Schizophrenia:
Epidemiology and Aetiological theories
MRCPSYCH LEP MODULE: PSYCHOSIS -1
Contents
o Epidemiology
o Methodological problems
o Epidemiological statistics
o Aetiological theories
o Current hypotheses
o Genetics
o References & Further reading
Epidemiology – methodological problems
o 1st: Lack of diagnostic uniformity.
o Improved with the advent on DSM-IV & ICD-10 combined with standardised interview e.g.
Present State Examination (PSE), etc.
o Good reliability but issues with validity.
o 2nd: Case finding
o Most common- clinical case detection from hospital admission data, population surveys and
follow-up studies of birth cohorts
o Various biases, pros and cons of each method
Epidemiology
o Schizophrenia is a disorder with a low incidence but a relatively high prevalence. It is fairly evenly
distributed around the globe.
o Annual incidence – between 0.17 and 0.54 / 100 population {using broad definition}
- 2 to 3 times lower using DSM-IV or ICD-10 criteria
o Age of onset: usually 15-45 yrs (but may start at any age)
o Occurs equally in men and women but mean age of onset is about 5 years earlier in men. Peak onset
in men is 20-24 age group but female onset is more common with increasing age.
o Prevalence: 1.4-4.6 /1000 of the population at risk (Data from 23 prevalence studies between 19311999, Jablensky 2003)
o Worldwide lifetime prevalence is approximately 1%
[Shorter Oxford Textbook of Psychiatry, 4th Ed. & Seminar Series, General Adult Psychiatry, 2nd Ed]
Epidemiology
o The literature is divided on the question of whether lower socio-economic group is a risk factor
for Schizophrenia.
o Current literature emphasises a true urban effect: a high proportion of patients are born in
inner cities or deprived areas and they do not merely drift into them.
o Urban effect is a complex interplay of factors related to genes, selective migration into and out
of cities, possibly over several generations, cultural and socio-economic factors e.g. higher rates
of social deprivation and dysfunctional families within urban areas; the interplay possibly
occurs early in life or even in utero rather than at the time of illness onset.
o Studies from different countries show that immigrants tend to have a higher risk of
Schizophrenia than the general population of either their native or their adopted country.
[Seminar Series, General Adult Psychiatry, 2nd Ed]
Epidemiology
Family member affected
Risk
Identical twin
46%
One sibling/ fraternal twin
Both parents
12-15%
40%
One parent
12-15%
One grandparent
No relatives affected
6%
0.5-1%
Schizophrenia liability based on affected relatives
[Oxford Handbook of Psychiatry, 2nd Ed]
Mortality
o SUICIDE is the most common cause of premature death in Schizophrenia- 10-38% of all deaths
in Schizophrenia.
o Highest risk probably in the year after 1st presentation
[Oxford Handbook of Psychiatry, 2nd Ed]
Aetiological theories
o No ‘unified theory’ of Schizophrenia yet
o Neurodevelopmental hypothesis
o Neurochemical abnormality hypothesis
o Disconnection hypothesis
o There are other (historical) theories as well but they lack scientific evidence
Neurodevelopmental hypothesis
o Excess of obstetric complications
o Motor and cognitive problems precede the onset
o Abnormal cerebral structure at first presentation
o Dermatoglyphic and dysmorphic features
o Possibly acquired in utero – abnormal brain but absent gliosis
Neurochemical abnormality hypothesis
o Not fully attributable to any single neurotransmitter abnormality
o Dopaminergic overactivity
o Glutaminergic hypoactivity
o Serotonergic (5HT) overactivity
o Alpha- adrenergic overactivity
o GABA hypoactivity
Disconnection hypothesis
o SPET, PET, fMRI scans
o Widespread reduction of grey matter (particularly temporal lobe)
o Disorder of memory and frontal lobe function on a background of widespread cognitive
abnormalities.
o Reduced correlation between frontal and temporal blood flow on specific cognitive tasks
o Reduction in white matter integrity in tracts connecting the frontal and temporal lobes
Genetics
o
Linkage studies - family based analyses that utilize genetic markers and the information from multiple affected
individuals present in a given family to identify linked regions of the genome that is, regions co-inherited or segregating
with the disease.
o
Candidate gene association studies [Hypothesis: common diseases are a result of interactive contribution of common
variants with small effect sizes and the susceptibility alleles will be shared by a significant proportion of unrelated
affected individuals].
o
GWAS – Genome wide association studies (with individual genotyping or using DNA pooling) to identify SNPs (Single
Nucleotide Polymorphisms)
o
Studies to identify CNVs (Copy Number Variations)- submicroscopic deletions or duplications stretching from a few
kilobases to several megabases covering several or many genes. E.g. velocardiofacial/DiGeorge (VCFS) syndrome region
(22q11)
o
GxE studies: Gene-environment interaction studies
Major Schizophrenia candidate genes
Gene
Locus
Function
Meta-analysis
COMT
22q11
Catecholamine metabolism
++
DAOA (G72)
13q32-34
D-serine metabolism
++
DISC1
1q42
Neurodevelopment and synaptic function
+++
DRD2
11q23
Dopamine signalling
++
DTNBP1
6p22
Neurodevelopment and synaptic function
+++++
GABRB2
5q32
GABA signalling
++++
GRIN2B
12p12
Glutamate signalling
++
NOTCH4
6p21.3
Neurodevelopment
+++
COMT= Catechol-O-methyltransferase; DAOA (G72) = D-amino acid oxidase activator; DISC-1=Disrupted in schizophrenia 1; DRD2= Dopamine receptor 2;
DTNBP1=Dystrobrevin binding protein 1; GABRB2=Gamma-aminobutyric acid (GABA) A receptor, beta 2; GRIN2B=Glutamate receptor, ionotropic, N-methyl Daspartate 2B; NOTCH4= Notch homolog 4 (Drosophila); ‘+’ indicates strength of association.
Tiwari AK, et al (2010)
References & Further Reading
o Gelder M, Andreason N, Lopez-Ibor J, Geddes J (Eds.) 2012. New Oxford textbook of Psychiatry.
Oxford University Press.
o Stein G & Wilkinson G (Eds.) 2007. Seminars in General Adult Psychiatry (2nd Ed). The Royal
College of Psychiatrists. Gaskell, London.
o Semple D & Smyth R (Eds.) 2013. Oxford Handbook of Psychiatry. Oxford University Press.
o Tiwari AK, Zai CC, Muller DJ, Kennedy JL (2010) Genetics in Schizophrenia: where are we and
what next? Dialogues Clin Neurosci 12(3) 289-303.