Acceleration of beta-receptor desensitization in combined administration of antidepressants and phenoxybenzamine

The delayed therapeutic effects of antidepressants (usually between 10 and 14 days) and of the tricyclic antidepressants in particular, are believed (on the basis of animal experiments) to lie in a progressive decrease of the sensitivity of cortical beta-adrenergic receptors. This is thought to be due to an increase in the synaptic concentration of noradrenaline, in turn accomplished by a decrease in the sensitivity of the presynaptic alpha 2 receptors which normally regulate noradrenaline secretion by a negative feedback mechanism. This model suggests that the desensitization of postsynaptic beta-receptors by antidepressants should be accelerated by the inhibition of the presynaptic alpha 2- adrenergic system, and we have indeed observed such an effect in preliminary studies with desipramine and phenoxybenzamine (PBZ) combined. We now show that the administration of either tricyclic or monoamine oxidase inhibitor antidepressants in combination with PBZ, an irreversible alpha-adrenergic blocker, accelerates and intensifies the desensitization of beta-adrenergic receptors. Our observations may have therapeutic implications.