Screening of Antidepressant Drugs

Screening of Antidepressant Drugs

1. Rationale, definitions & the central problem of modelling depression

• Depression is a major affective disorder — a heterogeneous group of mood disturbances that adversely affect cognition and psychomotor function; it is a psychobiologic phenomenon resulting from abnormal brain mechanisms, with an imbalance in central cholinergic and adrenergic tone as a critical pathophysiologic mechanism (SK Gupta Ch.27, p.404).
• The Biogenic Amine (monoamine) Hypothesis frames the target for screening: depression is attributed to reduced serotonin (5-HT), dopamine (DA) and GABA with dysregulated norepinephrine (NE); most classical screening assays are built on the empirical relationship between clinical antidepressant efficacy and effects on monoamine systems (SK Gupta Ch.27, p.404).
• The core problem of the field: there is a genuine lack of an animal model that fully resembles human depressive illness and is selectively sensitive to effective antidepressant treatment. Most available methods are empirical/predictive rather than aetiological — they detect a compound "behaving like a known antidepressant" rather than modelling the disease (SK Gupta Ch.27, p.404; Vogel p.1429–1430, "General Considerations").
  • Classical screening methods are largely inadequate for detecting novel (non-monoaminergic) antidepressants and were historically insensitive to selective serotonin reuptake inhibitors (SSRIs) until modified (SK Gupta Ch.27, p.404, p.406).
• Serendipity in the history of the drug class shapes why screens are validation-driven: iproniazid (developed for tuberculosis) revealed mood elevation → led to MAO-inhibition discovery; imipramine (a phenothiazine analogue trialled as a neuroleptic) was ineffective in agitated psychotics but benefited depressed patients → led to the monoamine-reuptake-inhibition mechanism and β-receptor downregulation concept (Vogel p.1430; Kuhn 1958; Vetulani et al. 1976).
• Specificity strategy — the antidepressant : stimulant ratio. Because behavioural despair endpoints are also reduced by psychostimulants, activity is validated by running the test alongside a locomotor/motor-activity measure. A ratio between the "antidepressant" dose and the "stimulant/sedative" dose near 1 predicts a non-specific stimulant; a wide separation predicts a true antidepressant (SK Gupta Ch.27, p.404; Bourin 1990).

Validity framework (Willner) — how a depression model is judged

• Animal models of depression are evaluated against three validity criteria (Willner; the SK Gupta chapter cites Willner "The validity of animal models of depression", Psychopharmacology 1984; Vogel General Considerations cites Willner & Muscat 1991) — an examiner-favourite framework:
  • Face validity — phenomenological resemblance of the animal behaviour to human depressive symptoms (e.g. immobility/behavioural despair ≈ psychomotor retardation/hopelessness; sucrose anhedonia ≈ loss of pleasure) (Vogel p.1429; SK Gupta Ch.27, ref. Willner 1984).
  • Predictive validity — the model responds correctly to clinically effective antidepressants (and not to inactive drugs); this is the property every screening assay must have (Vogel p.1429–1430).
  • Construct validity — the model shares an underlying theoretical/aetiological rationale with the human disorder (e.g. chronic-stress→anhedonia; HPA-axis dysregulation) (Vogel Chronic Stress Model, p.1462; SK Gupta Ch.27, p.406).
• Reviews of the whole field of animal models of depression are anchored to Porsolt et al. (1991), Panksepp et al. (1991), Willner & Muscat (1991) and Cryan, Markou & Lucki (2002) (Vogel p.1429–1430).