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This is a corrected version of the article that appeared in print.

Am Fam Physician. 2022;106(4):388-396

Related Letter to the Editor: Long-Acting Injectable Clozapine Not Available in the United States

Patient information: See related handout on schizophrenia.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Schizophrenia is the most common psychotic mental disorder, and those affected have two to four times higher mortality than the general population. Genetic and environmental factors increase the risk of developing schizophrenia, and substance use disorder (particularly cannabis) may have the strongest link. Schizophrenia typically develops in young adulthood and is characterized by the presence of positive and negative symptoms. Positive symptoms include hallucinations, delusions, and disorganized speech. Negative symptoms include blunted affect, alogia, avolition, asociality, and anhedonia. Symptoms must be present for at least six months and be severe for at least one month to make a diagnosis. Because schizophrenia is debilitating, it should be treated with antipsychotics, and early treatment decreases long-term disability. Treatment should be individualized, and monitoring for effectiveness and adverse effects is important. Patients with a first episode of psychosis who receive a formal diagnosis of schizophrenia should be treated in a coordinated specialty care program. Second-generation antipsychotics are the preferred first-line treatment because they cause fewer extrapyramidal symptoms. Patients with schizophrenia who are treated with second-generation antipsychotics are at increased risk of cardiovascular disease and should receive at least annual metabolic screening and counseling with interventions to prevent weight gain and encourage smoking cessation. Treatment-resistant schizophrenia should be treated with clozapine. Adjunctive treatments include electroconvulsive therapy, antidepressants, and cognitive behavior therapy for psychosis. Family and social support are keys to improved outcomes.

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.24 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

Clinical recommendation Evidence rating Comments
Patients with schizophrenia should be treated with first- or second-generation antipsychotics and continue maintenance therapy while being monitored for effectiveness and adverse effects.20,24,31,52,53 A Practice guideline, Agency for Healthcare Research and Quality systematic review, Cochrane review, and cohort studies that showed improvement in symptoms and mortality
Schizophrenia resistant to first- or second-generation anti-psychotics should be treated with clozapine (Clozaril).20,44 B Practice guideline and systematic review of randomized controlled trials that showed improved symptom control and mortality
Adjunctive treatments with psychosocial therapies such as cognitive behavior therapy for psychosis, psychoeducation, supported employment services, assertive community care, and family interventions should be offered.24 B Agency for Healthcare Research and Quality systematic review of multiple cohort and randomized controlled trials that showed improved social function
Patients with a first episode of psychosis who receive a formal diagnosis of schizophrenia should be treated in a coordinated specialty care program.20,24 B Practice guideline and Agency for Healthcare Research and Quality systematic review that showed decreased recurrences of psychosis and improved social outcomes
RecommendationSponsoring organization
Do not prescribe antipsychotic medications to patients for any indication without appropriate initial evaluation and ongoing monitoring.American Psychiatric Association
Do not routinely prescribe two or more antipsychotic medications concurrently.American Psychiatric Association


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


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.

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