Chapter 1. Epidemiology

The concept of ethnicity includes a wide range of features, including cultural, racial, national, tribal, religious, and linguistic origins and backgrounds. Culture is a collection of beliefs, attitudes, shared understandings, knowledge, customs, habits, and patterns of behavior that influence cognitions and social development of individuals. Culture plays a significant role in conceptions of both normality and deviance through which abnormality is defined and identified. The varying prevalence estimates for schizophrenia reported by country are affected by cultural differences. DSM-5 underscores the value of cultural studies to demonstrate the challenge of reliably diagnosing schizophrenia among different populations (American Psychiatric Association 2013). Similarities and differences in the expression of symptoms are closely linked to a patient’s ethnicity, social context, cultural background, and degree of comfort and willingness to cooperate during a psychiatric assessment (Eack et al. 2012; McLean et al. 2014). Cultural differences are also likely to impact differences in reporting of disease by native and foreign-born residents.

Immigrants and their descendants have been found to be approximately 2.5 times more likely to have a psychotic disorder than the majority ethnic group in given settings (Cantor-Graae and Selten 2005). There are a number of plausible explanations for immigrants’ increased risk for psychosis. Migrants can experience a grief reaction to the loss of language, social structures, and social support. Resettlement can bring difficulties in resuming education, finding work, and obtaining adequate housing and health care. Immigrants are less likely than native-born counterparts to be referred to or to seek out mental health treatment, and finding affordable and linguistically and culturally accessible services presents additional challenges (Shekunov 2016).

The male germ line is a major source of new mutations in humans. Advanced age of the father at conception increases the mutation rate, likely due to an accumulation of replication errors in spermatogonial cell lines. In a large Israeli birth cohort, older paternal age was a strong and significant predictor of schizophrenia diagnosis. Compared with the risk in offspring of fathers younger than age 25 years, the relative risk (RR) of schizophrenia increased in each 5-year-older age group, doubling the risk in offspring of men ages 45–49 years and almost tripling the risk in children of men 50 years or older (Malaspina et al. 2001). Analyses of data from the Prenatal Determinants of Schizophrenia study also showed that advanced paternal age increased the risk of adult schizophrenia (Brown et al. 2002).

Numerous studies have found evidence that infection is a risk factor for schizophrenia. Microbial pathogens that cause disease such as influenza and toxoplasmosis have long been known to cause congenital brain abnormalities. The original studies on influenza and schizophrenia were limited because they were based on whether the individual was in gestation during an influenza epidemic, with no actual confirmation of maternal influenza infection. Consequently, a new approach was necessary to corroborate a connection between schizophrenia and prenatal exposure to infection. Advances were made through birth cohort studies, in which biological specimens were obtained during pregnancy and offspring were systematically assessed longitudinally. Maternal exposure during pregnancy to herpes simplex virus type 2, Toxoplasma gondii, and the influenza virus has been found to be associated with increased risk for schizophrenia in offspring (Brown and Derkits 2010). A more recent analysis of Finnish Prenatal Studies data including inflammatory factors revealed that serum C-reactive protein was higher in pregnant women whose offspring later developed schizophrenia (Canetta et al. 2014). One potential mechanism by which infection and inflammation during pregnancy could increase the risk for schizophrenia in offspring is the reduction of iron bioavailability to the developing fetus (Aguilar-Valles et al. 2010).

Khandaker et al. (2012) conducted a systematic review and meta-analysis of seven large population-based cohort studies that included minors with central nervous system (CNS) infection (n=13,458) and control subjects (n=1,218,776). Participants in the studies were followed for the development of schizophrenia (n=1,035). The most commonly identified viral agents—cytomegalovirus, Coxsackie B5, and mumps—accounted for about half of the identified cases. CNS viral infections in childhood were shown to be associated with a greater than twofold increased risk of adult nonaffective psychosis (RR=2.12; 95% confidence interval [CI]=1.17–3.84). The authors proposed that a link between the CNS infection, an inflammatory process, and an immune system dysfunction might explain the increased risk of adult schizophrenia (Khandaker et al. 2012).

