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.

View all comments by Elizabeth Cantor-Graae

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,...  Read more

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.”

References:

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

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...  Read more

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.

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.

References:

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

This is another high-quality study from the National Centre for Register-based Research in Aarhus, Denmark. The researchers find that the yet-to-be-identified risk factor(s) associated with urban birth do not seem to have changed in magnitude over most of the last century. This is a very curious finding, and difficult to explain. The research community now has to generate candidate exposures that may underlie the urban-rural gradient. In light of (a) the large population-attributable risk that seems to be associated with this exposure, and (b) the fact that many nations are becoming increasingly urbanized, this task needs to be addressed with a sense of urgency.

View all comments by John McGrath

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory...  Read more

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).

The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).

The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.

Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 Feb;26(2):204-15. Abstract Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9. Abstract Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001 Nov;58(11):1032-7. Abstract Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33. Abstract Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. Abstract Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297-302. Abstract Zuckerman L, Rehavi M, Nachman R, Weiner I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003 Oct;28(10):1778-89. Abstract

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and...  Read more

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.

However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.

References:

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15;175(12):8096-104. Abstract

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11. Abstract

Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia. 2006 Feb;53(3):248-56. Abstract

Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother. 2005 May-Jun;28(3):220-8. Abstract

Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005 Jan 15;174(2):992-1002. Abstract

Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13. Abstract

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract

Tracking down the agent(s) responsible for the elusive “migrant” effect in schizophrenia bears similarities with the clever plot twists in a well-crafted crime novel. The new study by Jeremy Coid and coworkers makes substantial headway toward narrowing down the list of suspects, with the spotlight increasingly focused on ethnicity. The current venture has a number of outstanding strengths: large sample size, robust denominator data, and stringent methods of case ascertainment, including leakage analysis. The choice of venue of East London, an area characterized by socioeconomic deprivation, is a strategic advantage, in that the effect of ethnicity can be teased out from socioeconomic disadvantage. The findings indicate that ethnicity had a stronger effect on risk magnitude than did generational status (i.e., place of birth). Black Caribbeans were the only ethnic group where generational status “mattered,” an effect that the authors attribute to differences in the age structures of the underlying populations at risk.

How best to interpret these results, and where do...  Read more

The large study from Nuevo and colleagues is very thought provoking. There was substantial between-site variation in response to various psychosis-screening items. Assuming that endorsement of these items is a mix of: 1) "true" psychotic-like experiences, 2) "true" responses that are understandable from the perspective of local cultures and beliefs, and 3) innocent misinterpretations of the questions, why is there such marked variation? For example, why do 46 percent of respondents from Nepal endorse at least one psychotic-like experience and a third report auditory hallucinations?

It seems self-evident that populations with strong religious and/or cultural beliefs related to psychotic-like experiences might endorse psychosis-screening items more readily (type 2 in the above list). But could it be feasible that these same populations might also “kindle” psychotic experiences in vulnerable people? This notion is pure speculation, but we should remain mindful that dopaminergic pathways related to psychosis are vulnerable to the process of endogenous sensitization (  Read more

The large study from Nuevo and colleagues is very thought provoking. There was substantial between-site variation in response to various psychosis-screening items. Assuming that endorsement of these items is a mix of: 1) "true" psychotic-like experiences, 2) "true" responses that are understandable from the perspective of local cultures and beliefs, and 3) innocent misinterpretations of the questions, why is there such marked variation? For example, why do 46 percent of respondents from Nepal endorse at least one psychotic-like experience and a third report auditory hallucinations?

It seems self-evident that populations with strong religious and/or cultural beliefs related to psychotic-like experiences might endorse psychosis-screening items more readily (type 2 in the above list). But could it be feasible that these same populations might also “kindle” psychotic experiences in vulnerable people? This notion is pure speculation, but we should remain mindful that dopaminergic pathways related to psychosis are vulnerable to the process of endogenous sensitization (Laruelle, 2000).

