Schizophrenia Research Forum - A Catalyst for Creative Thinking

Research Roundup —The Tapestry of Environmental Influences in Psychosis

31 October 2010. Epidemiological studies have been weaving a tapestry of environmental contributions to psychosis, even as studies about the latest “it” gene command more attention. From a recent survey to gauge the commonness of psychotic symptoms in nations around the world to studies that seek to clarify key threads of environmental data, these studies offer leads to factors that might explain why the identical twin of someone with schizophrenia has a good chance of avoiding the disease. They recognize that psychosis arises within a place, whether that place consists of a city or nation, a rung on the socioeconomic ladder, or the more intimate landscape of a brain affected by drugs. We now take the opportunity to survey some notable recent additions to the schizophrenia epidemiology literature.

Psychotic symptoms around the world
As if in defiance of DSM and ICD treatment of schizophrenia as a categorical disorder, psychotic symptoms appear in the absence of diagnosable disorders. However, limited research suggests that nations differ in the percentage of people who experience psychotic symptoms. In a new study, Somnath Chatterji of the World Health Organization (WHO), Geneva, Switzerland, and colleagues took a particularly thorough look at their prevalence in different nations. They examined nationally representative samples of 52 countries around the world and published their findings online in Schizophrenia Bulletin on September 13.

The researchers, including first author Roberto Nuevo of the Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain, analyzed data on 256,445 subjects from the WHO’s World Health Survey. They found that the percentage of subjects who reported experiencing psychotic symptoms over the past 12 months differed greatly from one country to the next. For example, less than 1 percent of those in Vietnam, versus 45.8 percent of those in Nepal, reported at least one symptom. Worldwide, 7.1 percent of subjects reported delusional mood, 8.4 percent delusions of reference and persecution, and 5.8 percent hallucinations, but only 1.0 percent had ever been diagnosed with schizophrenia. The percentage of subjects with a putative schizophrenia diagnosis also varied among nations, but to a lesser extent than individual symptoms.

Despite the prevalence differences, the health burden associated with psychotic symptoms remained constant across countries. In controlled analyses, even one symptom was enough to predict poorer health; additional symptoms came with increasingly worse outcomes in each of eight domains, including vision, mobility, self-care, cognition, interpersonal activities, pain and discomfort, sleep and energy, and affect. These findings led Nuevo and colleagues to call even mild psychotic symptoms without frank disorder “a problem of potential public health concern” that may warrant increased screening efforts, but not without awareness of the perils of stigmatization and treatment side effects.

A capsule of sunlight
One reason that some nations carry a heavy psychosis load may be their lack of sunshine. Clues that this may affect schizophrenia risk come from a body of work showing that subjects born in winter or early spring are more likely to develop the illness than those born in summer or fall, at least in the Northern Hemisphere (for a review and meta-analysis, see Davies et al., 2003). Vitamin D, which the body makes when sunlight hits the skin, may be involved.

In a high-latitude country like Denmark, summer sunlight lasts well into the evening hours, and winter daylight fades too soon. Little vitamin D can be made during the short winter days. These seasonal differences make the nation a good epidemiological laboratory for testing the relationship between vitamin D levels at birth and the risk of developing schizophrenia. Preben Mortensen, University of Aarhus, Denmark, and colleagues concluded that optimizing vitamin D levels could prevent a whopping 44 percent of schizophrenia cases there. They presented their findings in the September Archives of General Psychiatry.

The researchers, including first author John McGrath, Queensland Centre for Mental Health Research, Wacol, Australia, linked records from national registries to dried blood spots routinely collected from newborns. They compared 424 cohort members who had been diagnosed with schizophrenia to an equal number of matched control subjects. This revealed a reversed U-shaped relationship between vitamin D levels in the blood and schizophrenia risk. Subjects whose vitamin D levels fell into the lowest three quintiles had double the risk, although those in the highest quintile also had a slightly increased risk. McGrath and colleagues raise the “tantalizing prospect” that low-cost supplements might avert many cases of schizophrenia, but note that the nonlinear relationship, if confirmed, might make this tricky.

