Noradrenergic transmission in depression: under- or overfunction?

The pros and cons of the noradrenaline hypothesis of depression are examined and a critical assessment is made of the recent theory that antidepressants act by reducing the sensitivity of postsynaptic beta-adrenergic receptors, implying that depressed patients suffer from a overfunction and not underfunction of cerebral noradrenergic systems. The evidence that the latter are in some way involved in depression, although very probably other transmitter systems are also involved in this disease, is considered quite convincing. On the other hand, the subsensitivity of postsynaptic receptors occurring after antidepressive treatment is seen as a counterregulatory mechanism responding to an increased noradrenaline concentration in the synaptic cleft rather than as the cause of the antidepressant effect. It is stressed that it is the intensity of noradrenergic synaptic transmission that matters, i.e. the functional activity of integral system and not that of the pre-or postsynaptic parts alone. A model of the sequential occurrence of events influencing noradrenergic transmission during treatment with an uptake inhibitor is suggested which could explain both the latency of onset of the therapeutic response and the fact that some patients do not respond to the treatment.