What does it mean to be a member of a cultural group that is more “prone” to psychotic-like experiences? Tanya Luhrmann, an anthropologist based at Stanford University, has examined individuals attending evangelical churches who “hear” the voice of God during prayer (Luhrmann et al., 2010). The vignettes suggest that some individuals reported more “hearing the voice of God” after improving their prayer skills. Practice makes perfect, but could it also kindle pathways related to schizophrenia?

Regardless of the underlying mechanisms, understanding variations in these symptoms is a fascinating topic worthy of more multidisciplinary research.

References:

Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev. 2000;31(2-3):371-84. Abstract

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

It seems to me that there may be two different patterns that show up in these large epidemiological studies: the psychotic continuum and phenomena associated with absorption. Absorption is basically a capacity for/interest in being caught up in your imagination. It is associated with hypnotizability and dissociation, but not identical to them (Tellegen and Atkinson, 1974).

In my own work on evangelical Christianity, I identify a pattern in which people report hallucination-like phenomena that are rare, brief, and not distressing (as opposed to the pattern associated with psychotic disorder, in which the hallucinations are often frequent, extended, and distressing). Those who report hearing God’s voice audibly or seeing the wing of an angel are also more likely to score highly on the Tellegen absorption scale (Luhrmann et al., 2010). This relationship between unusual experiences and absorption also shows up in a significant relationship between absorption and the Posey-Loesch hearing voices scale when these scales are given to...  Read more

It seems to me that there may be two different patterns that show up in these large epidemiological studies: the psychotic continuum and phenomena associated with absorption. Absorption is basically a capacity for/interest in being caught up in your imagination. It is associated with hypnotizability and dissociation, but not identical to them (Tellegen and Atkinson, 1974).

In my own work on evangelical Christianity, I identify a pattern in which people report hallucination-like phenomena that are rare, brief, and not distressing (as opposed to the pattern associated with psychotic disorder, in which the hallucinations are often frequent, extended, and distressing). Those who report hearing God’s voice audibly or seeing the wing of an angel are also more likely to score highly on the Tellegen absorption scale (Luhrmann et al., 2010). This relationship between unusual experiences and absorption also shows up in a significant relationship between absorption and the Posey-Loesch hearing voices scale when these scales are given to undergraduates. Among undergraduates, the rates for hallucination-like phenomena are also consistently far higher than the Nuevo paper reports, perhaps because neither the absorption scale nor the Posey-Loesch scale seems to probe for pathology (Luhrmann, forthcoming).

I am not the only one to have found a significant association between unusual sensory experiences and absorption. Aleman and Laroi (2008) report that a handful of other researchers have also found significant correlations between hallucination scales and the absorption scale. As a result of this work, I think that there may be different pathways to hallucination-like phenomena—some pathological, others less so.

Yet, I also wonder whether there is indeed something like “priming” psychosis, as John suggested. This would arise if there were some looseness in the relationship between psychosis and dissociation, which there appears to be. At least that's the way I interpret some of the phenomena that Romme and Escher (1993) report. If there is some kind of loose relationship, it would suggest that someone could have an absorption/dissociation response to trauma that would look psychotic; it might also suggest that an intensely absorbing negative imaginative experience (being pursued by demons, e.g.) might contribute to a vulnerable person exhibiting more psychotic-like symptoms.

How would we begin to pull this apart?

References:

Aleman A, Laroi F. Hallucinations: The science of idiosyncratic perception. Washington, DC: American Psychological Association, 2008.

Luhrmann TM. When God speaks back. New York: Knopf, forthcoming.

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

Romme M, Escher S. Accepting voices. London: Mind, 1993.

Tellegen A, Atkinson G. Openness to absorbing and self-altering experiences (“absorption”): a trait related to hypnotic susceptibility. J Abnorm Psychol. 1974;83(3):268-77. Abstract

This beautifully written piece serves to excite interest in the fascinating epidemiology of schizophrenia. In our search for the “missing heritability” of schizophrenia, we don’t have to look too far for clues. There are many contained in this piece. It just requires some Sherlock Holmes-type deductive reasoning to put them all together now!

