Figures
Citation: Moncrieff J, Cohen D (2006) Do Antidepressants Cure or Create Abnormal Brain States? PLoS Med 3(7): e240. https://doi.org/10.1371/journal.pmed.0030240
Published: June 6, 2006
Copyright: © 2006 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.
Funding: The authors received no funding to write this article.
Competing interests: Joanna Moncrieff is Co-Chairperson of the Critical Psychiatry Network, a group of psychiatrists who dispute the predominance of biological models of mental disorder and campaign for a less coercive psychiatry.
Abbreviations: RCT, randomised controlled trial; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant
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 [1]. 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).
Evaluation of Alternative Models
The disease-based approach in psychiatry has rarely been tested directly. Prior to the dominance of this approach, which began in the 1960s, a drug-based model was mostly employed [1]. A disease-based model could be considered established if (1) the pathology of psychiatric conditions or symptoms had been delineated independently from the characterisation of drug action, and drug action could be extrapolated from that pathology; (2) rating scales used to evaluate drug treatment in clinical trials reliably detected changes in the manifestations of an underlying disease process rather than detecting drug-induced effects; (3) animal models of psychiatric conditions selected specific drugs; (4) drugs thought to have a specific action in certain conditions were shown to be superior to drugs thought to have nonspecific effects; (5) healthy volunteers showed different or absent patterns of effects, compared with diagnosed patients, since drugs would be expected to exert their therapeutic effects only in an abnormal nervous system [2]; and (6) the widespread use of supposedly disease-specific drugs led to demonstrable improvements in short- or long-term outcome of psychiatric disorders. Conversely, the absence of such evidence could indicate that a drug-centred model is preferable to guide scientific inquiry and produce therapeutic advances.
Evidence for Disease-Based Action of Antidepressants
The pathology of depression—the monoamine hypothesis
Antidepressants are believed to exert their therapeutic effects by acting on brain monoamines, which are believed to be important determinants of mood. However, in a circular chain of logic, the monoamine theory of depression was itself formulated primarily in response to observations that early antidepressants increased brain monoamine levels [3].
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 [12], and the effect appears to be dependent on previous SSRI use [13]. Research on catecholamines (noradrenaline and adrenalin) is similarly confusing and inconclusive [14].
Depression rating scales
These 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 nonspecific sedative effects that occur with most tricyclic antidepressants (TCAs) and some other antidepressants. Hence, changes in rating scale scores may merely reflect drug-induced effects.
Animal models of depression
These models, which usually involve biochemical or behavioural processes thought to mimic aspects of depression in humans, do not select antidepressants reliably but produce numerous “false positives” with other drugs, including stimulants, opiates, and neuroleptics. They also produce some “false negatives” with supposed antidepressant drugs [15].
Antidepressants versus other drugs
Many drugs not normally considered to be antidepressants show comparable effects to antidepressants when given to patients who are depressed in some randomised controlled trials (RCTs) [1, 16]. These include benzodiazepines [17], opiates [18], buspirone [19], stimulants [20], reserpine, and other antipsychotics [21].
Healthy volunteer studies
The fact that antidepressants do not appear to elevate mood in healthy volunteers [22–26] might suggest that they have a disease-specific action. However, because of the nature of depression rating scales (as explained above), it is unclear that antidepressants specifically affect mood in patients who are depressed. Any effect they have over and above placebo may also be attributable to an “amplified” placebo response (see below). Although there are some reports of improved sleep in patients with depression who are given SSRIs versus volunteers' reports of decreased sleep when given SSRIs [27], in general, side effects in patient studies are consistent with effects on volunteers. For example, TCAs show sedation and cognitive impairment [28, 29], while SSRIs show gastrointestinal upset and drowsiness, both in patients and in healthy volunteers [22].
Outcome of depression
There is little evidence outside RCTs that the long- or short-term outcome of depression is changing as a consequence of antidepressant use. Recent sharp increases in antidepressant use have been accompanied by increased prevalence and duration of depressive episodes [30] and rising levels of sickness absence [31]. Naturalistic studies have also shown that depressive episodes are more frequent and last longer among antidepressant users than among nonusers [30] and that sickness absence is more prolonged [32], although severity is likely to explain some of this effect (i.e., it is likely that patients are on antidepressant drugs because they have more severe disease). Follow-up studies of people treated for depression indicate high levels of nonrecovery or relapse [33–35].
