Schizophrenia Introduction & etiology

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’spraecox 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.

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.

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

The Biological Model

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.

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.

Schizophrenia susceptibility loci & genes:

Whole genome linkage1q,2p,5q,6p,6q,8p,10p,11q,13q,15q,22q

Finer mapping

SNP associationdysbindin (6p) (seven)*

neuregulin (8p) (six)*

G72 (13q) (three)*

MRDS1 (6p) (four)*

Functional candidatesCOMT (22q) (eight)*

GRM3 (7q) (four)*

GAD 1 (2q) (four)*

CNRNA7 (15q) (two)*

PPP3CC (8p) (two)*

Akt1 (two)

Chromosomal translocationDISC1 (1q)

(three)*

PRODH (22q) (two)

Expression profiling

RGS4 (1q) (four)*

* Number of positive samples worldwide

Neurobiology

Structural changes Brain Imaging

Decreased brain volume

Enlarged Lateral ventricles

Enlarged third ventricles

Smaller medial temporal lobes

Decreased cortical gray matter

Altered gyrification

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

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.

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

Loss of gray matter in childhood schizophrenia

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.

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.

Dopamine Hypothesis

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.

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.

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.

The Psychological Model

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.

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.

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

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

The Social Model

Psychosocial factors

Occupation and Social Class

Residential place

Migration and Ethnicity

Social Isolation

Life Events & difficulties

Childhood Trauma

Environmental Risk factors

Prenatal Infections

Obstetric Complications

Maternal Malnutrition

Winter Birth

Paternal Age

Substance Use

Child Development

Current Aetiological Hypotheses

Neurodevelopmental hypothesis

Aberrant connectivity

Stress-vulnerability model

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