The ties that sensitize
Another environmental exposure linked to schizophrenia, cannabis use, often triggers fleeting psychotic symptoms in healthy people; it also predicts the emergence of outright psychosis (see SRF related news story and SRF news story). In the October 4 online edition of the Archives of General Psychiatry, a team led by Jim van Os of Maastricht University Medical Centre in the Netherlands, explored whether genetic risk for psychotic disorder goes hand-in-hand with sensitivity to the psychotomimetic effect of cannabis. The Genetic Risk and Outcome in Psychosis Group has recruited subjects from the Netherlands and Belgium, including 1,120 patients with nonaffective psychosis, their 1,057 siblings, and 590 control subjects whose first-degree relatives had never had psychosis.

The researchers compared subclinical psychotic experiences in patients versus their siblings to evaluate sensitivity to cannabis in those with increased genetic risk who shared other familial exposures. To examine sensitivity as a function of liability to psychotic illness, they examined schizotypal symptoms and behaviors in patients versus control subjects. The results showed that healthy siblings were much likelier than control subjects to show positive and negative schizotypy as a function of cannabis use. Furthermore, the severity of positive psychotic symptoms correlated more highly between siblings if the unaffected sibling used cannabis. Van Os and colleagues concluded that the association between genetic susceptibility and sensitivity to cannabis resulted from familial risk increasing sensitivity to cannabis rather than fostering cannabis use. In other words, people who are most genetically prone to schizophrenia are the ones most likely to experience psychotic symptoms if they partake of cannabis.

Psychosis and the city
Other well-known risk factors for schizophrenia include growing up in an urban rather than a rural setting, living in unfavorable neighborhoods, and migrating to another country (see SRF related news story; SRF news story; also see SRF Live Discussion on the social environment). Even so, doubt remains about whether they confer risk in themselves or piggyback on some other exposure. Three recent studies shed a neon light on their ties to psychosis.

A group led by Stanley Zammit, Cardiff University, Wales, U.K., performed a longitudinal study of 203,829 people, nearly everyone born in Sweden during a five-year period. In the September Archives of General Psychiatry, they describe how they used new multilevel statistical methods to probe the extent to which aspects of the person, school, municipality, and county explain the high risk of psychosis in urban areas. As it turned out, the risk of nonaffective psychosis related mainly to person-level factors, but the excess risk in urban areas mostly reflected social fragmentation in the schools. This measure indexes the fraction of students who migrated from another country, moved to or from another town, or grew up in single-parent homes.

Interactions between individual- and higher-level factors suggested that standing out in certain ways from most others in their school raised the risk of developing any psychosis. Specifically, subjects whose social fragmentation scores differed from most of their schoolmates and foreign-born students in schools full of natives showed extra risk. This brings to mind earlier reports of an ethnic density effect, whereby the risk of psychosis in ethnic minority subjects declines as the representation of their ethnic group in the region rises.

A paper released online by Psychological Medicine in September lends further support to this idea. Peter Schofield, Kings College London, and colleagues noted that ethnic density studies in the United Kingdom have yielded mixed results, perhaps because they assessed density within too broad an area. Instead, Schofield and colleagues focused on neighborhoods in South East London that housed one-fourth as many people as the larger wards usually studied. The results backed their suspicions: ethnic density at the neighborhood, but not the ward, level correlated with the incidence of psychosis in blacks during a 10-year period.

Although ethnic density made no difference for psychosis risk in whites, for blacks, living in a neighborhood in which 25 percent or fewer of the residents were also black tripled the risk of developing psychosis (odds ratio = 2.88, 95 percent confidence interval 1.89-4.39) relative to whites. In contrast, blacks whose neighborhoods were home to a higher-than-average percentage of blacks showed no increased risk. “We postulate that this protective effect is likely to be dependent on the social milieu within just a handful of streets, and that a sense of shared ethnicity is therefore felt more in social interactions with, for example, immediate neighbors and whom one meets on the way to the corner shop rather than with the broad ethnic composition of larger urban areas,” Schofield and colleagues write.