What Do Antidepressants Actually Do?
Since antidepressants come from a number of different chemical classes, they would be expected to produce different sorts of effects.
Most TCAs are strongly sedative and impair cognitive and motor performance [28, 29]. Amitriptyline causes profound electroencephalograph slowing similar to chlorpromazine [29]. 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 [22]). 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 [45]. More commonly, SSRIs also cause subjective drowsiness or sedation [43]. 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 [25].
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 [26]. 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.
Drug Effects in Clinical Trials
RCTs of antidepressants report that drug-treated trial participants show greater improvement on rating scale scores than placebo-treated participants. However, this difference was shown to be small in recent meta-analyses—about two points on the Hamilton Rating Scale for Depression, or small differences in improvement rates [46, 47]. Drug-induced effects could account for this difference in several ways. In the Hamilton Rating Scale for Depression, for example, three items on sleep, two on anxiety and one on agitation can score up to 16 points (a total score between 19–22 on the Hamilton Rating Scale for Depression indicates severe depression). On these items, any drug with sedative effects would be likely to outperform placebo.
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 [48]. In that case, outcomes for people on antidepressants are likely to be subject to amplified expectations compared with those on inert placebo [48]. This “placebo amplification” might be exacerbated in people who have taken antidepressants before and have not responded negatively [49]; 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 [52]. So far, however, there is no compelling evidence that there exists any drug-induced effect consisting of a sustained elevation of mood.
(Photo: J Troha/National Cancer Institute)
Clinical and Theoretical Implications
The idea that antidepressant drugs target a specific biological state that produces depression strongly justifies the disease model of depression and its medical treatment [53]. Therefore, abandoning the disease-centred model of antidepressant action squarely challenges the notion of depression as a biologically based medical disease. The argument presented here supports claims that the medical concept of depression obscures the diversity of problems and experiences that come to be so labelled, and that social explanations and interventions have been undervalued [54, 55]. By contrast, a drug-centred model allows drug treatment to be considered without necessarily accepting a disease model.
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.
Conclusion
Many patients are led to believe, by their physicians and by advertising, that antidepressant drugs will act on the biological cause of their depressed state by rectifying a “chemical imbalance” [56]. On the contrary, our analysis indicates that there are no specific antidepressant drugs, that most of the short-term effects of antidepressants are shared by many other drugs, and that long-term drug treatment with antidepressants or any other drugs has not been shown to lead to long-term elevation of mood. We suggest that the term “antidepressant” should be abandoned. We have proposed an alternative drug-centred model of drug action that is consistent with a demedicalised approach to depression.
Supporting Information
Text S1. Translation of Article Summary into French by David Cohen
https://doi.org/10.1371/journal.pmed.0030240.sd001
(38 KB DOC).
Article Summary
Antidepressants are assumed to work on the specific neurobiology of depressive disorders according to a “disease-centred” model of drug action. However, little evidence supports this idea. An alternative, “drug-centred,” model suggests that psychotropic drugs create abnormal states that may coincidentally relieve symptoms. Drug-induced effects of antidepressants vary widely according to their chemical class—from sedation and cognitive impairment to mild stimulation and occasionally frank agitation. Results of clinical trials may be explained by drug-induced effects and placebo amplification. No evidence shows that antidepressants or any other drugs produce long-term elevation of mood or other effects that are particularly useful in treating depression. (See Text S1 for French translation.)
References
- 1. Moncrieff J, Cohen D (2005) Rethinking models of psychotropic drug action. Psychother Psychosom 74: 145–153.
- 2. Hyman SE, Nestler EJ (1996) Initiation and adaptation: A paradigm for understanding psychotropic drug action. Am J Psychiatry 153: 151–162.
- 3. Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am J Psychiatry 122: 509–522.
- 4. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, et al. (2000) Brain serotonin 1A receptor binding measured by positron emission tomography with [11C]WAY-100635: Effects of depression and antidepressant treatment. Arch Gen Psychiatry 57: 174–180.
- 5. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, et al. (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46: 1375–1387.
- 6. Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, et al. (2004) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: Effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61: 1271–1279.
