Screening Methods for Antipsychotic Agents

Introduction & validity framework

• Definition — Antipsychotic (neuroleptic) screening = bench-to-animal assays that detect or quantify antipsychotic activity before clinical testing. The first agents (chlorpromazine) were found by clinical serendipity (Courvoisier 1956); pharmacological models were built retrospectively to reproduce and predict that activity.
• Biochemical anchor — The dopamine (DA) overactivity / D₂ supersensitivity hypothesis underpins nearly all models — schizophrenia is alleviated by drugs that block D₂ receptors, so most assays read out blockade of dopaminergic neurotransmission. Blockade of postsynaptic D₂ is the unifying target across in vitro and in vivo screens.
• Wider receptor array — Antipsychotics act beyond D₂ — on D₁, 5-HT₂ serotonergic and α-adrenergic receptors — which screening panels exploit to profile selectivity and side-effect liability.
• Typical vs atypical drives assay choice — Atypicals (clozapine prototype) were developed for lower extrapyramidal (EPS) liability, better efficacy on negative symptoms and activity in refractory disease — so screening must separate antipsychotic efficacy from EPS (catalepsy) liability.
• Three validity classes — Models are graded by predictive, face and construct validity (Ellenbroek & Cools 1990):
  • Predictive — model predicts drug response with pharmacologic isomorphism (animal drug rank-order ≈ clinic) — the workhorse screens (apomorphine/amphetamine antagonism, catalepsy, conditioned avoidance).
  • Face — model resembles symptoms (catatonia, stereotypy, social withdrawal); few, hard to replicate.
  • Construct — model mimics the underlying psychopathology — genetic models; behaviour often does not mimic disease, used to study mechanism.