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History of the monoamine hypothesis of depression

The monoamine theory of depression is important because it provides a model for the idea that antidepressant drugs act on the biological basis of depressive symptoms. It forms the basis for the modern idea that depression arises from a chemical imbalance.

‘Monoamines’ is the term used to refer to the neurotransmitters noradrenalin and serotonin. In the mid-20th century there was widespread interest in medicine in the catecholamines noradrenalin and adrenalin. In 1928 an enzyme called monoamine oxidase was described that was involved in their metabolism and inactivation. In 1938 the actions of the stimulant ephedrine were linked to inhibition of this enzyme. In 1952 it was demonstrated that iproniazid inhibited monoamine oxidase and subsequently it became known as a ‘monoamine oxidase inhibitor’. Its actions in various conditions including depression were attributed to this action. In the late 1950s there was a burst of interest in the use of iproniazid and other drugs referred to as monoamine oxidase inhibitor antidepressants for a number of indications including angina, hypertension and cancer, as well as depression. Drug companies looked for other compounds with monoamine oxidase inhibiting action, and several were produced and tested in depression as well as other medical conditions. Although no clear disease theory of depression had been articulated in writing by this point, there was already an understanding, described by psychiatrist Nathan Kline in a memoir, that elevating monoamine levels with stimulants or monoamine oxidase inhibitor antidepressants was necessary for its treatment. Despite the fact that stimulants were later not considered to have disease-specific action, their ability to induce a state of euphoria and heightened activity inspired the idea that depression was due to the opposite biochemical state from that produced by stimulants.

When imipramine was suggested to be an ‘antidepressant’ it did not readily fit into this picture. In fact its actions were similar to chlorpro-mazine and reserpine. Reserpine, a drug used briefly as a neuroleptic, was thought to induce depression by reducing the availability of monoamines. In the early 1960s Julius Axelrod, who was investigating catecholamine (adrenalin and noradrenalin) metabolism, discovered that one action of some drugs was to block the reuptake of neurotransmitters into nerve cell bodies. In a paper published in 1961, it was reported that imipramine, chlorpromazine, reserpine, amphetamine, tyramine and cocaine inhibited reuptake of noradrenalin into heart, spleen and adrenal gland tissue and caused a brief five-minute increase in blood concentration of noradrenalin. Subsequently Axelrod and his colleagues demonstrated that the uptake of noradrenalin by brain tissue of rats was reduced by imipramine and amitriptyline but not chlorpromazine. They concluded that this may be ‘a mechanism for the antidepressant action’ of the tricyclic drugs.

History of the monoamine hypothesis of depression

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and ‘influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones’. Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action. In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin.

However these inconsistencies were paid little attention. Reuptake was regarded as a major discovery and Julius Axelrod was later awarded the Nobel Prize for his work on the catecholamine system. The fact that reuptake properties were accorded so much importance, before their significance was fully elaborated, demonstrates that the monoamine hypothesis was influential before it was even properly articulated. The reuptake mechanism was considered important because it allowed imipramine, with its sedative and tranquillising profile of effects, to be incorporated into a more general theory of the biological origin and treatment of depression.

By the mid-60s there was a strong consensus that depression, at least in its severe endogenous form, was caused by an abnormal biochemical state consisting of reduced levels of monoamines in the brain. The theory was set out systematically in a well-known paper by Schildkraut (1965), who concentrated on the role of noradrenalin. Other authors focused on serotonin. Schildkraut asserted that ‘some if not all depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine … elation may conversely be associated with an excess of such amines’. The primary justification for the theory was the belief that stimulants and antidepressant drugs acted to increase monoamine levels. Schildkraut referred to how the supposed efficacy of imipramine had initially cast doubt on the theory, but the ‘riddle’ had been solved by Axelrod’s research on its ability to block tissue reuptake of noradrenalin.

Despite decades of research, there is no evidence to support the monoamine theory of depression. Studies of noradrenalin are inconsistent, with as many finding raised levels in people with depression as those finding reduced levels. Evidence on serotonin is similarly inconsistent, and eminent mainstream psychopharmacologists admit that there is no evidence of serotonin dysfunction in depression. Nevertheless, the monoamine hypothesis has survived and remains influential. Contradictory evidence has been overlooked or reframed as supportive. For example, Schildkraut reported research that clearly showed that imipramine decreased noradrenalin levels in the brain, but hypothesised that despite reduced concentrations, the activity of noradrenalin might nevertheless be increased.

Subsequently attention switched to neurotransmitter receptors in the 1970s and the monoamine hypothesis was reformulated in terms of monoamine receptors. It was found in animal experiments that several antidepressants reduced the density of beta-adrenoceptors (a type of noradrenalin receptor) in the brain after about two weeks of treatment.

Since this coincided with the commonly accepted two-week lag between starting antidepressants and clinical improvement, it was proposed that the reduction in beta-receptors was the mechanism of their antidepressant action. In line with this proposal, depression was now suggested to be due to ‘”supersensitive” receptors which need down regulation’. The fact that the theory now contradicted its old versions by proposing that depression was due to increased activity of the noradrenalin system was glossed over, as was research that showed that other sorts of drugs, including clozapine and thioridazine, also reduced the density of beta-receptors.

 

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