1. The cause of psychosis
Kwame McKenzie MD

2. Searching for answers for my
patients
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3. I wanted to know
 What is the cause of psychosis?
 Eventual aim to prevent it.
+

4. What does the webb say?
 Website of Canada’s largest mental health
research institution is enigmatic…
 “No single cause has been found for
schizophrenia, although there is a clear genetic
link. Research has given us clues in the search
for better ways to diagnose and treat the illness.”
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5. Two camps
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 Biological Social
 Professional view Community

6. Biological camp
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7. Genetics – highly heritable
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8. Genetics
 Multiple genes may
be involved
 These may be
inherited or sporadic
genetic changes
 Strongest evidence
for two genes
 dysbindin and
+ neuregulin

9. Obstetrics
 Obstetric problems
common
 Non specific risk factor
with small impact on
schizophrenia risk
 Hypoxia before or
during birth may impact
on brain development
increasing risk of later
schizophrenia
+

10. Obstetrics
+
Winter and spring births more likely to develop schizophrenia
 could be due to viral infection or vitamin D

11. Infections
+ Reports vary some show link between foetal exposure to flu and later risk of
schizophrenia others do not
 Other maternal infections have been studied but the results are not conclusive

12. Changes in structure
 Biological insult to the
developing brain leads
to problems later on.
 Decrease in grey matter,
enlargement of
ventricles, focal
alteration of white matter
+

13. Changes in function
 Problems in dopaminergic pathways in the
limbic system and parts of the pre-frontal
cortex but other pathways and
neurotransmitters are involved
 In acute psychosis increase in dopamine
synthesis, dopamine release, and synaptic
dopamine concentrations
+  Diminished brain response to new stimuli and
decreased ability to suppress brain activation
in response to repeated stimuli

14. Social camp
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15. Childhood
 A number of social factors increase the risk of developing
schizophrenia:
 Separation from parents for more than a year in childhood
 Social adversity in childhood (more adversity more risk)
+  Psychological trauma / Bullying
 Being born and brought up in a city

16. Stress
 Increased rates of schizophrenia if you:
 live in neighborhoods that are stressful
 have numerous daily hassles
+

17. Urban environment and mental illness
 Increased rates not due to drift
alone
 Being born and brought up in a city
are risk factors.
 The risk increases as the size of
the city increases.
 Longer you live in a city when you
are young, the higher your risk for
developing psychosis
+
 (Boydell and McKenzie, 2008).
17

18. Stress of Migration increases risk of
schizophrenia. Cantor Graae and Selten
2005
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19. Racism psychosis risk factor
for psychosis
Estimated prevalence of psychosis
All Ethnic Minority Groups
4.0%
3.0%
2.0%
+ 1.0%
0.0%
No Verbal Physical* No Some Most*
only*
Racial harassment British employers discriminate
 Karlsenn et al Psychological Medicine 2005 Sept 29-1-9

20. Social model
 Schizophrenia is the result of trauma and stress which
impact on the child or adult and lead to a breakdown
 The more social stress, the higher the risk of psychosis
 Mechanisms are psychological model put forward by
 Adverse experiences increase the likelihood of negative
self-esteem and induce an externalizing attributional style.
In concert with difficulties in theory of mind lead to
tendency to anticipate social encounters as a threat and
+ prevent reality testing

21. 50:50
+

22. Half full or half empty?
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23. Trade-offs are opportunities
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24. Models of causation
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25. Miasma theories
 Prior to modern medicine disease attributed to
spiritual or mechanical causes.
elements
humours
miasma – bad air arising out of dirt and decaying
organic matter
+

26. sanitising slums
 Early public health built on what came before –
miasma and humours etc
 Risk place based not due to individuals.
+

27. Germ theory
 Undermined by
 Cartesian revolution – mind and body dichotomy
 Discovery of bugs which cause disease. Germ theory
 Germ theory mono-causal approach
 Cause investigation moved from the community to
the laboratory
+

28. Epidemiological triangle
 Mono-causal germ theory has problems
Exposure does not always lead to illness
Generally exposure necessary but not sufficient
 Epidemiological triangle approach
Disease a product of an interaction between an agent, the
host and the environment.
Host & environment determine exposure and or
susceptibility
+

29. Web of causation
 Epidemiological triangle useful for infectious
disease
 Problematic for chronic illnesses or degenerative
illnesses,
 No specific agent or exposure but a web of
causation.
+  Complex interactions of many factors which form
interlocking chains of events.

