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The term antidepressant refers to a drug that helps to rectify specific biological abnormalities that give rise to the symptoms of depression. This exemplifies what we have called the “disease-centred” model of psychotropic drug action . Modelled on paradigmatic situations in general medicine—such as the use of insulin in diabetes, antibiotics in infectious disease, chemotherapy in cancer—the disease-centred model suggests that antidepressants help restore normal functioning by acting on the neuropathology of depression or of depressive symptoms.
In contrast, we propose in this Essay that an alternative “drug-centred” model can better explain observed drug effects in psychiatric conditions. This drug-centred model suggests that instead of relieving a hypothetical biochemical abnormality, drugs themselves cause abnormal states, which may coincidentally relieve psychiatric symptoms (Table 1). Alcohol's disinhibiting effects may relieve symptoms of social phobia, but that does not imply that alcohol corrects a chemical imbalance underlying social phobia. Sedation may lessen high arousal, present in many acute psychiatric situations. Drugs that induce indifference, such as neuroleptics or opiates, may help reduce the distress of acute psychotic symptoms. Low-dose stimulants may help improve attention and concentration in the short term.
The disease-centred model in psychiatry leads researchers to infer antidepressant effects from patients' scores on symptom rating scales presumed to assess the manifestations of the disease. The drug-centred model, on the other hand, suggests that physiological and subjective effects of drugs should be examined in their own right. These effects include various forms of sedation, stimulation, and a plethora of biopsychological states. Depending on individual inclination and context (including a person's emotional state upon drug ingestion), intoxication with some drugs produces euphoria or mood elevation. Because tolerance develops, however, euphoriant effects do not persist with long-term use. If antidepressants or any other psychotropic drugs could be shown to have mood-elevating effects that were long-term and not diminished by being in a depressed emotional state, this would distinguish them from psychotropic drugs that cause euphoria and might prove uniquely useful in depressed patients (see Sidebar).
Independent evidence has not confirmed that there is a monoamine abnormality in depression. For example, the findings of brain imaging studies of serotonin abnormality are contradictory. Some found reduced serotonin 1A receptor binding in drug-free patients who were depressed, consistent with the hypothesis that selective serotonin reuptake inhibitors (SSRIs) improve depression by correcting a deficiency of serotonin activity [4,5]. Other studies, however, have found no difference between patients who are drug-free and controls [6,7] or increased binding potential in depressed patients [7,8]. Postmortem findings of receptor changes in the brains of people who committed suicide have also been inconsistent [9–11]. In some studies, with patients who had recovered from depression, a tryptophan depletion challenge led to a transient increase in depressive symptoms. However, these results have not been confirmed in volunteer studies , and the effect appears to be dependent on previous SSRI use . Research on catecholamines (noradrenaline and adrenalin) is similarly confusing and inconclusive .
Most TCAs are strongly sedative and impair cognitive and motor performance [28,29]. Amitriptyline causes profound electroencephalograph slowing similar to chlorpromazine . Trazodone, mianserin, and mirtazapine also cause sedation and cognitive impairment [36,37]. Research on SSRIs has found a “lack of profound effects in healthy subjects” (p. 17 of ). Studies with volunteers taking single doses show increased attention-test performance and motor speed, as well as sleep impairment, suggesting a slight stimulating effect [22,27]. Studies with volunteers who have taken multiple doses over days or weeks show either no difference from placebo [37,38] or impaired concentration, vigilance, and memory, and reports of drowsiness [22,25,39–41] compared with placebo, suggesting that SSRIs have mild sedative effects. Patient studies suggest that SSRIs may sometimes cause extreme and unpleasant activation or agitation [42–44], which can resemble neuroleptic-induced akathisia . More commonly, SSRIs also cause subjective drowsiness or sedation . It is therefore difficult to characterise overall effects of SSRIs, which may have simultaneous mild stimulant and sedating effects. Reboxetine appeared to be subjectively mildly stimulant or “energy enhancing” in one volunteer study .
In volunteer studies, measures of mood specifically address subjective feelings and show either no effects after antidepressant administration or dysphoria [22–26]. Two volunteer studies found slightly improved recognition of positive emotional material and reduced recognition of negative emotional states compared with placebo [23,24]. Another found reduced reaction to negative events . However, without a comparison with other drugs, one cannot know whether these are specific effects of the antidepressants tested, or simply consequences of an intoxicated state. Possibly, some antidepressants share the opiates' and neuroleptics' particular emotional blunting effects. Alternatively, drug-induced states may nonspecifically reduce emotional sensitivity.
In addition, because inert placebos create nowhere near the range and intensity of effects (including side effects) that active drugs produce, RCTs of psychotropic drugs that use inert placebos (rather than active placebos, which mimic side effects of drugs) are not truly blinded . In that case, outcomes for people on antidepressants are likely to be subject to amplified expectations compared with those on inert placebo . This “placebo amplification” might be exacerbated in people who have taken antidepressants before and have not responded negatively ; modern trials are likely to select such patients above others [50,51].
Therefore, RCT evidence cannot confirm that antidepressants have a specific mood-elevating effect in patients. This is consistent with evidence that they have no mood-elevating effect in volunteers. Drugs known to produce short-term euphoria require an increasing dose to maintain this effect (tolerance) and are associated with a compensatory dysphoria on discontinuation. Drugs such as antipsychotics cause dysphoria and some depressive symptoms . So far, however, there is no compelling evidence that there exists any drug-induced effect consisting of a sustained elevation of mood.
A drug-centred model suggests that drug effects cannot easily be parcelled into “therapeutic” and “adverse” effects, since the same effect may have desirable and undesirable implications. Neuroleptic-induced indifference and sedation may help in acute psychosis but may impede long-term recovery. Increased passivity shown by a child on stimulants might help in a structured classroom but not in a summer camp. Drug use is always a fine balancing act, and patients' experiences are of primary importance in deciding whether there is more to be gained than lost. Such decisions require patients and professionals to cooperate to explore precisely what patients hope to achieve with drugs, matching these aims to known drug-induced effects.
Taking a drug-centred approach to the treatment of depression, we would conclude that no presently known effects of any drugs, including antidepressants, are likely to do more good than harm in the long term. In the short term, sedative effects of drugs may help people who are acutely anxious, highly aroused, or have difficulty sleeping. The common practice of prescribing short-term, low-dose sedative TCAs, for which general practitioners have frequently been criticised, may therefore be a rational one. Similarly, short-term benzodiazepine prescribing may occasionally be justified, bearing in mind the problem of dependency. On the other hand, although several drug classes (and possibly some antidepressants) are known to induce psychic indifference, the utility and desirability of this effect is doubtful.
This article is copyright (c) 2006 by Moncrieff and Cohen. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.