Another schizophrenia risk factor entangled with minority group status is socioeconomic hardship, the focus of a study in the October American Journal of Psychiatry. Susanne Wicks, Karolinska Institute, Stockholm, Sweden, and colleagues identified 13,116 adopted children using Swedish national registries. Adoptees whose biological parents had no history of psychosis were more likely to develop nonaffective psychosis if raised in families that experienced parental unemployment (hazard ratio = 2.0). Genetic risk seemed to aggravate the effects of this hardship on adopted children (hazard ratio = 15.0).

A little problem
The disadvantages faced by at least some ethnic minority groups who live in disadvantaged neighborhoods may include starting life too small (Janevic et al., 2010). To clarify the relationship between low birth weight and schizophrenia risk, Kathryn Abel, University of Manchester, U.K., and colleagues published a study in the September Archives of General Psychiatry. They linked national registries that covered 1.49 million births in Sweden and Denmark to records on 57,455 cases of adult psychiatric disorder, including 5,445 with schizophrenia.

Babies in the lowest birth-weight groups were most likely to develop schizophrenia later on, but the relationship between birth weight and risk extended into the normal range of birth weights and to other psychiatric diseases as well. According to Abel and colleagues, these findings suggest looking beyond the abnormal events, such as hypoxia and brain bleeding, that occur more often in the smallest babies (Cannon et al., 2002). They write, “This suggests that it might be appropriate to place equal emphasis on a broader understanding of the connections between fetal growth, its control, and brain development.” At the same time, they warn that low birth weight might be standing in for other risk factors. As in all of these studies, unsnarling the strands of correlated exposures and understanding how they might interact presents challenges.—Victoria L. Wilcox.

References:
Nuevo R, Chatterji S, Verdes E, Naidoo N, Arango C, Ayuso-Mateos JL. The Continuum of Psychotic Symptoms in the General Population: A Cross-national Study. Schizophr Bull. 2010 Sep 13. Abstract

McGrath JJ, Eyles DW, Pedersen CB, Anderson C, Ko P, Burne TH, Norgaard-Pedersen B, Hougaard DM, Mortensen PB. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry. 2010 Sep;67(9):889-94. Abstract

Genetic Risk and Outcome in Psychosis (GROUP) Investigators. Evidence That Familial Liability for Psychosis Is Expressed as Differential Sensitivity to Cannabis: An Analysis of Patient-Sibling and Sibling-Control Pairs. Arch Gen Psychiatry. 2010 Oct 4.

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

Abel KM, Wicks S, Susser ES, Dalman C, Pedersen MG, Mortensen PB, Webb RT. Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Arch Gen Psychiatry. 2010 Sep;67(9):923-30. Abstract

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

Comments on News and Primary Papers
Comment by:  John McGrath, SRF Advisor
Submitted 5 November 2010
Posted 5 November 2010

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.

View all comments by John McGrathComment by:  Tanya Luhrmann
Submitted 12 November 2010
Posted 12 November 2010

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

View all comments by Tanya LuhrmannComment by:  Mary Cannon
Submitted 15 November 2010
Posted 15 November 2010

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.

View all comments by Mary CannonComment by:  Jean-Paul Selten
Submitted 17 November 2010
Posted 17 November 2010
  I recommend the Primary Papers

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 SeltenComment by:  Chris Carter
Submitted 26 November 2010
Posted 26 November 2010
  I recommend the Primary Papers

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

View all comments by Chris Carter

Comments on Related News


Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Patricia Estani
Submitted 13 June 2006
Posted 13 June 2006
  I recommend the Primary Papers

Related News: Urban Schizophrenia Risk: A Family Affair?

Comment by:  Ella Matthews
Submitted 16 June 2006
Posted 5 July 2006

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

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

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

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

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

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

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

View all comments by Ella Matthews

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Jim van Os
Submitted 8 August 2007
Posted 8 August 2007

This excellent review confirms the previous meta-analysis by Henquet et al. (2005) and as such does not add anything new. The importance lies in the UK context: previously the Lancet has been mostly skeptical with regard to this issue. The fact that the leading UK medical journal now also allows these findings to see daylight is a significant event and helps stimulate further funding for the effort that several groups worldwide have started working on over the last five years: the search for the mechanism explaining the link.

