Screening Methods for Antipsychotic Agents

Screening Methods for Antipsychotic Agents

1. Definition, rationale & scope of antipsychotic screening

• Neuroleptics (antipsychotics) are operationally defined as therapeutics effective against schizophrenia; antipsychotic-screening models are bench-to-animal assays that detect or quantify this activity before clinical testing (Vogel 4e V2 Part V, p.1318).
• Historically, the first antipsychotics (chlorpromazine) were discovered by clinical serendipity, not predicted by pharmacological tests — pharmacological screening models were built retrospectively to reproduce and predict that clinical activity (Courvoisier 1956) (Vogel 4e V2 Part V, p.1318).
• Dopamine (DA) overactivity / D₂ supersensitivity hypothesis is the biochemical anchor of nearly all screening models: schizophrenia is alleviated by drugs that block dopamine D₂ receptors, so most assays read out blockade of dopaminergic neurotransmission (SK Gupta Ch.26, p.393).
• Blockade of postsynaptic catecholamine receptors, especially D₂, is the main mode of action of most neuroleptics — the unifying target across in vitro and in vivo screens (Vogel 4e V2 Part V, p.1318).
• Antipsychotics act on a wider receptor array than D₂ alone — D₁ dopaminergic, 5-HT₂ serotonergic, and α-adrenergic receptors — which screening panels exploit to profile a candidate's selectivity and side-effect liability (SK Gupta Ch.26, p.393).
• "Typical" vs "atypical" distinction drives assay choice: atypicals (clozapine prototype) were developed for lower extrapyramidal liability, better efficacy on negative/affective symptoms, and activity in refractory disease — screening must therefore separate antipsychotic efficacy from extrapyramidal (catalepsy) liability (SK Gupta Ch.26, pp.393–394).

Three validity classes of animal models (framework)

• Models are graded by predictive validity, face validity, and construct validity (Ellenbroek & Cools 1990) (SK Gupta Ch.26, p.394).
  • Predictive validity — model predicts pharmacotherapeutic response and shows pharmacologic isomorphism (drug rank-order in animal ≈ clinic). Most available screens fall here; they give least insight into disease processes (SK Gupta Ch.26, p.394).
  • Face validity — model resembles symptoms (catatonia, stereotypy, impaired performance, social withdrawal = behavioural isomorphism). Few in number, hard to design/interpret/replicate (SK Gupta Ch.26, p.394).
  • Construct validity — model mimics the underlying psychopathologic disturbance; genetic models of schizophrenia sit here. Behaviour often does NOT mimic the disease; serve mainly to study molecular mechanisms (SK Gupta Ch.26, pp.394, 399).
• Predictive-validity screens are the workhorses for drug discovery (apomorphine/amphetamine antagonism, catalepsy, conditioned avoidance); face/construct models are mechanistic adjuncts (SK Gupta Ch.26, p.394).