A hypothesis about the pathophysiology of AFFECTIVE DISORDER, largely derived from the observation that many effective ANTIDEPRESSANT drugs share the property of perturbing MONOAMINE systems. The monoamine hypothesis has focused on NORADRENERGIC and SEROTONERGIC systems, though DOPAMINERGIC systems are also increasingly implicated in the biology of rewarded behaviour, and by inference, in MOOD states.
The monoamine hypothesis emerged in the 1960s when it was noted that drugs which depleted neuronal noradrenaline and serotonin, such as RESERPINE (used as an ANTIHYPERTENSIVE) appeared to cause DEPRESSION in some individuals, leading to the idea that a relative deficiency of monoamines may represent the cause of mood disorder generally. This idea was supported by the finding that serendipitously discovered antidepressant agents, such as the TRICYCLICS and MONOAMINE OXIDASE INHIBITORS cause a short-term increase in levels of monoamines at the SYNAPTIC CLEFT. Furthermore, depletion of TRYPTOPHAN, a precursor of serotonin, leads to relapse in some patients who have responded to antidepres-sants. There are, however, several problems for the hypothesis, at least in this simple form. (1) Though antidepressants elevate synaptic monoamine levels within hours, their antidepressant effects are delayed for two to three weeks. (2) Tryptophan depletion does not appear to cause depression in individuals who have never suffered from a depressive disorder. (3) Some very effective antidepressants, such as MIANSERIN, do not appear significantly to block monoamine reuptake. (4) Efforts to demonstrate both conclusively and exclusively that monoamine function is abnormal in depressed patients have been largely unsuccessful.
The hypothesis has been modified over the last three decades, partly to try and take account of some of these problems and partly in the light of new observations. In the 1970s and 1980s, interest centred on the possibility that persistent activation of monoaminergic receptors by antidepressants would result in adaptation responses, such that RECEPTOR sensitivity or number might be downregulated.
The time course of such effects might be more in keeping with the delayed onset of antidepressant action. For example, it was observed that many antidepressants downregulate central beta- NORADRENALINE RECEPTORS following CHRONIC, rather than acute administration. The monoamine hypothesis in this form therefore postulated that depression might be caused by monoamine receptor SUPERSENSITIVITY, and that antidepressants downregulated and thus attenuated this proposed pathological state of affairs. However, not all antidepressant agents share this effect, and in any case, the time course for downregulation is still rather less than the time taken for antidepressant effects to emerge clinically. Furthermore, appropriate receptor antagonists (such as beta receptor antagonists) do not have antidepressant activity, as predicted by this new form of the hypothesis. More recent formulations have added a further dimension—the role of the inhibitory AUTORECEPTOR. It has been suggested, for example, that a serotonin specific reuptake inhibitor (SSRI; for example PROZAC) acting at the monoaminergic cell bodies in the BRAINSTEM could lead to increased activation of 5HT1a autoreceptors. These autoreceptors shut down cell firing in the short term, acting against expected increases in synaptic serotonin in the projection field in the CEREBRAL CORTEX and LIMBIC SYSTEM caused by ongoing reuptake inhibition. Once the cell body autoreceptors desensitize in the face of chronic REUPTAKE blockade, and cell firing increases again, then the effect of reuptake inhibition at the terminals now results in an increase in synaptic serotonin availability. This version of the monoamine hypothesis now predicts once more that the depressed state is due to lack of availability of serotonin at cell terminals. None the less, the monoamine hypothesis cannot fully account for depressive disorder, and other factors must operate in the genesis and maintenance of depressive disorder. Despite this, the hypothesis has proved a useful stimulus to research into the biology of affective disorder.
