Emerging evidence has demonstrated that stress and other environmental factors may contribute to the development of schizophrenia.1 Although genes do play a role in the disease, the genetic concordance rate of schizophrenia is approximately 50% — even in identical twins.1 That is why researchers continue to study the psychosocial and environmental inputs linked to the early-stage schizophrenia phenotype.1

Animal studies have suggested that unregulated stress during vulnerable developmental stages in childhood and adolescence can contribute to schizophrenia.1 Human studies point to physical and mental abuse, being socially disadvantaged, and living in an urban environment as risk factors for schizophrenia.1 Children who react poorly to stress and have high anxiety levels are especially vulnerable.1

What environmental triggers can lead to schizophrenia? “Stress is a big one. Cannabis use is one in susceptible individuals (ie, those with genetic predisposition),” said Anthony A. Grace, PhD, distinguished professor of neuroscience, professor of psychiatry and psychology from the University of Pittsburgh in Pennsylvania.

Prenatal and Maternal Stress

In a study of 240 adults with schizophrenia spectrum disorder (SSD), bipolar disorder, and major depressive disorder and 85 controls, psychiatrist Valentina Pugliese, MD, from the University “Magna Graecia” of Catanzaro in Catanzaro, Italy, and colleagues sought to determine an association between maternal stress and later mental illness in adulthood.2 Researchers interviewed mothers about stressful events during their pregnancies, as measured by the Social Readjustment Rating Scale, and drew data from medical records.2

“Our study found a 2-fold increased risk for schizophrenia in offspring whose mothers were exposed to psychological stress during pregnancy, including death or illness of a close loved one, health problems, serious disagreements with their partner, financial problems, major employment change of partner, serious problems with housing or with the law,” explained coauthor psychiatrist Pasquale De Fazio, MD, also from the University “Magna Graecia” of Catanzaro.

“We found a strong association between inadequate [weight] gain during pregnancy, prenatal infections, and schizophrenia, with an increased risk of 9-fold and 8-fold in the offspring, respectively. The probability of schizophrenia [developing] after exposure to peripartum asphyxia was increased 5-fold. Prenatal exposure to stress, malnutrition, and immune activation can negatively affect early fetal brain development and change the offspring’s neurodevelopmental trajectories, which can lead to the emergence of behavioral and cognitive disturbances in later life,” Dr De Fazio said.

Childhood Adversity and Schizophrenia Susceptibility

In a systematic review of 25 studies, Karolina I. Rokita, PhD, from the Center for Neuroimaging and Cognitive Genomics at the National University of Ireland in Galway, and colleagues sought to characterize the risk factors in childhood that contribute to major psychiatric illness in adulthood, including schizophrenia, bipolar disorder, major depression, personality disorder, and posttraumatic stress disorder.3 Caregiver response and support affected children’s later emotional, cognitive, and social development.3

“Emotional and sexual abuse as well as physical neglect have been shown to be the most powerful predictors of later psychopathology,” said coauthor Gary Donohoe, PhD, professor of psychology and director of the Center for Neuroimaging and Cognitive Genomics at the National University of Ireland. “As evident from our review, these adverse childhood experiences may also have a crucial role in the development of social cognitive abilities, which could mediate the association between early life adversities and later symptom severity.”

Early Events Affect Developing Adolescent Brains

As a time of major brain development, adolescence is a vulnerable period for early life stress.4 The brain regions affected in this development include the amygdala, hippocampus, and the prefrontal cortex, particularly when they are exposed to chronic stress.4 However, more research is needed to determine how changes in these regions manifest as major psychiatric disorders.4

“Clinicians working with teens should take into consideration — as many already do — stress management strategies as part of the overall treatment plan,” advised Russell D. Romeo, PhD, associate professor of psychology from Barnard College of Columbia University in New York City.

Chronicity Factors Into Stress Vulnerability

To better determine the nature of chronic stress and its relationship to schizophrenia, Anya Savransky, from the Maryland Psychiatric Research Center, University of Maryland School of Medicine in Baltimore, and colleagues compared data from 58 patients with SSD with that from 34 age- and sex-matched controls.5 Patients who had experienced a psychotic episode within the first 5 years of SSD were more likely to have had a greater allostatic load (AL) compared with the healthy control group, which suggests that AL may occur in the early stages of psychosis.5 In people with SSD with chronic psychosis, AL was still present, but not to the extent it was in patients with early-stage psychosis.5

“Young patients with psychosis likely have increased stress that not only affects their brains, but may also be associated with subclinical cardiovascular, metabolic, and stress response dysfunctions,” noted coauthor and psychiatry professor L. Elliot Hong, MD, also from the University of Maryland School of Medicine. “Early monitoring and preventive intervention of these systematic effects may be important to reduce the impacts of stress-related chronic cardiometabolic effects, in addition to the side effects from psychotropic medications.”

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Early Detection With Biomarkers

The sooner clinicians diagnose and treat schizophrenia, the better the prognosis.6 To that end, researchers are examining the roles of glutamate signaling dysfunction and oxidative stress dysregulation to better predict the prodrome of schizophrenia.6 Emerging evidence points to the N-methyl-D-aspartate receptor as a potentially useful biomarker to detect prodromal schizophrenia.6  

“Clinical manifestation of schizophrenia consists of not only psychotic symptoms but also cognitive deficits such as impaired memory, attention, and executive functions,” said psychiatrists Chieh-Hsin Lin, MD, PhD, and Hsien-Yuan Lane, MD, PhD, from China Medical University, Taichung, Taiwan. “Most individuals experience a period of prodromal symptoms prior to the diagnosis of schizophrenia. Before full-blown psychotic symptoms appear, individuals may experience changes in cognition, behavior, and function. Therefore, it is crucial to identify populations at high risk for schizophrenia.”

Summary and Clinical Applicability

Early life stressors, including those in utero, can trigger the processes that lead to schizophrenia and affective disorders in adulthood. Nascent evidence points to susceptibility during brain development that contributes to the early-stage schizophrenia phenotype.

References

1. Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia [published online January 30, 2019]. Schizophr Res. doi: 10.1016/j.schres.2019.01.030

2. Pugliese V, Bruni A, Carbone EA, et al. Maternal stress, prenatal medical illnesses and obstetric complications: risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder. Psychiatry Res. 2019;271:23-30.

3. Rokita KI, Dauvermann MR, Donohoe G. Early life experiences and social cognition in major psychiatric disorders: a systematic review. Eur Psychiatry. 2018;53:123-133.

4. Romeo RD. The impact of stress on the structure of the adolescent brain: implications for adolescent mental health. Brain Res. 2017;1654(Pt B):185-191.

5. Savransky A, Chiappelli J, Fisseha F, et al. Elevated allostatic load early in the course of schizophrenia. Transl Psychiatry. 2018;8(1):246.

6. Lin CH, Lane HY. Early identification and intervention of schizophrenia: insight from hypotheses of glutamate dysfunction and oxidative stress. Front Psychiatry. 2019;10:93.