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Key Points

  • Disease summary:

    • Schizophrenia (SCZ) is a severe, chronic psychiatric syndrome that is a complex genetic disorder involving the interactions of multiple genetic and nongenetic factors.

    • Clinical diagnosis is based on abnormalities in multiple domains including positive symptom domain, negative symptoms, cognition, and mood symptoms. No blood or neuroimaging tests are pathognomic.

    • Presentation is generally in adolescence or early adulthood but a premorbid prodrome is often apparent earlier suggesting a neurodevelopmental trajectory.

    • The course is most often chronic with significant impairments in social and work functioning.

    • Neuroimaging finds decreased activation in task-induced magnetic resonance imaging (MRI) paradigms in several brain regions including the dorsolateral prefrontal cortex and anterior cingulate. Diffusion tensor imaging has also identified white matter tract abnormalities.

  • Differential diagnosis:

    • Major differential is with other psychotic disorders (bipolar disorder [BD], schizoaffective disorder, delusional disorder, and depression with psychotic features). Other significant differential includes (1) psychotic disorder due to medical conditions (eg, epilepsy, dementia, brain tumor, infections, and metabolic abnormalities), (2) substance use (eg, drugs of abuse, medications, toxins), and (3) brief or SCZ spectrum syndromes.

  • Monogenic forms:

    • There are no agreed upon monogenic forms, no single gene has been demonstrated to cause SCZ.

  • Family history:

    • Strongest risk for SCZ is a positive family history. Affected first-degree relatives confer a relative risk of 5% to 16%. A recent large-scale study shows that first-degree relatives are also at increased risk of BD (3.7%).

  • Twin studies:

    • Monozygotic twins have 0.9 concordance rate, dizygotic twins have 0.5, with an estimated heritability of approximately 0.8.

  • Nonfamilial genetics: Advanced paternal age is associated with elevated relative risk (two- to threefold). De novo single-nucleotide polymorphism (SNP) and copy-number variants (CNV) rates are increased in SCZ.

  • Environmental factors:

    • Multiple environmental factors have been associated with modest increased risk including obstetrical complications, prenatal infections, socioeconomic status, immigration status, urban living, maternal starvation, head injury, and cannabis use.

  • Genome-wide associations:

    • Significant genome-wide associations exist for both CNVs and SNPs. Large CNVs are associated with larger risk, but produce pleiotropic phenotypes (ie, not specific for SCZ). Testing for CNVs or SNPs is not yet clinically validated for diagnosis or treatment selection.

  • Pharmacogenomics:

    • Most antipsychotic medication is metabolized by the cytochrome P450 (CYP) system. Clinical efficacy of CYP testing has not been established.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for SCZ

The clinical diagnostic criteria for SCZ are described in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV TR) and the International Classification of Diseases, 10th edition (ICD-10). DSM-IV TR is primarily used in the United States and ICD-10 in Europe. There is good agreement between the two systems.

  • DSM1V criteria: (1) Two or more characteristic symptoms of delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, or negative symptoms (only one if delusions are bizarre, or hallucinations with multiple voices or running commentary), (2) significant functional decline in work, ...

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