The realization that psychotic symptoms (or psychotic-like experiences) can be used as a proxy for schizophrenia risk has opened up new vistas for exploration (Kelleher and Cannon, 2010). For instance, the paper by Nuevo and colleagues will provide a fertile ground for testing ecological hypotheses on the etiology of schizophrenia—such as examining cross-national vitamin D levels (McGrath et al.) or fish oil consumption. Geneticists have yet to appreciate the potential value of studying such symptoms. Ian Kelleher, Jack Jenner, and I have argued in a recent editorial that the non-clinical psychosis phenotype provides us with a population in which to test hypotheses about the...  Read more

This beautifully written piece serves to excite interest in the fascinating epidemiology of schizophrenia. In our search for the “missing heritability” of schizophrenia, we don’t have to look too far for clues. There are many contained in this piece. It just requires some Sherlock Holmes-type deductive reasoning to put them all together now!

The realization that psychotic symptoms (or psychotic-like experiences) can be used as a proxy for schizophrenia risk has opened up new vistas for exploration (Kelleher and Cannon, 2010). For instance, the paper by Nuevo and colleagues will provide a fertile ground for testing ecological hypotheses on the etiology of schizophrenia—such as examining cross-national vitamin D levels (McGrath et al.) or fish oil consumption. Geneticists have yet to appreciate the potential value of studying such symptoms. Ian Kelleher, Jack Jenner, and I have argued in a recent editorial that the non-clinical psychosis phenotype provides us with a population in which to test hypotheses about the evolutionary benefit of psychosis genes (Kelleher et al., 2010; see also Nesse, 2004). This non-clinical psychosis phenotype gives rise to the possibility of moving beyond just-so stories into the realm of testable hypotheses.

References:

Kelleher I, Cannon M. Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis. Psychol Med. 2010 May 19:1-6. Abstract

Kelleher I, Jenner JA, Cannon M. Psychotic symptoms in the general population - an evolutionary perspective. Br J Psychiatry. 2010 Sep;197(3):167-9.

Nesse RM. Cliff-edged fitness functions and the persistence of schizophrenia. Behav Brain Sci. 2004;27:862-3.

With interest, I read Victoria Wilcox's summary of some thought-provoking papers published this year. It seems that schizophrenia, like cancer, has many different causes. I would like to point out that three of the studies (Zammit et al., 2010; Wicks et al., 2010; Schofield et al., 2010) support the idea that social defeat and/or social exclusion increase risk. The paper by Zammit et al. showed this in an elegant way: being different from the mainstream, no matter on what account, increased the subject's risk. The next step is to show that social exclusion has an impact on an individual's dopamine function. My group is examining this in young adults with an acquired hearing impairment, using SPECT.

References:

Zammit S, Lewis G, Rasbash J, Dalman C, Gustafsson J-E, Allebeck P. Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders. Arch Gen Psychiatry. 2010 Sep;67(9):914-22. Abstract

Wicks S, Hjern A, Dalman C. Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry. 2010 Oct;167(10):1240-6. Epub 2010 Aug 4. Abstract

Schofield P, Ashworth M, Jones R. Ethnic isolation and psychosis: re-examining the ethnic density effect. Psychol Med. 2010 Sep 22:1-7. Abstract

View all comments by Jean-Paul Selten

I have been collecting diverse references for environmental risk factors in schizophrenia at Schizophrenia Risk Factors. These include many prenatal influences due to maternal infection, usually with some sort of virus, or immune activation with fever. Several animal studies have shown that infection or immune activation in mice can produce schizophrenia-like symptoms in the offspring. Toxoplasmosis has often been cited as a risk factor in adulthood.

