Schizophrenia Research Forum - A Catalyst for Creative Thinking

Refining Schizophrenia Epidemiology

27 January 2012. In the vast search space of potential environmental contributors to schizophrenia risk, epidemiologists have homed in on a few sectors, such as drug use, migration, trauma, prenatal nutrition, and the immune system as risk factors. Several recent studies take a finer-grained look at these candidates to try to discern the nuances of their involvement in the disorder. The picture for cannabis is clouded by the most recent results, but the search may intensify around methamphetamine use, migration into a new country as a baby or toddler, child abuse, the immune system, and interactions between some of these factors.

In an editorial accompanying four of the new papers that appeared in the December issue of the American Journal of Psychiatry, John McGrath of the University of Queensland in Australia and Debbie Lawlor of the University of Bristol in the United Kingdom point to the new studies as not just replicating, but refining our understanding of schizophrenia risk. This should help discriminate true risk factors from proxies that flag some other yet-to-be-identified factor. As an example, they highlight the risk associated with migration: it could stem from the social stresses of navigating a new country (see SRF Live Discussion); a deficiency in vitamin D that may occur in dark-skinned people living in the Northern hemisphere (see SRF related news story); or higher infection rates as they encounter new bugs. Well-designed studies should help extract the true risk factors, and eventually deliver ideas for treatment and prevention.

Drug use
Cannabis use has been consistently associated with increased risk for psychosis (see SRF related news story), but this message has been tempered by findings that this cannabis-induced risk applies specifically to individuals carrying a certain variant of the gene encoding catechol-methyl-transferase (COMT) (Caspi et al., 2005). However, a study led by Stanley Zammit of Cardiff University in Wales, United Kingdom, published in November in the British Journal of Psychiatry, did not find evidence for this oft-cited gene-environment interaction in a cohort of adolescents followed from birth (the Avon Longitudinal Study of Parents and Children). Based on answers from 2,630 study participants who completed questionnaires about their cannabis use at age 14 and psychotic experiences at age 16, the study found a 2.5-fold increase in the risk of psychosis in those who had used cannabis by age 14 compared to those who hadn’t, but this risk was not consistently modulated by any one of six loci genotyped in the COMT gene. This suggests that the risk associated with cannabis use may apply more widely than just to certain COMT genotypes.

Even before the cannabis-psychosis connection emerged, other research had suggested that methamphetamine abuse could trigger persistent psychosis (Ujike et al., 2004). This possibility has not gained much traction in the West, which tends to attribute psychosis in these instances to an undiagnosed psychiatric condition. However, a new study published online November 8 in the American Journal of Psychiatry finds evidence for an association between methamphetamine and schizophrenia in a large, population-based Californian cohort that was free of psychosis prior to drug use. Led by Russell Callaghan at the University of Toronto, Canada, the study used hospital discharge records of 42,412 individuals who had been hospitalized for methamphetamine abuse, and found that they had a higher risk of a later hospital readmission with a schizophrenia diagnosis. This risk was nine times that of the control group, which consisted of individuals hospitalized for appendicitis. The methamphetamine risk was similar in magnitude to cannabis use, and greater than that found in groups of patients hospitalized for cocaine, opioid, and alcohol abuse. These findings require replication, and they leave open the question of whether substance-related psychosis is distinct from the state typically recognized in schizophrenia.

Early childhood
Building on previous studies that find increased risk for psychosis among migrants (see SRF related news story), Wim Veling of Parnassia Psychiatric Institute in The Hague, The Netherlands, and colleagues asked whether age at migration modulated this risk. In a study published in December in the American Journal of Psychiatry, the researchers found that 273 immigrants, 119 second-generation citizens, and 226 Dutch citizens living in The Hague had seen a physician for a suspected psychotic disorder during a seven-year period. Consistent with previous studies, this resulted in an incident rate for psychosis that was highest among the immigrants, which included individuals from Surinam, the Netherlands Antilles, Turkey, and Morocco.

When they looked at the individuals' ages, the researchers found that those who had migrated as young children, between zero and four years old, had the highest risk, with an incidence rate ratio of about 3 when compared to Dutch citizens. This risk decreased with older age at migration, thus singling out early childhood as a critical time. Though the precise migration-induced risk factor remains elusive—it could be related to diet, lifestyle, or social stress, for example—the findings indicate that probing the migrant experience early on may hold some clues. The researchers highlighted social adversity, writing: “It is conceivable that repeated or chronic exposure to social adversity in childhood and adolescence leads to the generation of cognitive biases and affective states that predispose an individual to symptom formation, such as paranoia and formation of persecutory delusions.”

Consistent with childhood as a particularly vulnerable time, another study published in December in the American Journal of Psychiatry associated childhood trauma and psychosis later in life. Though this association has been reported before, the findings have been dogged by confounds, leading Inez Myin-Germeys of Maastricht University in The Netherlands and colleagues in the Genetic Risk and Outcome in Psychosis (GROUP) project to look for the association in a careful comparison of childhood trauma reported by people with psychotic illness, their unaffected siblings, and healthy controls. First author Manuela Heins found that individuals with psychosis reported more childhood trauma than did their siblings, and siblings reported more trauma than controls. This resulted in an association between trauma and psychosis with an odds ratio of 2.6 between cases and siblings, 4.5 between cases and controls, and 1.6 between siblings and controls. Childhood abuse, rather than neglect, was strongly associated with positive symptoms in psychotic individuals.