View all comments by Jim van Os

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  John McGrath, SRF Advisor
Submitted 9 August 2007
Posted 10 August 2007
  I recommend the Primary Papers

It is reassuring to see that the results of the latest meta-analysis (Moore et al., 2007) are consistent with previous meta-analyses, and that the various meta-analyses are broadly consistent with the now much-tortured primary data. Despite the meta-analysis fatigue, the results are too important to ignore.

When thinking about the impact of cannabis on schizophrenia frequency measures, it is important to remember that cannabis use may translate to an increase in the prevalence of active psychosis via two mechanisms. The data suggest that as the prevalence of cannabis use increases in a population, the incidence of schizophrenia should also increase (Hickman et al., 2007). Furthermore, in those with established schizophrenia, cannabis use is associated with poorer outcomes (i.e., reduced remission rates). Thus, from a modeling perspective, increased cannabis use could lead to an increase in the prevalence of active psychosis via two mechanisms (i.e., increased “inflow” and decreased “outflow”) (McGrath and Saha, 2007).

The prevalence of active psychosis in the community may be “under the influence” of cannabis from more than one perspective.

References:

Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review. Lancet. 2007 July 28; 370:319-328. Abstract

McGrath J, Saha S. Thought experiments on the incidence and prevalence of schizophrenia “under the influence” of cannabis. Addictions 2007 Apr;102(4):514-5. Abstract

Hickman M, Vickerman P, Macleod J, Kirkbride J, Jones PB. Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and Wales. Addiction. 2007 Apr;102(4):597-606. Abstract

View all comments by John McGrath

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Dana MarchEzra Susser (SRF Advisor)
Submitted 20 August 2007
Posted 20 August 2007

The recent meta-analysis in the Lancet (Moore et al., 2007) regarding cannabis use and psychotic or affective mental health outcomes is, indeed, a necessary contribution. It is the first systematic review restricted to longitudinal studies of cannabis use and mental health outcomes. For this addition to the contours of the literature, Zammit and colleagues are to be commended.

We may be more optimistic than the authors, however, about the potential for future longitudinal studies to shed further light on the question of causality, and perhaps more cautious about the present state of the evidence. Given the public health and policy implications, we propose a concerted effort to complete observational studies that are designed to rule out the main alternative explanations for the association (e.g., genetic or social factors that independently influence both cannabis use and psychosis). The Swedish conscript study (Zammit et al., 2002) is a fine example of one such study. We should also be considering natural experiments and designs based on instrumental variables enabled by in order to complement this work. For instance, we might capitalize on situations created by policy changes that affect the availability—and therefore use—of cannabis in order to examine the impact on the development of psychosis. Whether at the individual or the population level, both creativity and rigor are required.

References:

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007 Jul 28;370(9584): 319-28. Abstract

Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002 Nov 23;325 (7374):1199. Abstract

View all comments by Dana March
View all comments by Ezra Susser

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Amresh Shrivastava
Submitted 20 October 2007
Posted 24 October 2007

Current interest in cannabis and the onset of psychosis is laudable. The Lancet paper no doubt establishes a causal link based upon what has been known in the literature (Raphael et al., 2005; Roberts et al., 2007; Rey et al., 2004; Wittchen et al., 2007). The authors need to be congratulated for taking extreme care to incorporate most of the studies and also for making conclusions with a sense of skepticism. That is where further questions arise.

1. Cannabis is used only in certain cultures and known to be involved in a maximum 50 percent of cases of psychosis, schizophrenia, and schizophreniform psychosis (Gregg et al., 2007). In that sense, are there two different phenotypes of schizophrenia, a) where exposure to cannabis is necessarily a factor and b) where a different set of potentiating or precipitating factors work, not cannabis?

2. Even if we focus only on the first possibility, there are few unanswered questions such as, what are the concurrent clinical conditions along with cannabis abuse? Do these patients have cognitive dysfunction? Is that reflective of broader brain mechanism changes?

