Schizophrenia

Definition and Epidemiology

• Lifetime prevalence: slightly under 1%
• Incidence: ~15 per 100,000/year (varies widely across populations)
• Peak onset: late adolescence to young adulthood; slightly earlier in males
• Slightly more common in males than females

Pathobiology

• Multifactorial - genetic factors account for up to ~50% of risk
• Multiple gene loci involved; highly heterogeneous with many ultrarare mutations affecting synaptic plasticity

• Nongliotic neuropathologic process with subtle disruptions of cortical cytoarchitecture (post-mortem brain studies)
• Neuroimaging and neuropsychologic evidence supports cerebral dysfunction

• Dopamine hypothesis: DA hyperfunction in subcortical regions (especially striatum) underlies positive symptoms; DA hypofunction in the prefrontal cortex (PFC) underlies negative/cognitive symptoms - these are treatment-refractory
• Glutamatergic systems also play a role
• Psychostimulants (which increase extracellular DA) can induce or worsen psychosis in schizophrenic patients

• Psychosocial factors and neurodevelopment interact with a brain lesion present at birth or acquired early in life
• Psychosocial stressors precipitate exacerbations

Diagnosis (DSM-5-TR Criteria)

• Brief psychotic disorder: < 1 month, return to full baseline
• Schizophreniform disorder: 1-6 months
• Schizoaffective disorder: psychotic episodes + mood episodes (major depression or mania); prevalence ~0.3%
• Delusional disorder: non-bizarre delusions ≥1 month, no full schizophrenia criteria met

Note: An acute first psychotic event can result from autoimmune encephalitis - always rule out medical causes affecting the CNS.

Treatment

Antipsychotic Medications

• Prototype: chlorpromazine (first antipsychotic); also haloperidol
• Mechanism: D2 receptor antagonism
• Effective for positive symptoms; limited benefit for negative/cognitive symptoms
• Significant extrapyramidal side effects (EPS): parkinsonism, tardive dyskinesia

• Originated with clozapine; distinguished by lower EPS and less prolactin stimulation
• Lower D2 affinity with faster receptor dissociation → less EPS
• Most are also 5HT2A antagonists/inverse agonists
• Serious metabolic side effects: weight gain, type 2 diabetes, hyperlipidemia, cardiovascular arrhythmias
• Also useful as adjuncts in major depression and bipolar disorder

• Aripiprazole: partial D2 agonist - reduces subcortical DA hyperfunction (competing with DA) while enhancing PFC dopaminergic tone; also exhibits functional selectivity (beta-arrestin vs G-protein signaling). May treat both positive AND negative symptoms
• Brexpiprazole: aripiprazole derivative; lower D2 agonist efficacy, high partial agonism at 5HT1A; also approved for adjunctive treatment of depression
• Cariprazine: D2/D3 partial agonist (higher affinity for D3); may have procognitive effects, potentially addressing negative symptoms; may be superior to risperidone for predominantly negative symptom presentations

Psychosocial Treatment

• Comprehensive psychosocial rehabilitation programs are important for functional outcomes
• Assertive use of these programs at initial psychosis onset may improve long-term course

Prognosis

• Often poor: recurrent psychotic exacerbations with progressively deteriorating baseline functioning
• Antipsychotic drugs significantly reduce relapse rates
• A small proportion may recover completely
• Poorer outcome predictors: male sex, prominent negative symptoms, younger age at onset, psychosocial stressors, family discord
• Life expectancy shortened by 10-15 years due to poor health behaviors, higher rates of metabolic syndrome, and other medical disorders
• Lifetime suicide risk: ~5-6%

Recent Evidence (2024-2026)