- 7. Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, et al. (2006) Altered serotonin 1A binding in major depression: A [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59: 106–113.
- 8. Reivich M, Amsterdam JD, Brunswick DJ, Shiue CY (2004) PET brain imaging with [11C](+)McN5652 shows increased serotonin transporter availability in major depression. J Affect Disord 82: 321–327.
- 9. Stockmeier CA, Dilley GE, Shapiro LA, Overholser JC, Thompson PA, et al. (1997) Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology 16: 162–173.
- 10. Lowther S, De Paermentier F, Cheetham SC, Crompton MR, Katona CL, et al. (1997) 5-HT1A receptor binding sites in post-mortem brain samples from depressed suicides and controls. J Affect Disord 42: 199–207.
- 11. Matsubara S, Arora RC, Meltzer HY (1991) Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims. J Neural Transm Gen Sect 85: 181–194.
- 12. Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology (Berl) 163: 42–53.
- 13. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, et al. (1999) Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: Implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 46: 212–220.
- 14.
Healy D (1999) The antidepressant era. New York: Harvard University Press. 336 p.
- 15. Bourin M, Fiocco AJ, Clenet F (2001) How valuable are animal models in defining antidepressant activity? Hum Psychopharmacol 16: 9–21.
- 16. Moncrieff J (2001) Are antidepressants overrated? A review of methodological problems in antidepressant trials. J Nerv Ment Dis 189: 288–295.
- 17. Imlah NW (1985) An evaluation of alprazolam in the treatment of reactive or neurotic (secondary) depression. Br J Psychiatry 146: 515–519.
- 18. Emrich HM, Vogt P, Herz A (1982) Possible antidepressive effects of opioids: Action of buprenorphine. Ann N Y Acad Sci 398: 108–112.
- 19. Robinson DS, Alms DR, Shrotriya RC, Messina M, Wickramaratne P (1989) Serotonergic anxiolytics and treatment of depression. Psychopathology 22: Suppl 127–36.
- 20. Rickels K, Gordon PE, Gansman DH, Weise CC, Pereira-Ogan JA, et al. (1970) Pemoline and methylphenidate in midly depressed outpatients. Clin Pharmacol Ther 11: 698–710.
- 21. Robertson MM, Trimble MR (1982) Major tranquillisers used as antidepressants. A review. J Affect Disord 4: 173–193.
- 22. Dumont GJ, de Visser SJ, Cohen AF, van Gerven JM (2005) Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 59: 495–510.
- 23. Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM (2004) Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry 161: 1256–1263.
- 24. Harmer CJ, Hill SA, Taylor MJ, Cowen PJ, Goodwin GM (2003) Toward a neuropsychological theory of antidepressant drug action: Increase in positive emotional bias after potentiation of norepinephrine activity. Am J Psychiatry 160: 990–992.
- 25. Tranter R, Healy H, Cattell D, Healy D (2002) Functional effects of agents differentially selective to noradrenergic or serotonergic systems. Psychol Med 32: 517–524.
- 26. Furlan PM, Kallan MJ, Have TT, Lucki I, Katz I (2004) SSRIs do not cause affective blunting in healthy elderly volunteers. Am J Geriatr Psychiatry 12: 323–330.
- 27. Mayers AG, Baldwin DS (2005) Antidepressants and their effect on sleep. Hum Psychopharmacol 20: 533–559.
- 28. Deptula D, Pomara N (1990) Effects of antidepressants on human performance: A review. J Clin Psychopharmacol 10: 105–111.
- 29. Herrmann WM, McDonald RJ (1978) A multidimensional test approach for the description of the CNS activity of drugs in human pharmacology. Pharmakopsychiatr Neuropsychopharmakol 11: 247–265.
- 30. Patten SB (2004) The impact of antidepressant treatment on population health: Synthesis of data from two national data sources in Canada. Popul Health Metr 2: 9.
- 31. Moncrieff J, Pomerleau J (2000) Trends in sickness benefits in Great Britain and the contribution of mental disorders. J Public Health Med 22: 59–67.
- 32. Dewa CS, Hoch JS, Lin E, Paterson M, Goering P (2003) Pattern of antidepressant use and duration of depression-related absence from work. Br J Psychiatry 183: 507–513.