3. There seems to be no reliable biological explanation as to why exposure to cannabis should precipitate psychosis. Cannabis is one of the most commonly used illicit drugs. Its active compound “cannabidols” has 64 active isomers, each having differing effects on health and behavior. There is strong support for a link between cannabis and development—exacerbation of psychosis as well as other mental health conditions (e.g., anxiety, depression). Further research is needed to determine the underlying neurochemical processes and their possible contributions to etiology, as well as the social factors that contribute to the increasing use of cannabis by young people.

4. There is a theory that preexisting cognitive dysfunction is a core feature of schizophrenia. Accepting this, there are no studies to show “causal relationship” between cannabis and cognitive dysfunction.

The current levels of information and understanding, though collected over last 25-30 years of research, are far from adequate to establish any direct relationship except “mere association.” It is hoped that more precise biological, imaging, and neuropsychological studies would be able to throw fresh light on this important area of research.

Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuroimaging, mainly done in non-psychotic populations, shows little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Δ9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Δ9-tetrahydrocannabinol induces psychotic-like states and memory impairments in healthy volunteers (Linszen et al., 2007).

On the basis of six studies, it is concluded that there was insufficient evidence to prove conclusively that long-term cannabis use causes or does not cause residual abnormalities. The results of several reviews were also inconclusive as to whether cannabis use during adolescence may have a lasting effect on cognitive functioning and brain structure. However, it could not rule out that a) certain cognitive and cerebral abnormalities existed in patients before cannabis use began and b) that patients were suffering from subacute effects of cannabis (Weeda et al., 2006).

Continued cannabis use by persons with schizophrenia predicts a small increase in psychotic symptom severity but not vice versa (Degenhardt et al., 2007). Currently, there is a lot of interest in cannabis use as a risk factor for the development of schizophrenia. Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. In this situation, we need to examine the similarities between these in the context of the neurobiology underlying cognitive dysfunction, particularly implicating the endogenous cannabinoid system, which plays a significant role in attention, learning, and memory, and in general, inhibitory regulatory mechanisms in the brain. Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. The theoretical and clinical significance of further research in this field is enhancing our understanding of underlying pathophysiology and improving the provision of treatments for substance use and mental illness (Solowij et al., 2007). Many studies now show a robust and consistent association between cannabis consumption and the ulterior development of psychosis. Furthermore, our better understanding of cannabis biology allows the proposal of a plausible hypothetical model, based notably on possible interactions between cannabis and dopaminergic neurotransmission (Jockers-Scherubl, 2006). Do they suffer from other disorders, which are underlying or may be causal or comorbid, and do these comorbid conditions also have neurocognitive changes, e.g., psychosis, ADHD, LD, Tourette disorder, and other movement disorders, or depression? Is there an interrelationship among these factors to cause abuse and degree of cannabis consumption?

References:

Raphael B, Wooding S, Stevens G, Connor J. Comorbidity: cannabis and complexity. J Psychiatr Pract. 2005 May; 11(3): 161-7.

Roberts RE, Roberts CR, Xing Y. Comorbidity of substance use disorders and other psychiatric disorders among adolescents: Evidence from an epidemiologic survey. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S4-13. Epub 2007 Feb 1. Abstract

Rey JM, Martin A, Krabman P. Is the party over? Cannabis and juvenile psychiatric disorder: the past 10 years. J Am Acad Child Adolesc Psychiatry. 2004 Oct; 43(10): 1194-205. Abstract

Wittchen HU, Frohlich C, Behrendt S. Cannabis use and cannabis use disorders and their relationship to mental disorders: A 10-year prospective-longitudinal community study in adolescents. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S60-70. Epub 2007 Jan 25. Abstract

Gregg L, Barrowclough C, Haddock G. Reasons for increased substance use in psychosis. Clin Psychol Rev. 2007 May;27(4):494-510. Epub 2007 Jan 19. Abstract

Linszen D, van Amelsvoort T. Cannabis and psychosis: an update on course and biological plausible mechanisms. Curr Opin Psychiatry. 2007 Mar; 20(2): 116-20. Abstract

Weeda MR, Peters BD, De Haan L, Linszen DH. Residual neuropsychological, structural and functional brain abnormalities after long-term cannabis use] Tijdschr Psychiatr. 2006; 48(3): 185-93. Abstract

Degenhardt L, Tennant C, Gilmour S, Schofield D, Nash L, Hall W,McKay D. The temporal dynamics of relationships between cannabis, psychosis and depression among young adults with psychotic disorders: findings from a 10-month prospective study. Psychol Med. 2007 Feb 9; 1-8.