Mounting evidence has identified increased distance from the equator and birth during winter or spring as risk factors for schizophrenia. A meta-analysis including 49 prevalence study samples from Africa, east and south Asia, Europe, North America, Argentina, and New Zealand revealed that the prevalence of schizophrenia across these samples varied widely, from 0.09% in Accra, Ghana, near the equator to 2.8% in Oxford Bay, Canada, near the Arctic Circle. The prevalence was greater among samples from geographical locations of higher latitude and colder climate. The correlations of schizophrenia prevalence with latitude (r=0.46, P <0.001) and mean temperature (r=–0.60, P <0.001) were both significant. These findings suggest that the risk of developing schizophrenia may increase with perinatal exposure to adverse environmental factors associated with higher latitudes and lower temperatures (Kinney et al. 2009). In addition, a widely replicated finding indicates that compared with births in the summer or fall, births in the winter or spring are associated with a higher risk of developing schizophrenia (Brown 2011). The seasonal risk has been seen to become even more elevated as the distance from the equator increases. Researchers hypothesize that higher latitude and lower temperature are associated with greater prenatal exposure to infections such as influenza and toxoplasmosis, which in turn may increase the incidence of schizophrenia (Kinney et al. 2009).

Schizophrenia is overrepresented in the most deprived sectors of society. In 1939, it was reported that there were more schizophrenia-related hospital admissions in the poorer central areas of Chicago than in the suburbs. For a long time, this disparity was explained as the result of preschizophrenic individuals “drifting” into the deprived inner cities. However, studies from Sweden, the Netherlands, Denmark, the United Kingdom, and other countries have shown that the incidence of the disorder is higher among individuals born and raised in urban areas, especially in areas with less social cohesion (Stilo and Murray 2010). In results from analyses of data from the Environmental Risk (E-Risk) Longitudinal Twin Study, which tracks the development of a nationally representative birth cohort of 2,232 British twins, urbanicity was significantly associated with psychotic symptoms by age 12 years (odds ratio [OR]=1.76; 95% CI=1.15–2.69), with almost 25% of the effect explained by low social cohesion and crime victimization by age 5 years (Newbury et al. 2016). A prospective study in France found that the raw incidence of psychotic disorders in urban areas was 36.02 per 100,000 person-years versus 17.2 per 100,000 person-years in rural areas (Szöke et al. 2014). A systematic review of incidence rates of schizophrenia and other forms of psychosis in England from 1950 to 2009 found that the incidence of schizophrenia increased in larger cities (e.g., London) and decreased in smaller cities (e.g., Nottingham) during that time period. Changes in the clinical presentation of the disorder, as well as in diagnostic practice and the organization of mental health services, are thought to have led to these shifting patterns (Kirkbride et al. 2012).

A socioeconomic gradient is observed worldwide for a number of health outcomes (e.g., cancer, coronary heart disease); decrements in social class are associated with increased morbidity and mortality rates. It has long been thought that socioeconomic status may also be causally related to schizophrenia. An Israeli population-based cohort study from 1964 to 1976, which included 88,829 births, followed offspring until schizophrenia diagnosis. The study found that the offspring of fathers in the lowest socioeconomic status category had a 40% increased risk of developing the disorder (RR=1.4; 95% CI =1.1–1.8) (Corcoran et al. 2009). Another Israeli study reported that children born to parents with lower educational attainment or of lower occupational class had an elevated risk for developing schizophrenia (Werner et al. 2007). A systematic review of 110 studies from 28 countries published from 1975 to 2011 explored the relationship between a country’s incidence of schizophrenia and its Gini coefficient, a commonly used measure of income inequality in which a higher coefficient indicates a higher degree of income inequality. The investigators found that for each one-point increase in the Gini coefficient, there was a two-point increase in the incidence rate of schizophrenia after controlling for urbanization, migration, and unemployment (Burns et al. 2014).

Exposure to adverse events in childhood has been found to be associated with a twofold to fourfold increase in risk of psychosis (Morgan and Gayer-Anderson 2016). One cross-sectional study showed that patients with schizophrenia reported more severe childhood trauma (e.g., emotional, physical, sexual abuse), lower resilience, and worse physical health than did nonpsychiatric control subjects (Lee et al. 2018). Childhood traumatic experiences also tend to co-occur, with exposure to one type of adversity increasing the risk for exposure to others, resulting in a cumulative effect on psychosis (Shevlin et al. 2008).

