Summarising the evidence reviewed so far reveals that there are no grounds for considering antidepressants to be a disease-centred treatment:
(1) Is there a demonstrable pathological basis to depression from which the action of ‘antidepressant’ drugs can be understood?
Evidence about serotonin and noradrenalin levels in people with depression is inconsistent and confusing and most studies fail to control for the effects of potential confounders, such as previous drug treatment. Overall, there is little evidence to suggest that there is a characteristic abnormality in either of these systems that is associated with depression.
(2) Do rating scales for depression reliably measure the manifestations of a particular disease process?
Depression rating scales contain items that are not specific to depression, including sleeping difficulties, anxiety, agitation and somatic complaints. These symptoms are likely to respond to the non-specific sedative effects that occur with most tricyclics and many other antidepressants. Hence changes in rating scale scores may merely reflect drug-induced effects.
(3) Do animal models of depression reliably select antidepressant drugs?
It is rarely mentioned that all animal models of depression produce variable results according to where they are conducted. In other words, they are unreliable. In addition to this, they fail to specifically select antidepressants and responses are obtained with drugs that are not generally considered to have antidepressant activity in humans. In the forced swim test, one of most common antidepressant screening tests, rats are placed in a tank of water from which they cannot escape. The time until they give up trying to escape is measured, on the assumption that the state of giving up is akin to depression. It is thought that antidepressants should prolong the time to giving up. In this test positive results have frequently been obtained with amphetamines and also occasionally with opiates, antihistamines, some antipsychotics, atropine, pentobarbital, as well as zinc and antibiotics. In line with the underlying assumption that ‘antidepressant activity’ can be specifically identified or isolated, these results are usually referred to as ‘false positives’. Conversely, the Selective Serotonin Reuptake Inhibitors, widely considered to be specific antidepressants, typically fail to be detected by the forced swim test. Other tests for depression also frequently yield ‘false positive’ results with non-antidepressant drugs, especially stimulants.
(4) Do antidepressants have superior actions to drugs not generally considered to have specific effects in depression?
Antidepressants are only minimally different from inert placebos and this difference may be accounted for by amplified placebo effects and other methodological artefacts. In addition, many drugs not normally considered to be antidepressants show comparable effects to antidepressants in studies with depressed people. Drugs that are considered to be antidepressants show a confusing array of pharmacological actions.
(5) Do studies with healthy volunteers show different or absent effects?
Antidepressants do not appear to elevate mood in healthy volunteers, but neither, as we have seen, is there good evidence that they do so in depressed patients. Although reports of effects of Selective Serotonin Reuptake Inhibitors suggest that effects on sleep may sometimes differ between patients and volunteers, in general side effects of antidepressants in patient trials are consistent with those found in healthy volunteers. For example, tricyclics show sedation and cognitive impairment, while Selective Serotonin Reuptake Inhibitors show gastrointestinal upset and drowsiness in both patients and volunteers.
(6) Is the outcome of depression improved by the use of antidepressant drugs?
As reviewed above, outside randomised controlled trials there is little evidence that antidepressants have changed the outcome of depression, and what evidence exists suggests they may possibly have made it worse. Certainly depression is more common today than before antidepressants were introduced and the outcome has not improved. It may be that antidepressants increase the liability to recurrence.