Shifting depression

Biological studies into antidepressant drug action and into the aetiology of depression were highly active areas of research in the 1960s and 1970s but, arguably, have now lost some of their impetus and direction. Many investigations seem to have come to a natural end and there is a need for the subject to make a quantum leap to promote its development. It is recognized however, that advances have been made. Monoaminergic hypotheses of depression (Schildkraut, 1965; Coppen, 1967, for example) provided the basis of numerous clinical and laboratory investigations for over 25 years. From such studies, it was established that antidepressant drugs exert profound effects on noradrenergic (NA) and 5-hydroxytryptaminergic (5-HT) neurones in the central nervous system (CNS): they increase amine levels and/or their availability, they cause down regulation of several different receptor populations and they reduce the firing rates of central NA and 5-HT neurones arising from the locus coeruleus and the raphe nuclei respectively. Despite these discoveries, however, the information which is now available is related primarily to brain physiology and pharmacology rather than to the aetiology of depression or to the therapeutic action of antidepressants. It can even be argued on the basis of observations such as the fact that cocaine is a potent inhibitor of noradrenaline uptake and is not an antidepressant whereas iprindole is an antidepressant with no obvious effects on these monoaminergic systems, that many of the observed biochemical changes may be epiphenomena. Thus, some 35 years after the introduction of imipramine (Kuhn, 1958), the clinical perception of depression remains largely in the domain of the mind rather than the brain. Studies on urine, blood and CSF have provided extensive details on the metabolism of both neurotransmitters and drugs but, unfortunately, have been largely negative as far as providing markers for diagnosis of affective illness, for prediction of outcome or prediction of treatment response. In addition, numerous avenues of research have been pursued and abandoned. Nonetheless, substantial changes have been made: (a) in the way the CNS is conceptualized; (b) in the way drug trials are conducted; (c) in the way that diagnosis has become operational/descriptive rather than based on aetiological assumptions; (d) in the general management of patients; and (e) in our knowledge of the epidemiology of the problem. But equally, it has to be accepted that (for example) there is still no real clue to the mode of action of ECT or an explanation for the delay in onset of action of antidepressants. In addition, even with the introduction of 5-HT specific antidepressant drugs, the relative roles of 5-HT and NA in the aetiology of depression remain contentious: it is probable that with the introduction of serotonin specific reuptake inhibitors (SSRI) such as paroxetine, fluoxetine and fluvoxamine into clinical use, the pendulum is at present swinging towards 5-HT. It is likely, however, that since serotonergic and noradrenergic systems are so interconnected anatomically, a clear separation of behavioural effects will remain elusive. There is, of course, the possibility that as new syndromal types are defined, association with one or other of the monoaminergic systems may emerge.