Individuals with schizophrenia are at greater risk for metabolic and other chronic diseases. A Swedish population-based study found that the most common comorbidities among 7,284 individuals diagnosed with schizophrenia were essential hypertension, diabetes, and obesity. Those ages 50–59 years were seen to have the highest prevalence of these comorbidities compared with other age groups (Brostedt et al. 2017). The higher risk for cardiometabolic disorders may be attributable to metabolic effects of antipsychotic medications, poor nutrition, and lack of physical activity. In spite of having high rates of these disorders, patients with schizophrenia have lower than expected rates of diagnosis and treatment for cardiovascular disorders (Smith et al. 2013).

Individuals with schizophrenia have a significant reduction in life expectancy. Mortality increase is due to both natural and unnatural causes, which result in an estimated 10- to 15-year decrease in life expectancy (Bushe et al. 2010; Healy et al. 2012). A review of eight studies identified suicide (0%–46%), cardiovascular disease (12%–49%), cancer (7%–21%), accidents (4%–10%), cerebrovascular disease (3%–8%), and respiratory disease (17%) as the most common causes of premature death in those with schizophrenia (Bushe et al. 2010). Individuals with schizophrenia are two to three times more likely to die at younger ages than the general population (World Health Organization 2016, 2018).

Up to 40% of the excess risk for premature death among those with schizophrenia is attributable to suicide and other unnatural deaths (Bushe et al. 2010). For individuals with schizophrenia, the lifetime suicide risk is estimated at 4%–6% (Palmer et al. 2005; Popovic et al. 2014). A systematic review conducted by a task force of experts and clinicians (Popovic et al. 2014) found that suicide risk in individuals with schizophrenia is highly correlated with affective symptoms, a history of suicide attempts, and number of psychiatric admissions. Other risk factors identified for suicide include younger age, proximity to illness onset, older age at illness onset, male sex, substance use, and the period during or following psychiatric discharge. Other causes of unnatural death include homicide and accidents. In a study of Medicaid recipients in the United States, accidents were found to account for more than twice as many deaths as suicide among adults with schizophrenia (Olfson et al. 2015). Drug-induced deaths, whether accidental or intentional, were a common source of mortality.

Substance use and misuse are common among people with schizophrenia, and their presence increases the risk of suicide, nonpsychiatric comorbidities, and premature mortality (Fazel et al. 2009; Sharifi et al. 2015). A large Swedish study found a 7.9% 1-year prevalence of substance use disorder among individuals with schizophrenia and a 24.8% 12-year prevalence (Brostedt et al. 2017). A review of the association between cannabis use and psychosis found that cannabis use increased the risk for development of schizophrenia. After controlling for multiple factors, Radhakrishnan and colleagues (2014) found that more frequent consumption (50 times or more in lifetime) and earlier use (<15 years of age) were associated with psychotic symptoms. The legalization of medicinal and recreational use of cannabis in certain parts of the world has therefore raised questions about its impact on mental health and specifically on the incidence of schizophrenia. A statewide study conducted in Colorado, where recreational cannabis use has been legal since 2012, showed a fivefold higher prevalence of mental health diagnoses in cannabis-associated emergency department visits compared with visits not involving cannabis (Hall et al. 2018).

Individuals with schizophrenia and other psychoses are at increased risk for engaging in violent behavior. A systematic review and meta-analysis of 20 studies found that schizophrenia and other psychoses were associated with interpersonal violence and violent criminality, particularly homicide. For men, the ORs for violence committed by those with schizophrenia and other psychoses versus those of general population samples ranged from 1 to 7 with considerable heterogeneity; in women, the ORs ranged from 4 to 29 with substantial variation. Most excess risk was attributable to substance use (Fazel et al. 2009). In a systematic review and meta-regression analysis of 110 studies, nonadherence to treatment regimens, recent substance misuse, poor impulse control, and criminal history were found to be risk factors for violence in adults with schizophrenia and adults with other psychoses (Witt et al. 2013).