Solowij N, Michie PT. Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci. 2007 Jan; 32(1): 30-52. Abstract

Jockers-Scherubl MC. [Schizophrenia and cannabis consumption: epidemiology and clinical symptoms] Prax Kinderpsychol Kinderpsychiatr. 2006; 55(7): 533-43. Abstract

Curtis L, Rey-Bellet P, Merlo MC. [Cannabis and psychosis] Rev Med Suisse. 2006 Sep 20; 2(79): 2099-100, 2102-3.

Costentin J. [Neurobiology of cannabis--recent data enlightening driving disturbances] Ann Pharm Fr. 2006 May; 64(3): 148-59. Abstract

View all comments by Amresh Shrivastava

Related News: Researchers Probe Generation Gap in Migrants’ Psychosis Risk

Comment by:  Elizabeth Cantor-Graae
Submitted 21 November 2008
Posted 21 November 2008

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 they lead us?
Coid and colleagues argue that the cumulative effect of the various “pressures” operating on migrants might be roughly similar across generations, with some exceptions. In this case, the exceptions are all the more interesting, and likely to be the most informative. The fact that second-generation black Caribbeans had markedly higher rates of psychoses than black Caribbeans born in the Caribbean suggests differential pressures operating on these two groups. Although these pressures have yet to be identified (more detective work needed!), some mechanisms suggest themselves. The generation of black Caribbeans that emigrated to the U.K. during the 1950s and 1960s were more readily incorporated into the labor market than today’s generation (second-generation immigrants). Although their jobs might have primarily been in the service or unskilled sectors, the ability to get a “foot” into society and earn a living could have represented substantial gains for this generation in terms of positive self-esteem and protection against feelings of negative self-worth and/or outsider status. In contrast, the second generation of African-Caribbean immigrants seems to have more difficulty securing a place within U.K. society. Their difficulties may be compounded by unstable home environments. Ethnic groups with strong familial ties, such as Asians or the example of the Turks in The Netherlands (Selten et al., 2001), appear better able to buffer the negative effects of discrimination and marginalization. Thus, the extent to which families are able to provide stable home environments seems to be a crucial modifier of minority group “stress,” and we may very well see a resurgent interest in the near future in studies focusing on the schizophrenogenic family.

It may be noted that Coid and coworkers’ results are well in line with the social defeat hypothesis (Cantor-Graae and Selten, 2005; Selten and Cantor-Graae, 2005; Selten et al., 2007), which suggests that a key contributor to the migrant psychosis phenomenon is long-term chronic exposure to social defeat, possibly resulting in dopamine disturbances in the brain. While discrimination may play a key role in the experience of social defeat, the mechanisms that enhance vulnerability to psychosis in any specific minority group are probably complex. Certainly there is a need for confirmatory studies from settings where waves of migration span several generations, for example, countries such as France and Spain, in order to re-test Coid and colleagues’ findings. However, results from Israel, a country with a long history of heterogeneous migration, confirm the notion that “outsider” status may vary from group to group (Weiser et al., 2008) and across generations (Corcoran et al., 2008) and that this may in turn determine that group’s risk for schizophrenia. In other words, context may well prove to be “everything.” Thus, investigations that can shed further light on the elements that make up the contextual environment are likely to be especially fruitful.

The broader implications of Coid and coworkers’ important new migrant study are several. We need to once and for all accept the notion that schizophrenia is not uniformly distributed among groups, and to intensify research efforts that may further elucidate the nature of the underlying exposure variable(s). Although it may take considerable effort to track down the “culprit,” the good news is that social factors lend themselves to preventative interventions. There may well be a glimpse of light at the end of the tunnel.

