How do antipsychotics work in the body, specifically in pediatric patients with schizophrenia?

How Antipsychotics Work in the Body

Antipsychotics work primarily by blocking dopamine D2 receptors in the brain, which reduces psychotic symptoms like hallucinations and delusions, while atypical agents also block serotonin 5-HT2A receptors, which provides additional benefits for negative symptoms and reduces movement-related side effects. 1

Mechanism of Action by Drug Class

Traditional (Typical) Antipsychotics

• Traditional neuroleptics work exclusively through dopamine D2 receptor antagonism, which is the mechanism responsible for both their antipsychotic properties and their characteristic side-effect profile including extrapyramidal symptoms. 1
• The degree of D2 receptor blockade determines potency: high-potency agents like haloperidol produce more extrapyramidal symptoms, while low-potency agents like thioridazine and chlorpromazine cause more anticholinergic side effects including sedation and memory deficits. 1

Atypical (Second-Generation) Antipsychotics

• Atypical agents derive their antipsychotic properties from being serotonin 5-HT2A antagonists in addition to dopamine D2 antagonists, which distinguishes them fundamentally from traditional neuroleptics. 1, 2
• These medications affect multiple neurotransmitter systems simultaneously, including both antidopaminergic and antiserotonergic activity. 1
• The preferential 5-HT2A blockade relative to D2 blockade accounts for their lower risk of extrapyramidal symptoms, with D2 occupancy remaining in the 71-80% range at standard doses, below the 80% threshold associated with increased movement side effects and prolactin elevation. 2

Specific Drug Mechanisms

Olanzapine

• Olanzapine's effectiveness against positive symptoms (hallucinations, delusions) occurs primarily through D2 blockade, while its effectiveness against negative symptoms (social withdrawal, flat affect) is enhanced by 5-HT2A antagonism. 2

Clozapine

• Clozapine's efficacy for both positive and negative symptoms stems from weak D2 receptor antagonism combined with potent 5-HT2 receptor inhibition, explaining why it produces fewer extrapyramidal symptoms than typical antipsychotics. 3
• This unique receptor binding profile makes clozapine the only effective medication for treatment-resistant schizophrenia. 3, 4

Aripiprazole

• Aripiprazole functions as a D2 partial agonist rather than a pure antagonist, providing a distinct pharmacodynamic profile from other antipsychotics. 5
• This partial agonism allows for dopamine system stabilization rather than complete blockade. 5

Clinical Effects in Pediatric Patients

Efficacy

• Antipsychotics reduce psychotic symptoms, help prevent relapse, and improve overall long-term functioning in both adults and youth with schizophrenia. 1
• The pattern of response in youth is similar to that in adults, though youth with early-onset schizophrenia may be less likely to respond adequately since treatment resistance in adults is associated with earlier age of onset. 1
• Haloperidol (0.02–0.12 mg/kg) was superior to placebo in reducing thought disorder, hallucinations, and persecutory ideation in children with schizophrenia. 1
• Both 10 mg and 30 mg daily doses of aripiprazole were superior to placebo in reducing total PANSS scores in adolescents aged 13-17 years with schizophrenia. 6

Side Effect Profile in Youth

• Children and adolescents experience the same spectrum of side effects as adults, including extrapyramidal symptoms, sedation, tardive dyskinesia, and neuroleptic malignant syndrome. 1
• Pediatric patients may be at higher risk for extrapyramidal side effects than adults—in one trial, 25% of aripiprazole-treated adolescents experienced EPS-related events versus 7% on placebo. 6
• Youth appear to have greater difficulties communicating side effect concerns due to developmental issues, requiring careful monitoring. 1

Important Clinical Considerations

Therapeutic Window

• Striatal dopamine D2 receptor blockade is central to clinical response but also causes endocrine and motor side effects, indicating a narrow therapeutic window for D2 blockade. 7
• Current drugs act downstream of the major dopamine abnormalities in schizophrenia and potentially worsen cortical dopamine function, which may contribute to cognitive and negative symptoms. 7

Common Pitfall

• All currently available antipsychotics require D2 receptor blockade for efficacy—molecules that do not block the D2 receptor have shown disappointing or equivocal results for treating psychotic disorders. 8
• The long-term use of neuroleptics in early-onset schizophrenia has not been studied, creating uncertainty about extended treatment effects. 1