Early formulations of the monoamine theory of depression cited two strands of evidence. One was the effects of antidepressant drugs and the other was the effects of reserpine. Skildkraut believed that ‘studies have shown a fairly consistent relationship between drug effects on catechloamines, especially norepinephrine, and affective or behavioural states’. He went on to describe how drugs that ’cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioural stimulation or excitement and generally exert an antidepressant effect in man’.
The idea that antidepressants have a specific action on a biological process is still cited as the main justification for the idea that depression is caused by a biochemical abnormality. A recent review article states that ‘The indisputable therapeutic efficacy of these drugs suggests that serotonergic and/or noradrenergic underactivity is the key to the pathophysiology of clinical depression’. However the evidence reviewed above suggests that antidepressant drugs do not exert a specific effect in depression. In addition, although tricyclic antidepressants were found to inhibit reup-take of noradrenalin and serotonin, the significance of this action among their other numerous actions has not been established, and nor has its specificity. In fact, several studies show that instead of increasing noradrenalin levels, tricyclic antidepressants appear to reduce noradrenalin concentrations. In addition, amphetamine, cocaine and other stimulants, which are known to increase noradrenalin levels in the brain, are not regarded as effective antidepressants.
The neuroleptic drug reserpine was commonly thought to cause a depressive illness in a high proportion ol people who took it and lor this reason its sedative effects in animals were used as an animal model ol human depression. Since reserpine had been found to reduce levels ol serotonin and noradrenalin in the brain, it was suggested that the mechanism ol reserpine-induced depression was monoamine depletion. At this time there was relatively little interest in dopamine and so it was not considered a candidate. In the 1950s, it had been found that iproniazid blocked the sedative actions ol reserpine, which would be consistent with its stimulant proffle. Subsequently Italian researchers claimed that imipramine was also able to reduce the effects ol reserpine, which seemed to conlirm that the different types ol antidepressants had some linal common pathway ol action on a coherent underlying disease process.
This research is generally presented as demonstrating that tricyclic antidepressants block the depressive state induced by reserpine. However the original research only demonstrated that imipramine reduced the hypothermic effect ol reserpine and not other effects such as sedation. One ol these studies showed that chlorpromazine also appeared to block reserpine-induced hypothermia. This research is curious il one considers that chlorpromazine induces hypothermia and imipramine is closely related to it. It is difficult to know how reliable it was and in any case it did not demonstrate any effect ol imipramine on the sedating or depressogenic effects ol reserpine. In contrast, another group ol researchers found that imipramine appeared to potentiate the sedative effects ol reserpine, which would be consistent with it being a neuroleptic-type substance.
It is also clear in retrospect that the reserpine-induced state was a state ol dopamine blockade, characterised by sedation and inactivity, rather than a valid model ol depression. Whether it commonly caused a true depressive state in humans has also been disputed. One review suggested that it did so in 6% ol cases, but mostly in people who had a previous history ol depression. The only controlled study ol reserpine on mood found no true cases ol depression, but several patients were noted to show signs ol ‘excessive tranquillisation’ or ‘pseudodepression’.
Numerous studies of noradrenalin and serotonin activity have been conducted since the 1960s to try and demonstrate the elusive biochemical basis of depression. As with dopamine studies, there has been little attempt to control for other possible influences on neurotransmitter levels. Most studies involved people who were taking or had recently taken antidepressants or other psychotropic drugs that may have affected brain biochemistry. Comparison groups consisted of ‘healthy controls’ and the effects of stress, anxiety and other factors related to having an acute psychiatric condition were not considered.
This research has looked at levels and availability of tryptophan, a chemical precursor of serotonin, effects of depletion of tryptophan and of noradrenalin precursors; serotonin and noradrenergic uptake in platelets; prolactin response to fenfluramine, a drug that is thought to stimulate presynaptic serotonin release; growth hormone response to clonidine, an adrenergic alpha-receptor-blocking drug; serotonin and noradrenergic receptor density in brains of suicide victims; serotonin-receptor binding in living subjects using imaging techniques and arterial assays of noradrenalin and serotonin metabolites. Research on noradrenalin is highly inconsistent with studies showing increased, decreased and normal levels in depressed patients compared with controls.
Research on serotonin is similarly confusing. For example, some imaging studies found reduced serotonin lA-receptor binding in drug-free depressed patients, consistent with the hypothesis that there is a deficiency of serotonin activity in depression. Other studies, however have found no difference between drug-free patients and controls and some found increased binding potential in depressed patients. Although they are widely thought to show evidence of abnormality, post-mortem findings in the brains of people who committed suicide have also been inconsistent. Many studies have failed to find any differences in serotonin receptors between brains of suicide victims and those of people who have died in other circumstances. Tryptophan depletion studies are sometimes claimed to provide ‘powerful evidence of a causal link between reduced serotonergic function and depression’.
Depletion of tryptophan, the chemical precursor of serotonin is thought to lead to a reduction of serotonin, although this cannot be shown empirically because of the impossibility of directly measuring serotonin. Some of these studies showed that dietary tryptophan depletion (by drinking a drink of amino acids devoid of tryptophan, a technique that has been shown to reliably lower blood-tryptophan levels) leads to a transient increase in depressive symptoms in patients who had recovered from depression. However most studies showed that this effect was only present in patients who had been treated with Selective Serotonin Reuptake Inhibitors and not those treated with other drugs. It may therefore, be related to prior drug treatment, rather than depression itself. Studies with volunteers have not found that dietary tryptophan depletion causes depression and administering large doses of tryptophan as a sole treatment has no effect on depression.
Other research into tryptophan depletion was conducted in the 1970s using the chemical parachlorophenylalanine, which has a stronger effect, producing a 60-80% reduction of serotonin metabolites in humans. References to this research have disappeared from the literature but it provides a better exposition of the effects of serotonin deficiency and a ready explanation for the effects seen in patients with the dietary methods. In animals, this technique has been found to induce a state characterised by insomnia, hypersexual behaviour, increased aggression, irritability, increased motor activity and hyper-reactivity to the environment which can be reversed by administration of tryptophan.
However it does not produce anything resembling depression. In humans a variety of effects have been found including tiredness, restlessness, unease, anxiety, and at higher doses confusion, agitation and paranoid thinking. Again depression is not a characteristic of this state. In the dietary studies milder effects of this sort may have been interpreted as a recurrence of depression, bearing in mind that the studies were only set up to look for depression and not other sorts of behavioural change.
However as Jeffrey Lacasse and Jonathan Leo have suggested in a recent article, there is a ‘disconnect between the advertisements and the scientific literature’. The publicity produced by the pharmaceutical industry and the psychiatric profession have convinced much of the general public that a link between serotonin abnormality and depression has been demonstrated. People I speak to are often shocked to hear that the evidence is tenuous and unconvincing. But psychiatric specialists admit that this is the case. The primary American textbook of psychiatry sums up the inconsistency of the evidence: ‘studies of serotonin function in depression suggest both hypofunction and hyperfucntion’.
A psychopharmacology textbook states that ‘so far, there is no convincing evidence that monoamine deficiency accounts for depression; that is there is no real monoamine deficit’. When interviewed in 2003, award-winning psychopharmacology researcher David Burns said: ‘I never saw any convincing evidence that any psychiatric disorder, including depression, results from a deficiency of brain serotonin’.