Schizophrenia Research Forum - A Catalyst for Creative Thinking

Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol. 2006 Jun 1 ; 163(11):971-8. Pubmed Abstract

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Primary Papers: Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals?

Comment by:  Elizabeth Cantor-Graae
Submitted 19 May 2006
Posted 19 May 2006
  I recommend this paper

Using a creative epidemiological approach, the authors take the urban-rural phenomenon one step higher and examine the risk associated with the birthplace of the older sibling. Their observation that the risk conferred by urban birth persists even after the family has moved to a rural area sugggests that familial influences play an important role in the "urban" effect.

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Primary Papers: Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals?

Comment by:  John McGrath, SRF Advisor
Submitted 3 June 2006
Posted 4 June 2006
  I recommend this paper

This paper needs to be read carefully. It is worth the effort as the methods and results are very thought-provoking. The study uses variables available in Danish registers (i.e., place of birth of next eldest sibling) to tease out more clues about the association between urbanicity of birth and risk of schizophrenia. The cause (or causes) underlying the urban birth/residence risk factor remain stubbornly obscure. The new study suggests that candidate exposures should also be drawn from factors operating at the “family level” (i.e., where did the family reside before the affected individual was born/conceived). Some researchers will default to tortuous selective-migration theories to explain these results. However, the findings can also provide clues to help generate candidate environmental factors. The study forces us to address new questions. When is the critical window of exposure? After exposure, what is the duration of the risk period? For example, perhaps maternal and/or paternal exposures that are more likely to be acquired in cities (e.g., nutritional factors, toxins, infections, etc.), could “hang over” and continue to influence risk status for offspring conceived/born after internal migration from the city to the country. However, if this was the case, one would predict that the impact of the exposure would fall over time after the move to non-urban regions. When the investigators looked at birth interval between the proband and the next eldest sibling, they did not find evidence of any weakening or decay of this signal.

So, once again, schizophrenia epidemiology provides a challenge to the research community. We have good data but rather unimpressive explanatory hypotheses. We need good theories! One is reminded of the playful quip from Eddington (1935): “It is also a good rule not to put too much confidence in the observational results that are put forward until they are confirmed by theory.”


Eddington A. (1935) New Pathways in Science. Cambridge, Cambridge University Press. p 211.

View all comments by John McGrathComment by:  Patricia Estani
Submitted 13 June 2006
Posted 13 June 2006
  I recommend the Primary PapersComment by:  Ella Matthews
Submitted 16 June 2006
Posted 5 July 2006

Questions on the different rates of occurrence of the schizophrenia spectrum of brain disorders between northern (developed) and southern underdeveloped countries, between urban and rural, as well as the birth order within the family of those suffering from schizophrenia are important ones.

However, when thinking about family exposure to environmental factors, I think that there is much to learn from social science. Say that a 1970s family moved from the country to the city just at the time when the birth control pill had been developed and began to be widely available in urban industrialized areas: Estrogen levels on the early formulations of the "pill" were too high, causing women to search for other legal birth control methods which they could tolerate more easily. About the only other things that doctors could offer women back then were the highly touted IUDs.

Say also that a woman tried the birth control pill but, because her taking of the pill was spotty, she became pregnant with her first child. After delivering their first children, many 1970s women then turned to IUDs, which did not cause bloating or the other nasty physical side effects of the pill. What IUDs did have was a hidden wicking string. Those strings were ladders for infection moving into the uterus. So when thinking of environmental factors at the level of the family, one has to ask broad-spectrum socioeconomic questions about what families were actually up against in the 1970s.

Birth control methods could also add insight into why schizophrenia was identified in the late 1800s, a time when women were moving into paid labor outside the home. It had been common knowledge since ancient times that any foreign object inserted into the uterus (IUD) would interfere with pregnancy. Working women had to limit the number of children they had. There was information-sharing among female coworkers.

Think about the implications of IUD use in Catholic countries such as Ireland, which has a high rate of schizophrenia. Catholic mothers of schizophrenics would be loath to discuss birth control methods used prior to or during the birth of a child born with schizophrenia. Moreover, during the Dalkon Shield scandal and IUD birth defect lawsuits of the 1970s and 1980s, the schizophrenias did not get any coverage because children born with these disorders hadn't reached the age of onset yet.

I am a parent of a second-born adult daughter suffering from schizophrenia. Families, especially mothers, do not want to go back to the days when it was said that bad mothering caused schizophrenia. Yet, we who carried these children to term have to ask ourselves what was different going into and throughout these pregnancies?

Skilled researchers need to formulate and ask probing questions about what the mother was exposed to prior to and during these pregnancies.

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Primary Papers: Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals?

Comment by:  Karl-Ludvig Reichelt (Disclosure)
Submitted 11 July 2006
Posted 12 July 2006

The usual reason for moving to the city/urban environment is poverty. In the beginning of their existence in urban surroundings, such families remain poor and probably have a change in diet. More grains and less of yams, casava, vegetables, etc., which are more expensive in urban settings. This is especially pronounced when moving to Western countries from the developing nations. In industrialized countries the only "cheap" food is usually milk and bread. There, this difference becomes even more pronounced, and rates of schizophrenic development are several times higher than in natives in the same economic group.


Dohan FC, Harper EH, Clark MH, Rodrigue RB, Zigas V. Is schizophrenia rare if grain is rare? Biol Psychiatry. 1984 Mar;19(3):385-99. Abstract

Lorenz K. (1990) Cereals and schizophrenia. Adv Cereal Sci Technol X:435-469.

For a comprehensive discussion see
Reichelt KL, Seim AR, Reichelt WH. Could schizophrenia be reasonably explained by Dohan's hypothesis on genetic interaction with a dietary peptide overload? Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct;20(7):1083-114. Review. Abstract

View all comments by Karl-Ludvig Reichelt