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.
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.
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.
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