Schizophrenia Research Forum - A Catalyst for Creative Thinking

IPRN 2011: Seeking Mileposts for the Road to Psychosis

8 June 2011. The push to intervene early to lessen the burden of psychosis faces a challenge: many people who are at ultra-high risk for psychosis will never become psychotic, and interventions could harm them. Offering interventions only to those who need them when they need them requires predicting who will become ill and when. In lieu of a crystal ball, researchers have been searching for neurobiological, clinical, and cognitive markers of psychosis risk and progression.

This was the subject of a symposium in Colorado Springs, Colorado, on 2 April 2011, organized by the International Prodromal Research Network. The symposium formed part of the Prodromal Satellite Meeting, which took place in conjunction with the 2011 International Congress on Schizophrenia Research. The day had begun with a session on interventions to keep psychosis from taking its toll (see SRF related news story) and continued with updates on the hunt for markers—the subject of this story.

Less invasive than colonoscopy
Neuroimaging research to identify brain changes that could flag subjects who are on the edge of psychosis has taken its cue from studies of diagnosed schizophrenia. In the first talk on biomarkers, Christos Pantelis, University of Melbourne, Australia, said that voxel-based morphometry studies have found reduced gray matter in frontal and temporal regions in established schizophrenia. These losses appear particularly large in the anterior cingulate/medial prefrontal cortex and insula. In contrast, Pantelis said researchers have had less luck finding reliable markers of impending psychosis.

Given that the brain is still maturing at the typical ages of psychosis onset, Pantelis thinks trajectories of structural and functional change in the brain will reveal more than static markers for the transition to psychosis. Therefore, he said, researchers should “search for a moving target” by conducting longitudinal studies. In new data, he and his colleagues found ventricular differences among subject groups that were defined by illness stage. Ventricular enlargement correlated with illness duration in those with established schizophrenia but did not appear in clinical high-risk subjects before psychosis; rather, it occurred after schizophreniform first-episode psychosis appeared.

Previously, Pantelis and colleagues found that thinning of the anterior cingulate cortex predicted which ultra-high-risk subjects would develop schizophrenia-spectrum psychosis (Fornito et al., 2008). In a recent longitudinal study, they used voxel-based morphometry to compare regional gray matter volumes in ultra-high-risk subjects. Those analyses revealed a smaller subcallosal cingulate gyrus in subjects who transitioned to affective psychosis than in those who converted to schizophrenia (Dazzan et al., 2011), hinting that the brain may change differently depending on the kind of psychosis brewing.

The next speaker, Philip McGuire, Institute of Psychiatry, London, U.K., has been seeking structural, functional, and chemical clues in the brain that would predict transition to psychosis. In a five-site study (Mechelli et al., 2011), he and his colleagues paired magnetic resonance imaging with voxel-based morphometry to assess the volume of gray matter in the inferior frontal, parahippocampal, and superior temporal cortices. Reduced parahippocampal volume predicted which at-risk subjects would develop psychosis during the follow-up period, which lasted an average of two years. In contrast, volumes of the inferior frontal and superior temporal gyri failed to foretell who would become ill.

As for neurochemical markers, McGuire's group had previously found striatal dopamine abnormalities in subjects with first-episode schizophrenia and, to a lesser extent, in ultra-high-risk subjects (Howes et al., 2009). More recently, he and his colleagues tied dysfunction of the prefrontal and medial temporal lobes, as reflected in the blood-oxygen-level-dependent signal, to high striatal dopamine in high-risk subjects. Those who went on to develop psychosis showed the most marked abnormalities. Using positron emission tomography, the researchers also found that striatal dopamine production increased in prodromal patients around the time that psychosis developed (Howes et al., 2011).

