Abstract: Maprotiline (also known as Ludiomil) (MAP) is a tetracyclic antidepressant that is chemically and functionally similar to tricyclic antidepressants (TCAs). It is a selective norepinephrine (NE) re-uptake blocker. The side effects of MAP include: nausea, nervousness, increased sweating, cholinergic blockade, cardiac complications such as ventricular tachycardia and atrial fibrillation and allergic reactions. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MAP and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically and therefore less likely to react readily with biomolecules. However, their low solvation energy and hence high lipid solubility suggest that the compounds would have low clearance rate. It is suggested that the toxicity of MAP and its metabolites may be associated with their low clearance rate.