Many of the genes implicated in schizophrenia are also involved in the life cycles of these pathogens, and interactions between genes and risk factors can together contribute to endophenotypes; for example, MICB and Herpes simplex infection have single and combined effects on grey matter volume in the prefrontal cortex.

Over 600 genes have been associated with schizophrenia. When these were pumped through a Kegg pathway analysis, the usual suspects (neuregulin, dopamine, and glutamate pathways, among others) figure highly in the   Read more

I have been collecting diverse references for environmental risk factors in schizophrenia at Schizophrenia Risk Factors. These include many prenatal influences due to maternal infection, usually with some sort of virus, or immune activation with fever. Several animal studies have shown that infection or immune activation in mice can produce schizophrenia-like symptoms in the offspring. Toxoplasmosis has often been cited as a risk factor in adulthood.

Many of the genes implicated in schizophrenia are also involved in the life cycles of these pathogens, and interactions between genes and risk factors can together contribute to endophenotypes; for example, MICB and Herpes simplex infection have single and combined effects on grey matter volume in the prefrontal cortex.

Over 600 genes have been associated with schizophrenia. When these were pumped through a Kegg pathway analysis, the usual suspects (neuregulin, dopamine, and glutamate pathways, among others) figure highly in the list of pathways. Immune-related pathways are also highly represented, as are many pathogen entry pathways, including that for toxoplasmosis, which heads the list. Some of the more exotic pathways, for example, Chaga’s disease, should be considered as generic, as well as specific.

These Kegg-generated data suggest that there are strong relationships between genes and risk factors. Perhaps stratification of GWAS data in relation to infection could take this into account.

References:

Bortolato M, Godar SC. Animal models of virus-induced neurobehavioral sequelae: recent advances, methodological issues, and future prospects. Interdiscip Perspect Infect Dis . 2010 Jan 1 ; 2010():380456. Abstract

Carter CJ. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. Schizophr Bull . 2009 Nov 1 ; 35(6):1163-82. Abstract

Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry . 1999 Mar 1 ; 4(2):145-54. Abstract

Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse . 2005 Aug 1 ; 57(2):91-9. Abstractx

Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry . 2006 Mar 15 ; 59(6):546-54. Abstract

Prasad KM, Bamne MN, Shirts BH, Goradia D, Mannali V, Pancholi KM, Xue B, McClain L, Yolken RH, Keshavan MS, Nimgaonkar VL. Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia. Schizophr Res . 2010 May 1 ; 118(1-3):232-9. Abstract

Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry . 2008 May 1 ; 13(5):470-9. Abstract

Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res . 2005 May 1 ; 39(3):311-23. Abstract

The findings from Lederbogen et al. are very thought provoking. The dissociation between the fMRI correlates of current versus early life urbanicity is unexpected. The authors have replicated their finding in an independent sample, reducing the chance that the finding was a type 1 error.

It is heartening to see important clues from epidemiology influencing fMRI research design. With respect to schizophrenia, the findings provide much-needed clues to the neurobiological correlates of urban birth (Pedersen and Mortensen, 2001; Pedersen and Mortensen, 2006; Pedersen and Mortensen, 2006). Somewhat to the embarrassment of the epidemiology research community, the link between urban birth and risk of schizophrenia has been an area of research where the strength of the empirical evidence has been much stronger than hypotheses proposed to explain the findings (McGrath and Scott, 2006;   Read more

The findings from Lederbogen et al. are very thought provoking. The dissociation between the fMRI correlates of current versus early life urbanicity is unexpected. The authors have replicated their finding in an independent sample, reducing the chance that the finding was a type 1 error.

It is heartening to see important clues from epidemiology influencing fMRI research design. With respect to schizophrenia, the findings provide much-needed clues to the neurobiological correlates of urban birth (Pedersen and Mortensen, 2001; Pedersen and Mortensen, 2006; Pedersen and Mortensen, 2006). Somewhat to the embarrassment of the epidemiology research community, the link between urban birth and risk of schizophrenia has been an area of research where the strength of the empirical evidence has been much stronger than hypotheses proposed to explain the findings (McGrath and Scott, 2006; March et al., 2008). The new findings should trigger more focused research exploring the fMRI correlates in urban- versus rural-born individuals with schizophrenia.

