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

The delayed therapeutic effects of antidepressants (usually between 10 and 14 days)^1,2 and of the tricyclic antidepressants in particular, are believed (on the basis of animal experiments^3-8) to lie in a progressive decrease of the sensitivity of cortical β-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 α₂ receptors which normally regulate noradrenaline secretion by a negative feedback mechanism. This model suggests that the desensitization of postsynaptic β-receptors by antidepressants should be accelerated by the inhibition of the presynaptic α₂-adrenergic system, and we have indeed observed such an effect in preliminary studies with desipramine and phenoxybenzamine (PBZ) combined⁹. We now show that the administration of either tricyclic or monoamine oxidase inhibitor antidepressants in combination with PBZ, an irreversible α-adrenergic blocker^9,10, accelerates and intensifies the desensitization of β-adrenergic receptors. Our observations may have therapeutic implications.