- 33. Goldberg D, Privett M, Ustun B, Simon G, Linden M (1998) The effects of detection and treatment on the outcome of major depression in primary care: A naturalistic study in 15 cities. Br J Gen Pract 48: 1840–1844.
- 34. Tuma TA (2000) Outcome of hospital-treated depression at 4.5 years. An elderly and a younger adult cohort compared. Br J Psychiatry 176: 224–228.
- 35. Kennedy N, Abbott R, Paykel ES (2003) Remission and recurrence of depression in the maintenance era: Long-term outcome in a Cambridge cohort. Psychol Med 33: 827–838.
- 36. Knegtering H, Eijck M, Huijsman A (1994) Effects of antidepressants on cognitive functioning of elderly patients. A review. Drugs Aging 5: 192–199.
- 37. Wingen M, Bothmer J, Langer S, Ramaekers JG (2005) Actual driving performance and psychomotor function in healthy subjects after acute and subchronic treatment with escitalopram, mirtazapine, and placebo: A crossover trial. J Clin Psychiatry 66: 436–443.
- 38. Ramaekers JG (2003) Antidepressants and driver impairment: Empirical evidence from a standard on-the-road test. J Clin Psychiatry 64: 20–29.
- 39. Ramaekers JG, Muntjewerff ND, O'Hanlon JF (1995) A comparative study of acute and subchronic effects of dothiepin, fluoxetine and placebo on psychomotor and actual driving performance. Br J Clin Pharmacol 39: 397–404.
- 40. Robbe HW, O'Hanlon JF (1995) Acute and subchronic effects of paroxetine 20 and 40 mg on actual driving, psychomotor performance and subjective assessments in healthy volunteers. Eur Neuropsychopharmacol 5: 35–42.
- 41. Raptopoulos P, McClelland GR, Jackson D (1989) The clinical pharmacology of paroxetine in healthy subjects. Acta Psychiatr Scand Suppl 350: 46–48.
- 42. Breggin PR (2003) Fluvoxamine as a cause of stimulation, mania and aggression: A critical analysis of the FDA-approved label. Ethical Hum Sci Serv 4: 211–227.
- 43. Beasley CM, Dornseif BE, Pultz JA, Bosomworth JC, Sayler ME (1991) Fluoxetine versus trazodone: Efficacy and activating-sedating effects. J Clin Psychiatry 52: 294–299.
- 44. Beasley CM, Sayler ME, Weiss AM, Potvin JH (1992) Fluoxetine: Activating and sedating effects at multiple fixed doses. J Clin Psychopharmacol 12: 328–333.
- 45. Leo RJ (1996) Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry 57: 449–454.
- 46. Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002) The emperor's new drugs: An analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prev Treat 5: 23.
- 47. Moncrieff J, Kirsch I (2005) Efficacy of antidepressants in adults. BMJ 331: 155–157.
- 48. Fisher S, Greenberg RP (1993) How sound is the double-blind design for evaluating psychotropic drugs? J Nerv Ment Dis 181: 345–350.
- 49. Niklson IA, Reimitz PE, Sennef C (1997) Factors that influence the outcome of placebo-controlled antidepressant clinical trials. Psychopharmacol Bull 33: 41–51.
- 50. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, et al. (2004) Sequenced treatment alternatives to relieve depression (STAR*D): Rationale and design. Control Clin Trials 25: 119–142.
- 51.
Cohen D (2005) Clinical psychoparmacological trials: “Gold standard” or fool's gold? In: Kirk SA, editor. Mental disorders in the social environment: Critical perspectives. New York: Columbia University Press. pp. 347–367.
- 52. Van Putten T, Marder SR (1987) Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 48: (Suppl)13–19.
- 53. Malhi GS, Parker GB, Greenwood J (2005) Structural and functional models of depression: From sub-types to substrates. Acta Psychiatr Scand 111: 94–105.
- 54.
Mirowsky J, Ross CE (2003) Social causes of psychological distress. Chicago: Aldine de Gruyter. 320 p.
- 55. Pilgrim D, Bentall RP (1999) The medicalisation of misery: A critical realist analysis of the concept of depression. J Ment Health 8: 261–274.
- 56. Lacasse JR, Leo J (2005) Serotonin and depression: A disconnect between the advertisements and the scientific literature. PLoS Med 2: e392.