References:

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and place. Epidemiol Rev . 2008 Jan 1 ; 30():84-100. Abstract

McGrath J, Scott J. Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiol Psichiatr Soc . 2006 Oct-Dec ; 15(4):243-6. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry . 2001 Nov 1 ; 58(11):1039-46. Abstract

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. Abstract

Pedersen CB, Mortensen PB. Urbanization and traffic related exposures as risk factors for schizophrenia. BMC Psychiatry . 2006 Jan 1 ; 6():2. Abstract

The study by Lederbogen et al. linking neural processes to epidemiology opens up an exciting avenue of inquiry, It suggests that exposure to urban upbringing could modify brain activity. Whether that could lead to schizophrenia per se remains to be seen.

Still, one might want to keep in mind that there is no evidence that urban-rural differences in schizophrenia risk are causally related to individual exposure. Pedersen and Mortensen (2006) showed that the association between urban upbringing and the development of schizophrenia is attributable both to familial-level factors as well as individual-level factors. Thus, the link between urbanicity and schizophrenia may be mediated by genetic factors, and if so, the social stressors shown by Lederbogen may in turn be related to those same genes.

Although it might be tempting to speculate whether Lederbogen’s findings have implications for migrant research, the “migrant effect” does not seem neatly explained by urban birth/upbringing. To the contrary, our findings show that the...  Read more

The study by Lederbogen et al. linking neural processes to epidemiology opens up an exciting avenue of inquiry, It suggests that exposure to urban upbringing could modify brain activity. Whether that could lead to schizophrenia per se remains to be seen.

Still, one might want to keep in mind that there is no evidence that urban-rural differences in schizophrenia risk are causally related to individual exposure. Pedersen and Mortensen (2006) showed that the association between urban upbringing and the development of schizophrenia is attributable both to familial-level factors as well as individual-level factors. Thus, the link between urbanicity and schizophrenia may be mediated by genetic factors, and if so, the social stressors shown by Lederbogen may in turn be related to those same genes.

Although it might be tempting to speculate whether Lederbogen’s findings have implications for migrant research, the “migrant effect” does not seem neatly explained by urban birth/upbringing. To the contrary, our findings show that the dose-response relationship between urbanization and schizophrenia (Pedersen and Mortensen, 2001) could be replicated only among persons born in Denmark whose parents had both been born in Denmark, and not in second-generation immigrants (Cantor-Graae and Pederson, 2007). Second-generation immigrants had an increased risk of developing schizophrenia independently of urban birth/upbringing (Cantor-Graae and Pedersen, 2007).

References:

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; 163:971-8. Abstract

Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry. 2001; 58:1039-46. Abstract

Cantor-Graae E, Pedersen CB. Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychol Med. 2007; 37:485-94. Abstract

Mannheim, Germany, has long played a pivotal role in unearthing links between the environment and schizophrenia (Hafner et al., 1969). Using administrative incidence data from Mannheim in 1965, Hafner and colleagues were amongst the first groups to independently verify Faris and Dunham’s seminal work from Chicago in the 1920s, which showed that hospitalized admission rates of schizophrenia were higher in progressively more urban areas of the city (Faris and Dunham, 1939). Now, almost 50 years later, Mannheim’s historical pedigree in this area looks set to endure, following the publication of the landmark study by Lederbogen et al. in Nature, which reported for the first time associations of urban living and upbringing with increased brain activity amongst healthy volunteers in two brain regions involved in determining environmental threat and processing stress responses.

