The mechanism of action of antidepressants: a unitary hypothesis based on transport-p.

Endogenous depression is a common mental illness which is associated with significant morbidity and mortality. Tricyclic antidepressants and their newer derivatives are the main treatment for this disease. However, there are serious deficiencies in the use of existing antidepressants for the treatment of depressive illness. An obstacle in the development of better antidepressants is that the mechanism of the therapeutic action of these compounds is unknown. The prevailing view is that antidepressants exert their therapeutic effect by inhibiting the pre-synaptic re-uptake of the neurotransmitter amines, noradrenaline and serotonin. However, there are objections to this hypothesis. Transport-P is a new factor in this field; it is an antidepressant-sensitive, proton-dependent, V-ATPase linked uptake process for amines in peptidergic neurones. It differs from other uptake processes in its anatomical location in post-synaptic (peptidergic) neurones, in its functional properties and in the structure of its ligands. Therapeutic concentrations of antidepressants are active at Transport-P. This review describes a hypothesis which postulates that antidepressants exert a therapeutic effect by an action on Transport-P [1]. According to this hypothesis, Transport-P accumulates antidepressants in acidified vesicles in post-synaptic neurones. The normal function of the vesicles is to degrade internalised post-synaptic receptors. As their amine groups are basic, the antidepressants tend to neutralise the acidity of the vesicles. This slows the rate of degradation of post-synaptic receptors, and makes post-synaptic neurones more responsive to the excitatory actions of neurotransmitter amines. This hypothesis resolves the problems with the pre-synaptic re-uptake hypothesis and offers a unitary explanation for hitherto inexplicable observations. If the hypothesis is correct, compounds which act as potent and selective ligands for Transport-P would have a more rapid onset of action and would represent an advance in the treatment of depressive illness. The data on Transport-P which are described in this article are derived entirely from the work of the author who is not aware of any other research groups working on Transport-P. Therefore, the amount of work which has been done so far is relatively limited. The evidence on which the hypothesis is based is derived from work on alpha(1) adrenoceptors in hypothalamic, peptidergic neurones. There are large gaps in the evidence which would be required to support a mechanistic hypothesis: for example, the serotonergic system, which is likely to be involved in depressive illness, has not been investigated. Further, no attempt has been made so far to address the applicability of the phenomena which were observed in the hypothalamus to other brain regions which may be involved in depressive illness. Nevertheless, the hypothesis, as it stands at present, appears to solve problems which have been inexplicable on the basis of the pre-synaptic re-uptake hypothesis. More work is required to determine the validity of the solutions which are proposed in this review.