Combinations of complications
A third study in the December issue of the American Journal of Psychiatry explored an immunological hypothesis of schizophrenia, building on previous reports of autoimmune disease (Eaton et al., 2006) and infection (see SRF related news story) as risk factors for schizophrenia. Led by Michael Benros at the University of Aarhus in Denmark, the study found that these two factors interacted in a population-based cohort drawn from 30 years' worth of Danish registry information, which included 39,076 people with schizophrenia. An autoimmune disease increased the risk of schizophrenia (incidence rate ratio = 1.29), as did hospitalization for infection (incidence rate ratio = 1.60), whereas having both elevated risk further than expected from adding the two together (incidence rate ratio = 2.25), and worsened with multiple hospitalizations for infection. This supports the idea that a faulty or overworked immune system allows autoantibodies to slip into the brain, promoting inflammation and dysfunction that may tilt the brain toward schizophrenia (see SRF related news story).

An interaction between developmental delay and obstetric complications—both risk factors for schizophrenia with considerable support—was also reported in a study in the December American Journal of Psychiatry. Led by Mary Clarke and Mary Cannon at the Royal College of Surgeons in Ireland, Dublin, the researchers used health registers in Helsinki to track the early health histories of individuals born there between 1962 and 1969. They found that individuals with delays in motor development had two to three times the odds of developing schizophrenia compared to those without delays, and obstetric complications further increased this risk (odds ratio = 4.6). This suggests that motor problems may reflect a neurodevelopmental vulnerability, which may be exacerbated by problems at delivery.

Together, the studies add to the sense that epidemiology is delivering some consistent candidate risk factors, rather than fleeting one-offs. A hard question, posed by McGrath and Lawlor in their editorial, is knowing when these factors are delineated well enough to act upon for schizophrenia treatment or prevention.—Michele Solis.

References:
McGrath JJ, Lawlor DA. The search for modifiable risk factors for schizophrenia. Am J Psychiatry. 2011 Dec 1; 168: 1235-1238. Abstract

Zammit S, Owen MJ, Evans J, Heron J, Lewis G. Cannabis, COMT and psychotic experiences. Br J Psychiatry. 2011 Nov; 199: 380-385. Abstract

Callaghan RC, Cunningham JK, Allebeck P, Arenovich T, Sajeev G, Remington G, Boileau I, Kish SJ. Methamphetamine Use and Schizophrenia: A Population-Based Cohort Study in California. Am J Psychiatry. 2011 Nov 8. Abstract

Veling W, Hoek HW, Selten JP, Susser E. Age at migration and future risk of psychotic disorders among immigrants in the Netherlands: a 7-year incidence study. Am J Psychiatry. 2011 Dec 1; 168: 1278-1285. Abstract

Heins M, Simons C, Lataster T, Pfeifer S, Versmissen D, Lardinois M, Marcelis M, Delespaul P, Krabbendam L, van Os J, Myin-Germeys I; the GROUP project. Childhood Trauma and Psychosis: A Case-Control and Case-Sibling Comparison Across Different Levels of Genetic Liability, Psychopathology, and Type of Trauma. Am J Psychiatry. 2011 Dec 1; 168: 1286-1294. Abstract

Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011 Dec 1; 168: 1303-1310. Abstract

Clarke MC, Tanskanen A, Huttunen M, Leon DA, Murray RM, Jones PB, Cannon M. Increased Risk of Schizophrenia From Additive Interaction Between Infant Motor Developmental Delay and Obstetric Complications: Evidence From a Population-Based Longitudinal Study. Am J Psychiatry. 2011 Dec 1; 168: 1295-1302. Abstract

Comments on Related News


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: Research Roundup —The Tapestry of Environmental Influences in Psychosis

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 McGrath

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment 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 Luhrmann

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment 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 Cannon

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment 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 Selten

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment 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

Related News: Evidence Mounts for the Maternal Inflammation Hypothesis of Schizophrenia

Comment by:  Stephen Marder, SRF Advisor
Submitted 10 July 2014
Posted 11 July 2014

Accumulating evidence indicates that activation of the maternal immune system—from infectious and non-infectious sources—increases the risk of schizophrenia. This interesting study using data from the Finnish Prenatal Study of Schizophrenia measured C-reactive protein, a general marker of inflammation, in maternal serum from 777 schizophrenia subjects and an equal number of controls. The importance of this study derives from the size of the sample and the strength of the relationship between immune activation and schizophrenia risk.

View all comments by Stephen Marder

Related News: Evidence Mounts for the Maternal Inflammation Hypothesis of Schizophrenia

Comment by:  Chris Carter
Submitted 16 July 2014
Posted 16 July 2014
  I recommend the Primary Papers

If the development of schizophrenia depends upon maternal infection, perhaps a large number of susceptibility genes (possibly related to infection susceptibility and the immune system) would be concentrated in maternal alleles, with other maternal/paternal genes contributing later in life, and in different ways, for the offspring.

Have there been , or are there programmed, any genome-wide association studies on non-schizophrenic mothers of schizophrenic patients? A comparison of maternal/paternal genetic donation might perhaps be a useful means of dissecting out the various pathways leading to disease.

View all comments by Chris Carter