30. Multi-level causation
 Susser & Susser – public health and psychiatrist
come together
 Chinese box / Russian dolls model of causation:
inter-connected but separate levels of causation
and investigation
+

31. Multilevel causation of psychosis
Environmental
Interpersonal
Individual
+ Genetic
molecular
31

32. Russian dolls
 molecular level
 metabolic patho-physiology
 individual level
 group level
 societal
+

33. 4 D model
 Risk factors act at different levels
 Individual – eg bullying
 Ecological – eg Urban upbringing
 Interaction …
+  Time – eg sensitive periods for cannabis use

34. Causation models build on each
other and are not in competition.
Trade-offs are a chance to think
in a different way.
+

35. The interest is in the
interactions
+

36. Urban environment and mental illness
 Urban environment changes the
exposure to risk factors
 Malnutrition and infection during pregnancy
 Drug use
 Life events and chronic daily hassles
 Social isolation
 And changes the action of risk factors
+
 Clustering of individuals with schizophrenia in deprived
areas occurs only in urban environments
 Genetic vulnerability amplified
36

37. Urban environment
 Impact on schizophrenia risk
dependent on genetic risk
 No genetic risk no increased risk of
urban environment
 Impact growing
+

38. Incidence of psychosis by ethnicity and
social cohesion
Predicted incidence rate (per 100,000
80
70
60
person-years)
50
40 White
BME
30
20
+ 10
0
Low Medium High
Social cohesion and trust (ward-level)
38

39. +

40. Social and biological are not
two solitudes
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41. A new science
 Mind not the Brain
 Epi-genetics not genetics
 Social impacts on biological mechanisms
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42. How does all this cause mental illness
 Mental illness lies in the mechanisms we use to
adapt
 Biology and psychology that adapts to the
environment
 They are problems of adaptation and
acceptance of different types of adaptation
 Both lead to changes in behavior and thoughts
Our biology and psychology are linked
+


43. Development of brain depends on
environment
 Development of brain and mind depend on
environmental stimulation
 Normal development of neuronal connectivity
depends on impacts of environment during
sensitive periods of development
+

44. Environment changes molecular function
 Epi-genetics refers to the reversible regulation
of various genomic functions, occurring
independently of DNA sequence,
 Mediated through changes in DNA methylation
and chromatin structure.
 Epigenetic mechanisms help us develop and
regulate gene function and mediate
+ environmental effects on genes
 Other candidates – neurogenesis and
inflammation

45. Early neglect has a longer-term
trajectory
 Early neglect and other environmental insults that
impact on stress signaling.
 This causes impaired neuronal responsiveness
and symptoms of pre-frontal cortical dysfunction.
+
Impaired pre-frontal cortex functioning observed in
schizophrenia.

46. Trajectory then medicated by social
world
 Sensitive periods reflect the chronology of
development of psychological processes in
children
 Psychotic symptoms in adolescence transient and
sub-clinical
 But repeated exposure to environmental risk
factors may cause persistent and more severe
+ symptoms

47. Vicious cycle can develop
 Likelihood and severity of symptoms also reflect
sensitization
 Early life adversity makes you more sensitive to
stress and more likely to produce sub-clinical
psychotic symptoms
 Early life adversity or psycho-stimulant use leads to
altered dopamine transmission and sensitization of
+ mesolimbic system neurons linked to development
of psychotic symptoms

48. van Os and Kapur Lancet
2009
 A mixture of dopamine dysregulation and
aberrant assignment of salience to stimuli,
together with a cognitive schema that attempts
to grapple with these experiences to give them
meaning, might lead to the development of
psychotic symptoms.
 Alterations in affective state (depression or
mania) and some ways of thinking, such as a
+ tendency to jump to conclusions, might combine
with the dopamine dysfunction to increase the
risk of delusion formation

49. Searching for answers for my patients
 Causes of psychosis are multi-level
 Problems is mind not the brain
 Social and biological working together
is the way forward
 Where there is a difference between
two group there is a chance for new
+ knowledge
 This new knowledge brings the
possibility of prevention

50. Thank you
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