Pharmacological Studies with Nialamide, A New Antidepressant Agent

Abstract
By a series of tests comparing nialamide [l-(2-(benzylcarbamyl)ethyl)-2-isonicotinoyl hydrazine] with iproniazid for antidepressant and monoamine oxidase (MAO) inhibiting activity, the former was found more potent, less toxic, and with some properties suggesting unique activity. Antidepressant activity as measured by protection against reserpine induced depression was about 3 times that of iproniazid in dogs and 10 to 12 times in cats and mice. MAO inhibition in vivo was suggested by the potentiation by mialamide of the pyretic response of rabbits to injected 5-hydroxytryptophan (5-HTP). Nialamide was about 2 1/2 times as active as iproniazid. MAO activity and brain stem content of norepinephrine (NE) and serotonin (5-HT) were measured in dogs treated orally for 5 days and for 6 months. Nialamide was more potent than iproniazid as an inhibitor. Whereas, nialamide, iproniazid, and [beta]-phenylisopropyl hydrazine (JB-516,PIH) all increased 5-HT levels, only the former increased NE. The duration of MAO inhibitory action was measured as protection against reserpine facilitation of metrazol. A single oral dose produced significant protection for at least 2 weeks. Interference with liver function was tested by potentiation of hexobarbital. Nialamide had very little potentiating action, which suggested low hepatotoxicity. This was confirmed by chronic toxicity studies in dogs which showed no liver pathology. Trials in humans showed no postural hypotensive effect at doses which gave substantial MAO inhibition and a therapeutic response.