Schizophrenia is the most common psychotic mental disorder in the United States. It affects approximately 1% of the population and accounts for up to $23 billion in U.S. health care expenditures.¹ Black people have disproportionately higher rates of being diagnosed with schizophrenia compared with non-Latino White people, which may be because of physician bias, less access to health care, and underdiagnosis of other psychiatric conditions, such as bipolar depression.^2–4 According to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., men tend to have a syndromic phase between 18 and 25 years of age.⁵ In women, there are two peaks of syndromic presentation, the first between 25 years of age and mid-30s, and the second after 40 years of age.⁵ Initial presentation before 15 years of age is possible but rare.⁵ Medication adherence is associated with decreased risk of relapse into active-phase schizophrenia.⁶ Primary care physicians should be aware that patients with schizophrenia have an increased risk of cardiovascular disease as well as overall mortality.⁷

Pathophysiology

The pathways associated with the development of psychotic symptoms involve altered neurotransmission of glutamate, serotonin, and dopamine in the hippocampus, midbrain, corpus striatum, and prefrontal cortex.⁸ Although the pathogenesis is unclear, proinflammatory cytokines may play a role in the development of schizophrenia and have recently prompted an interest in the therapeutic use of anti-inflammatory and immunomodulatory agents.⁹ Disrupted neural function during adolescent development and subcortical dopamine dysregulation are the neuromolecular processes that may account for symptoms ranging from cognitive deficits to psychosis.¹⁰

Etiology

The development of schizophrenia is best understood as a multifactorial process involving the interaction of genetic predisposition and environmental factors, also known as the polygenic threshold model.¹¹ Epidemiologic studies suggest a hereditary pathogenesis for psychotic disorders, with higher rates in siblings and parents with a psychotic disorder and a 50% concordance of genetic loci between identical twins.⁸

Environmental factors that increase the risk of schizophrenia during fetal development and early life include infections (e.g., rubella, influenza, Toxoplasma gondii, herpes simplex virus type 2), and nutritional deficiencies (e.g., folic acid, iron, vitamin D).¹² Pregnancy and birth complications, specifically neonatal hypoxic events, appear to be significant risk factors for the development of schizophrenia.¹³ Other observed risk factors include cannabis use, childhood trauma, and socioeconomic status.¹² These risk factors work at the epigenetic level to show genetic and inflammatory predispositions.

A large longitudinal prospective study of adolescents in New Zealand showed a relationship between cannabis use and the development of schizophrenia.¹⁴ A meta-analysis that studied the association between the degree of cannabis consumption and psychosis revealed an odds ratio of 3.90 (95% CI, 2.84 to 5.34) for the risk of schizophrenia in the heaviest cannabis users compared with nonusers, with a dose-response relationship between all levels of use and the risk for psychosis.¹⁵ It is hypothesized that the release of dopamine resulting from excess stimulation of cannabinoid receptor 1 can at least partially trigger schizophrenia in genetically predisposed individuals.¹² Other studies have suggested a strong association between substance use disorder and risk of developing or exacerbating symptoms of schizophrenia.^16,17 When primary care physicians are screening for substance use disorders in adolescents, they should discuss the association of cannabis use with schizophrenia, especially when a family history or other identifiable risk factors are present.

Clinical Presentation