Other work explored whether changes in glutamate would reflect the transition to psychosis in ultra-high-risk subjects. According to McGuire, thalamic glutamate levels at baseline failed to flag those who would develop psychosis later on; however, at the time of transition, these levels decreased. Furthermore, using both positron emission tomography and magnetic resonance spectroscopy, the study found interactions between striatal dopamine and hippocampal glutamate in high-risk subjects, especially those who transitioned, but not in healthy controls.

Taking a different tack, the group led by René Kahn, University Medical Centre, Utrecht, The Netherlands, has been weighing the effects of genetic factors versus illness progression on brain changes in schizophrenia. For instance, he and others in the STAR (Schizophrenia Twins and Relatives) Consortium performed a large, international study in which twins and their siblings underwent magnetic resonance imaging. The study found that genetic effects explained most of the correlation between schizophrenia and reduced cerebral volume.

In another study, Kahn and colleagues used fiber-tract diffusion tensor imaging to evaluate white matter integrity in patients with schizophrenia, their non-psychotic siblings, and healthy subjects. Cross-sectional analyses showed decreased fractional anisotropy in the genu of the corpus callosum in patients as they aged. Neither siblings nor controls showed an age effect or differed from each other. According to Kahn, the results show a possible effect of illness progression in the genu.

Kahn also presented findings from a recent study that compared brain changes in youngsters who were at ultra-high risk for psychosis and their healthy peers (Ziermans et al., 2010). Subjects received magnetic resonance imaging at baseline and two years later. Compared to control subjects, at-risk young people who became psychotic lost more total brain volume and white matter volume; they also lost more total brain volume than those at similar risk who did not become psychotic. Furthermore, those who developed psychosis showed more thinning than control subjects in the left anterior cingulate, precuneus, and temporo-parietal-occipital regions. These findings, which Kahn said did not result from antipsychotic drugs, suggest that brain structure changes as psychosis appears.

As for the implications of the neuroimaging findings, discussant Charles Schulz, University of Minnesota, Minneapolis, said that biomarkers could be crucial for personalizing treatment. He noted that most of the scans are noninvasive and painless, but their risks must be weighed against potential benefits. Drawing parallels to heart disease treatment, which takes into account multiple risk factors such as cholesterol levels, chest pain, and smoking history, he cautioned against relying on just one measure of psychosis risk.

Back to behavior
The last session of the day discussed clinical and cognitive markers of psychosis risk and progression. Barbara Cornblatt, Zucker Hillside Hospital, Glen Oaks, New York, focused on functional measures, particularly the ability to carry out roles at work or school, and to interact with other people. She said that researchers typically study social and role functioning as outcomes, but she sees them also as long-standing risk states that arise independently of psychosis and affect illness progression. Accordingly, she has been studying their determinants and consequences in clinical high-risk young people.

In the model that guides Cornblatt’s work (Cornblatt et al., 2003), the road to psychosis goes from negative symptoms alone to positive symptoms of increasing severity, then to psychosis-like symptoms that stop short of diagnosable psychosis, and finally to frank psychosis. In new work, Cornblatt and colleagues grouped prodromal subjects from the RAP (Recognition and Prevention) program according to their prodromal stage vis-à-vis the model and examined their subsequent outcomes. Results showed that groups further along in the model showed higher rates of conversion to psychosis. Furthermore, at the three-year follow-up, nearly 30 percent of those who had started with only negative symptoms now reported positive symptoms, and 16 percent of those with moderate positive symptoms had them worsen.

Regression analyses to identify predictors of psychosis found that disorganized communication, a higher number of symptoms, poor verbal memory, and worsening social functioning upped the risk, whereas mood disorder lessened it. In further analyses, subjects with positive symptoms showed deficits in social and role functioning that stayed stable over three years. Cornblatt sees both social and role functioning as ripe for early intervention.

After Cornblatt’s talk, Larry Seidman, Harvard Medical School, talked about the usefulness of neuropsychological measures during the prodrome. He asked whether they could help with defining “caseness” and, in particular, with identifying subgroups of prodromal subjects with different treatment needs. Noting that some people show no neuropsychological deficits before they become ill, he said that combining disparate groups might yield misleading conclusions.

