 Decreased cortical gray matter
 Altered gyrification

11. Neuropathology
 Decreased brain weight
 Absence of neurodegenerative changes and of gliosis
 Decreased synaptic markers
 Decreased oligodendroglia
 Decreased makers of some interneurons
 Smaller pyramidal neurons in some areas
 Fewer thalamic neurons

13. Functional Brain Imaging
 PET Scan, fMRIs, SPET have been used to assess patterns of brain activity in
Schizophrenia.
 Cerebral blood flow- Igvar & Franzen found decreased perfusion of the
frontal cortex compared with the posterior regions in chronic, medicated
schizophrenics.
 ‘hypofrontality’ feature has been considered to be a feature of
Schizophrenia.
 BOLD Signal on fMRI- Alterned Pre-frontal activity was noted.

15. Functional changes in brain
 Hypofrontality hypothesis
 Wisconsin card sorting task
 Schizophrenics can’t shift attention to other
criterion.
 Functional imaging: frontal lobe activity lower at
rest, esp. in right hemisphere, does not increase
during task.
 Drug treatment increased activation of frontal
lobes

17. Loss of gray matter in childhood
schizophrenia

18. Neurophysiological Findings
 EEG: Shows increased amounts of Theta activity, Fast activity & paroxysmal
activity. Also decreased synchronization of electrical activity in pre-frontal
cortex which suggests ‘noisy’ processing.
 Sensory Evoked Potentials: P300 & P50
 The response provides a measure of auditory information processing.
 Schizophrenics & a proportion of 1st degree relatives showed reduced
amplitude of P300 and abnormalities in P50 were studied.
 P50 deficits suggest underlying alterations in cholinergic neurotransmission.

19. Neurochemical Findings
 Dopamine Hypothesis
 Amphetamine usage induces similar features & worsen psychotic symptoms.
 All antipsychotic medications are dopamine-receptor antagonists and their activity at
D2 receptors is the property that correlates with their potency.
 Hyperdopaminergia in acute schizophrenia
 Exact cause unclear, possibly dysregulation secondary to glutamatargeric and
developmental abnormalities.

20. Dopamine Hypothesis

21. Neurochemical Findings
 Glutamate
 Krystal & Moghaddam (2011)- the key finding was that the antagonist of
the NMDA type of glutamate receptor antagonists (Phencyclidine and
Ketamine) can induce schizophrenia like psychosis.
 Origin unclear but suggested that there’s a developmental abnormality in
the receptor.

22. Neurochemical Findings
 GABA
 Major inhibitory transmitter and is implicated in Schizophrenia for several reasons.
 There is a decrease in it’s synthetic enzyme, glutamic acid decarboxylase (GAD) in the
cerebral cortex.
 The density of a particular GABA-ergic neuron type & their synaptic terminals are
reduced.
 There’s alterations in the expression of GABA receptors.

23. Neurochemical Findings
 Serotonin
 Role of Serotonin (5-HT) in schizophrenia suggestible from halluniogen,
lysergic acid diethylamide (LSD) is 5-HT agonist.
 5-HT-2 receptor antagonism may contribute to the atypical properties of
some antipsychotics and alterations in receptor densities.
 Possible involvement of interaction between Serotonin, Glutamate &
Dopamine.

24. The Psychological Model

25. Personality Factors
 Premorbid abnormal personality factors such as paranoid or schizotypal
likely to develop into schizophrenia and is found in their first degree
relatives.
 Many people have no obvious disorder of personality before the onset of
illness.

26. Neuropsychological factors
 It has been noted that schizophrenia patients have widespread cognitive
deficits, particularly in tasks requiring learning & memory.
 Gray et all (1991) proposed that the positive symptoms arise from failure to
integrate stored memories with current stimuli. Frith (1996) argued that there
is a breakdown in the internal representation of mental events.
 The concept of social cognition is impaired in schizophrenia. Abnormalities
of face recognition, and theory of mind result from involvement of neural
circuits implicating the frontal cortex and amygdala.

27. Dynamic & interpersonal factors
 Freud (1924):
 Believed schizophrenia was a result of TWO processes:
1) Regression to a pre-ego state
2) Attempts to re-establish ego control
- Parents being cold/uncaring
- Causing child to regress back into infantile state
- Where the ego is not yet properly formed
- Symptoms include: Delusions of grandeur (believing you can fly etc)
- But also, auditory hallucinations could be seen as an individual’s attempt to re-
establish ego control

28. Supporting Freud – Fromm-Reichmann (1948):
 Overprotective, rejecting, dominant, and moralistic mothers can contribute
to children developing schizophrenia
 Supports Freud in that the condition stems from childhood

29. The Social Model

30. Psychosocial factors
 Occupation and Social Class
 Residential place
 Migration and Ethnicity
 Social Isolation
 Life Events & difficulties
 Childhood Trauma

31. Environmental Risk factors
 Prenatal Infections
 Obstetric Complications
 Maternal Malnutrition
 Winter Birth
 Paternal Age
 Substance Use
 Child Development

32. Current Aetiological Hypotheses
 Neurodevelopmental hypothesis
 Aberrant connectivity
 Stress-vulnerability model

33. Thank You