What are the differences in pharmacokinetics between first generation antipsychotics (e.g. haloperidol, chlorpromazine) and second generation antipsychotics (e.g. olanzapine, risperidone, quetiapine) in terms of efficacy and side effect profiles?

Pharmacokinetics of First and Second Generation Antipsychotics

The distinction between first-generation and second-generation antipsychotics is not valid from either a pharmacological or clinical perspective and should not guide treatment selection. 1

Critical Paradigm Shift in Classification

The traditional categorization of antipsychotics into "first-generation/typical" versus "second-generation/atypical" is fundamentally flawed. 1, 2 The most recent international guidelines explicitly state that these classifications are neither pharmacologically distinct nor clinically useful. 1 Instead, antipsychotic selection should be based on:

• Individual receptor profiles (half-life and receptor binding characteristics) 1
• Side-effect profiles specific to each compound 1
• Pharmacodynamic properties rather than generational categories 1

Pharmacokinetic Characteristics

Absorption and Bioavailability

Risperidone demonstrates well-characterized absorption with 70% absolute oral bioavailability, reaching peak plasma concentrations at approximately 1 hour for the parent compound and 3 hours for its active metabolite 9-hydroxyrisperidone in extensive metabolizers. 3 Food does not affect absorption rate or extent. 3

Olanzapine exhibits similar food-independent absorption characteristics, allowing flexible administration timing. 4

Metabolism and Genetic Polymorphism

A critical pharmacokinetic distinction involves CYP2D6 metabolism, which creates significant inter-individual variability:

• Risperidone is extensively metabolized via CYP2D6 to 9-hydroxyrisperidone, an equipotent active metabolite. 3
• Approximately 6-8% of Caucasians are poor CYP2D6 metabolizers, converting risperidone much more slowly. 3
• Poor metabolizers have higher risperidone and lower 9-hydroxyrisperidone concentrations, though combined pharmacokinetics remain similar. 3
• CYP2D6 inhibitors (notably quinidine) can convert all patients to a poor metabolizer phenotype. 3

Olanzapine metabolism primarily involves CYP1A2 and glucuronyl transferase pathways, with different drug interaction profiles than risperidone. 4 Omeprazole and rifampin can increase olanzapine clearance. 4

Distribution and Protein Binding

• Risperidone: 90% plasma protein binding (albumin and α1-acid glycoprotein), volume of distribution 1-2 L/kg 3
• 9-hydroxyrisperidone: 77% protein binding 3
• Neither compound displaces the other from binding sites 3

Half-Life and Steady-State Considerations

Risperidone reaches steady-state in 1 day for extensive metabolizers and approximately 5 days for poor metabolizers. 3 The active metabolite 9-hydroxyrisperidone reaches steady-state in 5-6 days. 3

This pharmacokinetic profile directly informs switching strategies, which should involve gradual cross-titration based on half-life and receptor profiles. 1

Efficacy Considerations

No Generational Superiority

All currently available antipsychotics function as dopamine blockers or dopamine partial agonists. 2 The clinical effect results from combined parent drug and active metabolite concentrations (particularly relevant for risperidone). 3

Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages around 5 mg/day risperidone equivalents for schizophrenia. 2

Switching Between Agents

When switching antipsychotics due to inadequate efficacy or tolerability:

• Switch to a compound with a different pharmacodynamic profile 1
• Use gradual cross-titration informed by half-life and receptor profile 1
• For patients on D2 partial agonists, consider switching to amisulpride, risperidone, paliperidone, or olanzapine 1

Side Effect Profiles

Extrapyramidal Symptoms

Low-quality evidence suggests chlorpromazine causes significantly more extrapyramidal symptoms than quetiapine (8 RCTs, N=644; RR 8.03,95% CI 4.78-13.51). 5 Similarly, chlorpromazine produced more extrapyramidal symptoms than olanzapine (2 RCTs, N=298; RR 34.47,95% CI 4.79-248.30). 5

Metabolic Effects

Olanzapine requires concurrent metformin to attenuate weight gain when used as a treatment option. 1

Drug Interactions

Risperidone is subject to two major interaction types:

• CYP2D6 inhibitors interfere with conversion to active metabolite 3
• Quinidine creates a poor metabolizer phenotype in all patients 3

Olanzapine demonstrates minimal CYP enzyme inhibition potential (CYP1A2, 2C9, 2C19, 2D6, 3A), making clinically important drug interactions unlikely. 4

Clinical Application Algorithm

1. Select based on receptor profile and side effects, not generational category 1
2. Consider pharmacokinetic factors: CYP2D6 status for risperidone, CYP1A2 inducers for olanzapine 3, 4
3. Monitor plasma levels to detect non-adherence 2
4. Use once-daily dosing at night when possible (feasible with many agents) 2
5. If switching, employ gradual cross-titration based on half-life and receptor binding 1