Seidman and researchers at eight sites have been conducting the North American Prodrome Longitudinal Study (NAPLS), which previously found below-normal cognitive performance in clinical high-risk subjects, especially those who later developed psychosis (Seidman et al., 2010). Their new study classified subjects at baseline as having a normal, borderline, or abnormal neuropsychological profile, based on a cognitive test battery that spanned eight domains.

In data hot off the computer, Seidman and colleagues found that less than half of prodromal subjects who developed psychosis had an abnormal neuropsychological profile; even so, profile severity doubled the odds of psychosis. Subjects with poor profiles showed greater deficits in social, role, and global functioning at baseline. More importantly, the profiles predicted all three kinds of functioning a year later, over and above conversion status. According to Seidman, the results show the usefulness of neuropsychological measures for predicting conversion, social function, and role function.

Longer-term outcomes concern Alison Yung, University of Melbourne, Australia. She noted that the longest published follow-up of at-risk subjects has been about five years, during which nearly four of every 10 subjects developed psychosis. In contrast, her new study looks at outcomes of up to 15 years. She and her colleagues followed up subjects who had participated in studies at the PACE (Personal Assessment and Crisis Evaluation) clinic years ago. In a process that she said exhausted the research assistants, they tracked them not only through traditional sources, such as death records, but also newer ones like Facebook.

During the follow-up period, 27 percent of the subjects became psychotic. Most did so during the first two years, and no one transitioned after a decade. In adjusted regression models, long duration of symptoms, low Global Assessment of Functioning scores, and year of joining the study predicted who would develop psychosis. For each 10-point gain in function, the likelihood of transitioning to psychosis declined by 61 percent. Later cohorts were less likely than earlier ones to transition, but the gap between cohorts was narrowing as time went on and could have been an artifact.

To Yung, transition seems arbitrary, so she has been exploring how well transition status predicts long-term functional outcome. In preliminary findings, transitioning quadrupled the odds of poor global function at follow-up. However, only about 40 percent of those who transitioned had a poor functional outcome, and nearly half of those who functioned poorly had not transitioned. The results back Yung’s view that not all transitions matter in real life (see Yung et al., 2010).

After Yung’s talk, discussant Deanna Barch, Washington University, St. Louis, Missouri, said that most prodromal studies have focused on symptomatic help-seeking patients with poor role functioning and cognitive deficits, but she is glad to see population-based studies that aim to disentangle functioning from psychosis. In addition, she hopes prodromal researchers will think about how social and role deficits might raise psychosis risk.

Rather than pit behavioral and biological markers against each other, Barch said the two kinds of information complement each other; they might point to different mechanisms and different levels of analysis for the same mechanisms. She noted that brain measures might be less clinically feasible than behavioral measures in some settings; social and role function may be further from neurobiology, but could help clarify outcomes. She encouraged researchers to pursue both behavioral and biological markers of emerging psychosis.—Victoria L. Wilcox.

Comments on Related News

Related News: A Tale of Two City Exposures and the Brain

Comment by:  John McGrath, SRF Advisor
Submitted 22 June 2011
Posted 22 June 2011

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.


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

View all comments by John McGrath

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Elizabeth Cantor-Graae
Submitted 23 June 2011
Posted 23 June 2011

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).


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

View all comments by Elizabeth Cantor-Graae

Related News: A Tale of Two City Exposures and the Brain

Comment by:  James Kirkbride
Submitted 27 June 2011
Posted 27 June 2011

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.


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

View all comments by James Kirkbride

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Wim Veling
Submitted 5 July 2011
Posted 5 July 2011

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.


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.

View all comments by Wim Veling

Related News: A Tale of Two City Exposures and the Brain

Comment by:  Dana March
Submitted 7 July 2011
Posted 7 July 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.


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

View all comments by Dana March