Schizophrenia

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 dementia 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 of 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 2 nd 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

10. 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

11. Functional Brain Imaging PET Scan, fMRIs, SPET have been used to assess patterns of brain activity in Schizophrenia. Cerebral b lood 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.

12. 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

13. Loss of gray matter in childhood schizophrenia

14. 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 1 st degree relatives showed reduced amplitude of P300 and abnormalities in P50 were studied. P50 deficits suggest underlying alterations in cholinergic neurotransmission.

15. 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.

16. Dopamine Hypothesis

17. 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.

18. 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.

19. 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.

20. The Psychological Model

21. 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.

22. 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.

23. Dy namic & interpersonal factors Freud (1924 ): Believed schizophrenia was a result of TWO processes: Regression to a pre-ego state 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

24. 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

25. The Social Model

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

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

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

29. Thank You