Tantalizingly, their work bridges epidemiology and neuroscience, and provides some of the first empirical data to directly implicate functional neural alterations in stress processing associated with...  Read more

Mannheim, Germany, has long played a pivotal role in unearthing links between the environment and schizophrenia (Hafner et al., 1969). Using administrative incidence data from Mannheim in 1965, Hafner and colleagues were amongst the first groups to independently verify Faris and Dunham’s seminal work from Chicago in the 1920s, which showed that hospitalized admission rates of schizophrenia were higher in progressively more urban areas of the city (Faris and Dunham, 1939). Now, almost 50 years later, Mannheim’s historical pedigree in this area looks set to endure, following the publication of the landmark study by Lederbogen et al. in Nature, which reported for the first time associations of urban living and upbringing with increased brain activity amongst healthy volunteers in two brain regions involved in determining environmental threat and processing stress responses.

Tantalizingly, their work bridges epidemiology and neuroscience, and provides some of the first empirical data to directly implicate functional neural alterations in stress processing associated with living in urban environments. One important step will now be to discover whether such neural changes (following exposure to urban environments) are associated with clinical phenotypes, such as schizophrenia. This would support long-speculated paradigms of social stress (Selten and Cantor-Graae, 2005) as an important mechanism in a causal pathway between the environment and psychosis, although alternative environmental exposures in urban areas, including viral hypotheses and vitamin D, should not yet be excluded.

The work by Lederbogen et al. opens many avenues for possible study, including replication of their findings in clinical samples (via case-control designs) and using population-based rather than convenience samples. One of the greatest challenges in the social epidemiology of psychiatric disorders is to identify the specific suite of factors that underpin associations between the urban environment and the risk of clinical disorder. While Lederbogen et al. did not provide specific enlightenment on what these factors might be, their work also informs this search, because it suggests that focusing on factors likely to induce (or protect against) social stress would be potentially fruitful. To this end, their work should pave the way for mimetic studies, in both non-clinical and clinical populations, to investigate neural processing in relation to candidate social risk factors for psychiatric illness that were implicated in previous epidemiological studies (Cantor-Graae and Selten, 2005; March et al., 2008). These candidates may include migration or minority group membership (Coid et al., 2008), childhood traumas and other major life events (Kendler et al., 1992; Morgan et al., 2007), neighborhood socioeconomic deprivation (Croudace et al., 2000), income inequality (Boydell et al., 2004), and both individual-level social networks and neighborhood-level social cohesion and ethnic density (Kirkbride et al., 2008); some of these factors may also mitigate the effects of social stress.

The interface between social epidemiology and social neuroscience will also potentially provide new avenues by which to develop public health interventions. Presently, universal prevention strategies that focus on community-based interventions to prevent mental illness are not readily viable (Kirkbride et al., 2010), given both the absolute rarity of psychotic disorder and the relative ubiquity of broadly defined exposures such as urban living (many people live in urban environments, but only a handful of them will ever develop a psychotic illness). However, social neuroscience breakthroughs like those reported here may increase the viability of community-based public health initiatives by making it possible to move the focus of the intervention from preventing the clinical phenotype to preventing the abnormal neural changes associated with social-stress processing. Importantly, such strategies must also consider the possible benefits of enhanced social-stress processing in urban environments, which might be an important adaptation to more threatening environments. Because social stress may be associated with a range of neuropsychiatric and somatic disorders, public health strategies that target reductions in social stress rather than any single disorder may lead to significant improvements in population health across a range of morbidities. Such strategies, if justifiable, may also be cost effective, since a single intervention may prevent a range of disorders.

References:

Hafner H, Reimann H, Immich H, Martini H. Inzidenz seelischer Erkrankungen in Mannheim 1965. Soc Psychiatr. 1969;4:127-35.

Faris REL, Dunham HW. Mental disorders in urban areas. Chicago: University of Chicago Press; 1939.

Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? Br J Psychiatry. 2005 August 1;187(2):101-2. Abstract

Cantor-Graae E, Selten J-P. Schizophrenia and Migration: A Meta-Analysis and Review. Am J Psychiatry. 2005 January 1;162(1):12-24. Abstract

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and Place. Epidemiol Rev. 2008;30:84-100. Abstract

Coid JW, Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB. Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Arch Gen Psychiatry. 2008;65(11):1250-8. Abstract

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry. 1992 Feb;49(2):109-16. Abstract

Morgan C, Kirkbride JB, Leff J, Craig T, Hutchinson G, McKenzie K, Morgan K, Dazzan P, Doody GA, Jones P, Murray R, Fearon P. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med. 2007;37(4):495-503. Abstract

Croudace TJ, Kayne R, Jones PB, Harrison GL. Non-linear relationship between an index of social deprivation, psychiatric admission prevalence and the incidence of psychosis. Psychol Med. 2000 Jan;30(1):177-85. Abstract

Boydell J, van Os J, McKenzie K, Murray RM. The association of inequality with the incidence of schizophrenia--an ecological study. Soc Psychiatry Psychiatr Epidemiol. 2004 Aug;39(8):597-9. Abstract

Kirkbride J, Boydell J, Ploubidis G, Morgan C, Dazzan P, McKenzie K, Murray RM, Jones PB. Testing the association between the incidence of schizophrenia and social capital in an urban area. Psychol Med. 2008;38(8):1083-94. Abstract

Kirkbride JB, Coid JW, Morgan C, Fearon P, Dazzan P, Yang M, Lloyd T, Harrison GL, Murray RM, Jones PB. Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health. 2010;9(2):4-14. Abstract

This publication is interesting and important, as it is one of the first efforts to connect epidemiological findings to neuroscience. Both fields of research have made great progress over the last decades, but results were limited because epidemiologists and neuroscientists rarely joined forces.

Several risk factors that implicate preconceptional, prenatal, or early childhood exposures have been consistently related to schizophrenia in epidemiological studies, including paternal age at conception, early prenatal famine, urban birth, childhood trauma, and migration (Van Os et al., 2010). While some of these associations are likely to be causal, the mechanisms by which they are linked to schizophrenia are still largely unknown. A next phase of studies is required, the methods and measures of which link social environment to psychosis, brain function, and genes. The study by Lederbogen and colleagues is a fine example of such an innovative research design. Their findings are consistent with hypotheses of social stress mediating...  Read more

This publication is interesting and important, as it is one of the first efforts to connect epidemiological findings to neuroscience. Both fields of research have made great progress over the last decades, but results were limited because epidemiologists and neuroscientists rarely joined forces.

Several risk factors that implicate preconceptional, prenatal, or early childhood exposures have been consistently related to schizophrenia in epidemiological studies, including paternal age at conception, early prenatal famine, urban birth, childhood trauma, and migration (Van Os et al., 2010). While some of these associations are likely to be causal, the mechanisms by which they are linked to schizophrenia are still largely unknown. A next phase of studies is required, the methods and measures of which link social environment to psychosis, brain function, and genes. The study by Lederbogen and colleagues is a fine example of such an innovative research design. Their findings are consistent with hypotheses of social stress mediating the relationship between environmental factors and schizophrenia. It stimulates further research in this direction.

Two key issues need to be addressed. First, measures of social pathways should be refined (March et al., 2008). Which aspects of the daily social environment contribute to the onset of psychotic symptoms, how do these symptoms develop, and which individual characteristics moderate this outcome? It is extremely difficult to investigate daily social environments, because they are highly complex, cannot be controlled, are never exactly the same, and are strongly influenced by the individual’s behavior. Arguably, the only way to test mechanisms of psychotic responses to the social environment, and the moderators thereof, is to randomize individuals to controlled experimental social risk environments. Virtual reality (VR) technology, that is, substituting sense data from the natural world with sense data about an imaginary world that change in response to the user’s actions in an interactive three-dimensional virtual world, offers the possibility to do so. Freeman pioneered VR in psychosis research, investigating safety and feasibility (Fornells-Ambrojo et al., 2008; Freeman, 2008); however, there are no studies investigating mechanisms of risk environments. Our group recently found in a small pilot study that virtual environments with high population density or low ethnic density appear to elicit more physiological and subjective stress, as well as higher level of paranoia towards avatars (Brinkman et al., 2011). Larger studies and more experiments are needed.