References:

Selten JP, Veen N, Feller W, Blom JD, Schols D, Camoenië W, Oolders J, van der Velden M, Hoek HW, Rivero VM, van der Graaf Y, Kahn R. Incidence of psychotic disorders in immigrant groups to The Netherlands. Br J Psychiatry. 2001 Apr 1;178():367-72. Abstract

Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry. 2005 Jan 1;162(1):12-24. Abstract

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

Selten JP, Cantor-Graae E, Kahn RS. Migration and schizophrenia. Curr Opin Psychiatry. 2007 Mar 1;20(2):111-5. Abstract

Weiser M, Werbeloff N, Vishna T, Yoffe R, Lubin G, Shmushkevitch M, Davidson M. Elaboration on immigration and risk for schizophrenia. Psychol Med. 2008 Aug 1;38(8):1113-9. Abstract

Corcoran C, Perrin M, Harlap S, Deutsch L, Fennig S, Manor O, Nahon D, Kimhy D, Malaspina D, Susser E. Incidence of Schizophrenia Among Second-Generation Immigrants in the Jerusalem Perinatal Cohort. Schizophr Bull. 2008 Jul 22; Abstract

View all comments by Elizabeth Cantor-Graae

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.

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

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).

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

View all comments by Elizabeth Cantor-Graae

Related News: ICOSR 2011: Back to the Prenatal Environment

Comment by:  Segundo Mesa
Submitted 24 June 2011
Posted 24 June 2011

There is increasing evidence that favors the prenatal beginning of schizophrenia (Gourion et al., 2004; Cannon and Murray, 1998; Wintour et al., 2006). This evidence points toward intrauterine environmental factors that act specifically during the second pregnancy trimester, producing direct damage of the brain of the fetus. The currently available technology doesn't allow us to observe what is happening at the cellular level, since the human brain is not available for direct analysis in that stage of life. Most of the techniques that have accumulated evidence of prenatal cerebral damage have been of low resolution and by means of indirect methods. It is necessary to have a technique with high resolution that allows for obtaining the necessary information on the brain of the fetus and of the environmental factors that surround him or her.

In 1977, we began direct research of the brain with schizophrenia with electron microscopic techniques, using the brains of deceased adult schizophrenic patients, animals experimentally inoculated with cerebrospinal fluid from schizophrenic patients, and fetuses of schizophrenic mothers. The obtained results guide toward a viral etiology of the illness, specifically by herpes simplex hominis type 1 virus (Mesa-Castillo, 2001; Mesa-Castillo, 2011). Later results of other authors using other techniques and research designs relate damage of the brain to the direct action of a virus or indirect immunologic damage (Fruntes and Limosin, 2008; Brown et al., 2004; Shi et al., 2005). The objective of our research was not only to study the brain of the fetus, but also the environment that surrounds him or her; thus, we studied both the brain of the fetus and the placenta during the second trimester of schizophrenic mothers whose pregnancies were interrupted for medical indications.

References:

Gourion D, Gourevitch R, Leprovost JB, Olie H loo JP, Krebs MO. Neurodevelopmental hypothesis in schizophrenia. Encephale 2004; 30: 109-118. Abstract

Cannon M, Murray MR. Neonatal origins of schizophrenia. Arch Dis Child 1998; 78: 1-3. Abstract

Wintour EM, Owens AJ. Early Life Origins of Health and Disease. Auckland, New Zealand: Eurekah.com and Springer Science + Business Media; 2006.

Mesa-Castillo S. An ultrastructural study of the temporal lobe and peripheral blood in schizophrenic patients. Rev Neurol. 2001; 33: 619-23. Abstract

Mesa-Castillo S. Direct evidence of herpes simples hominis type I virus in the temporal lobe of schizophrenic patients, their offspring and experimental animals. Boletín de esquizofrenia y otras psicosis. 2011.

Fruntes V, Limosin F. Schizophrenia and viral infection during neurodevelopment: A pathogenesis model? Med Sci Monit 2008; 14: 71-77. Abstract

Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004; 61: 774-780. Abstract

Shi L, Tu N, Patterson PH. (2005): Maternal influenza infection is likely to alter fetal brain development indirectly: The virus is not detected in the fetus. Int J Dev Neurosci 23: 299-305. Abstract

View all comments by Segundo Mesa

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.

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

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.

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.

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.

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

View all comments by Dana March