Schizophrenia: Epidemiology and Aetiological theories

MRCPSYCH LEP MODULE: PSYCHOSIS-1

Contents

o Epidemiologyo Methodological problems

o Epidemiological statistics

o Aetiological theorieso Current hypotheses

o Genetics

o References & Further reading

Epidemiology – methodological problemso 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

Epidemiologyo Schizophrenia is a disorder with a low incidence but a relatively high prevalence. It is fairly

evenly distributed around the globe.

oAnnual incidence – between 0.17 and 0.54 / 100 population {using broad definition}

- 2 to 3 times lower using DSM-IV or ICD-10 criteria

oAge 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 1931-1999, Jablensky 2003)

o Worldwide lifetime prevalence is approximately 1%

[Shorter Oxford Textbook of Psychiatry, 4th Ed. & Seminar Series, General Adult Psychiatry, 2nd Ed]

Epidemiologyo 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 12-15%

Both parents 40%

One parent 12-15%

One grandparent 6%

No relatives affected 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.

oHighest risk probably in the year after 1st presentation

[Oxford Handbook of Psychiatry, 2nd Ed]

Aetiological theories

oNo ‘unified theory’ of Schizophrenia yet

oNeurodevelopmental hypothesis

oNeurochemical abnormality hypothesis

oDisconnection hypothesis

oThere are other (historical) theories as well but they lack scientific evidence

Neurodevelopmental hypothesis

oExcess of obstetric complications

oMotor and cognitive problems precede the onset

oAbnormal cerebral structure at first presentation

oDermatoglyphic and dysmorphic features

oPossibly acquired in utero – abnormal brain but absent gliosis

Neurochemical abnormality hypothesisoNot fully attributable to any single neurotransmitter abnormality

oDopaminergic overactivity

oGlutaminergic hypoactivity

oSerotonergic (5HT) overactivity

oAlpha- adrenergic overactivity

oGABA hypoactivity

Disconnection hypothesisoSPET, PET, fMRI scans

oWidespread reduction of grey matter (particularly temporal lobe)

oDisorder of memory and frontal lobe function on a background of widespread cognitive abnormalities.

oReduced correlation between frontal and temporal blood flow on specific cognitive tasks

oReduction 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-analysisCOMT 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 D-aspartate 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.