Second, how are early social experiences translated to brain dysfunction? Another recent development has been in the field of epigenetics. Epigenetic mechanisms may mediate the effects of environmental risk factors, as the epigenetic status of the genome can be modified in response to the environment during embryonic growth, and probably also in the early years of life (Heijmans et al., 2009). Preliminary evidence suggests that epigenetic differences may be related to schizophrenia (Mill et al., 2008), but these epigenetic studies have not yet included environmental exposures. Epidemiologic studies may be a tool to detect epigenetic mechanisms in schizophrenia. Environmental exposures such as prenatal famine or migration may be used, as these exposures have been related to schizophrenia, can be measured with sufficient precision, offer homogeneously exposed populations for study, and had plausible biological pathways suggested for them (Veling et al. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 2011). Comparing the epigenome of exposed and unexposed schizophrenia cases and controls may help us to understand how gene expression affects disease risk.

As far fetched and futuristic as these research designs perhaps may seem, the publication of Lederbogen and colleagues shows that novel approaches can be very fruitful. If we improve interdisciplinary collaboration and use new technology, we may advance from associations to understanding in etiologic schizophrenia research.

References:

Van Os J, Kenis G, Rutten BPF. The environment and schizophrenia. Nature. 2010;468:203-12. Abstract

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, et al. Psychosis and place. Epidemiological Reviews. 2008;30:84-100. Abstract

Fornells-Ambrojo M, Barker C, Swapp D, Slater M, Antley A, Freeman D. Virtual Reality and persecutory delusions: safety and feasibility. Schizophrenia Research. 2008;104:228-36. Abstract

Freeman D. Studying and treating schizophrenia using Virtual Reality: a new paradigm. Schizophrenia Bulletin. 2008;34:605-10. Abstract

Brinkman WP, Veling W, Dorrestijn E, Sandino G, Vakili V, Van der Gaag M. Virtual reality to study responses to social environmental stressors in individuals with and without psychosis. Studies in Health Technology and Informatics. 2011;167:86-91. Abstract

Heijmans BT, Tobi EW, Lumey LH, Slagboom PE. The epigenome; archive of the prenatal environment. Epigenetics. 2009;4:526-31. Abstract

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American Journal of Human Genetics. 2008;82:696-711. Abstract

Veling W, Lumey LH, Heijmans BT, Susser E. Environmental studies as a tool for detecting epigenetic mechanisms in schizophrenia. In: Petronis A, Mill J, editors. Epigenetics and Human Health: Brain, Behavior and Epigenetics. Heidelberg: Springer; 2011.

The paper by Lederbogen and colleagues represents a critical step in elucidating the mechanisms underlying the consistent association between urban upbringing and adult schizophrenia. As John McGrath rightly points out, the urbanicity findings have long been in search of hypotheses. We understand little about what the effects of place on psychosis might actually be (March et al., 2008). What it is about place that matters for neurodevelopment and for schizophrenia in particular can be greatly enriched by a translational approach linking epidemiological findings to clinical and experimental science (Weissman et al., 2011), which will in turn help us formulate and refine our hypotheses about why place matters. Lederbogen and colleagues have opened the door in Mannheim. Where we go from here will require creativity, persistence, and collaboration.

References:

March D, Hatch SL, Morgan C, Kirkbride JB, Bresnahan M, Fearon P, Susser E. Psychosis and place. Epidemiol Rev . 2008 Jan 1 ; 30:84-100. Abstract

Weissman MM, Brown AS, Talati A. Translational epidemiology in psychiatry: linking population to clinical and basic sciences. Arch Gen Psychiatry . 2011 Jun 1 ; 68(6):600-8. Abstract

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