Schizophrenia

Disease definition & pathophysiology

Schizophrenia is a chronic neuropsychiatric disorder characterized by altered perception of reality, cognitive dysfunction, and impaired emotional regulation. Pathophysiology involves dysregulated dopamine neurotransmission, particularly hyperactivity in mesolimbic pathways (causing positive symptoms) and hypoactivity in mesocortical pathways (causing negative and cognitive symptoms). Glutamate and serotonin dysregulation are also involved.

Commonly used Pharmacodynamic (PD) Models

• Dopamine receptor occupancy models predicting clinical response.
• Disease progression models capturing symptom severity over time (PANSS scale).
• Indirect-response models describing symptom modulation by antipsychotics (delayed treatment response).

Typical patient population

Schizophrenia commonly emerges during late adolescence to early adulthood (16–30 years). Incidence is slightly higher in males, with earlier onset compared to females. Global prevalence is about 0.5–1%.

Risk factors & disease progression indicators

Risk factors include genetics (family history), prenatal complications, neurodevelopmental disturbances, substance use (especially cannabis), and psychosocial stressors. Indicators of disease progression include severity of positive and negative symptoms, cognitive deficits, level of functioning, and frequency of psychotic relapses.

Key Clinical Biomarkers

Diagnosis is primarily clinical, based on symptom presentation and patient history (DSM-5 criteria). Biomarkers are limited, but neuroimaging (MRI, PET) may show structural brain changes or altered dopamine receptor activity. No specific laboratory tests currently exist for schizophrenia diagnosis.

Disease Severity Classification

Severity often assessed by clinical scales such as the Positive and Negative Syndrome Scale (PANSS):

• Mild: PANSS total score ~58–74
• Moderate: PANSS total score ~75–94
• Severe: PANSS total score ≥95

Treatment aim (PD-targets)

Main therapeutic aim is symptom reduction through modulation of neurotransmitter imbalance, primarily targeting dopamine (D2 receptors) and serotonin (5-HT2A receptors).

Common Drug Classes & Regimens

Commonly used PK-models

• Population PK models describing variability in exposure due to genetic factors (CYP2D6, CYP3A4 polymorphisms), smoking status, and patient demographics.
• One- or two-compartment models for antipsychotics.
• PK-PD models linking antipsychotic exposure (plasma levels, receptor occupancy) to changes in PANSS scores or side-effect incidence.