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Against the stream: Antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants

  • Joanna Moncrieff (a1)
Summary

Although antidepressants are regarded as effective and specific treatments, they are barely superior to placebo in randomised trials, and differences are unlikely to be clinically relevant. The conventional disease-centred understanding of drug action regards antidepressants as targeting an underlying brain process, but an alternative ‘drug-centred’ view suggests they are psychoactive substances that modify normal mental states and behaviour. These alterations, such as numbing of emotions, may reduce feelings of depression, and also create amplified placebo effects in randomised trials. Patients should be informed that there is no evidence that antidepressants work by correcting a chemical imbalance, that antidepressants have mind-altering effects, and that evidence suggests they produce no noticeable benefit compared with placebo.

Declaration of interest

The author is co-chairperson of the Critical Psychiatry Network.

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Copyright
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
Correspondence to Joanna Moncrieff (j.moncrieff@ucl.ac.uk)
Footnotes
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Against the Stream Series

Development and change often arise by challenging the status quo. In the arena of mental health and in the practice of psychiatry, the need to question and the importance of critiquing are paramount. Hence, we have decided to introduce a new series of articles to be published in this and forthcoming issues of the BJPsych Bulletin. Each piece will tackle controversial issues of relevance to psychiatrists and mental health professionals. The position taken by the authors will be contrary to received wisdom on the subjects, hence the title of the series – Against the stream. The articles will not be accompanied by an opposing view but, of course, readers are most welcome to contribute their views via eLetters and, indeed, we hope very much that lively discussion will ensue.

Philip Graham and Peter Tyrer

Footnotes
References
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1 Ilyas, S, Moncrieff, J. Trends in prescriptions and costs of drugs for mental disorders in England, 1998–2010. Br J Psychiatry 2012; 200(5): 393–8.
2 Royal College of Psychiatrists. Antidepressants. Royal College of Psychiatrists, 2009.
3 Smith, A, Traganza, E, Harrison, G. Studies on the effectiveness of antidepressant drugs. Psychopharmacol Bull 1969; Suppl: 153.
4 Khin, NA, Chen, YF, Yang, Y, Yang, P, Laughren, TP. Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. J Clin Psychiatry 2011; 72(4): 464–72.
5 Kirsch, I, Deacon, BJ, Huedo-Medina, TB, Scoboria, A, Moore, TJ, Johnson, BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5(2): e45.
6 Turner, EH, Matthews, AM, Linardatos, E, Tell, RA, Rosenthal, R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358(3): 252–60.
7 Leucht, S, Fennema, H, Engel, R, Kaspers-Janssen, M, Lepping, P, Szegedi, A. What does the HAMD mean? J Affect Disord 2013; 148(2–3): 243–8.
8 Moncrieff, J, Kirsch, I. Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Contemp Clin Trials 2015; 43: 60–2.
9 Fournier, JC, DeRubeis, RJ, Hollon, SD, Dimidjian, S, Amsterdam, JD, Shelton, RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303(1): 4753.
10 Gibbons, RD, Hur, K, Brown, CH, Davis, JM, Mann, JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69(6): 572–9.
11 Walsh, BT, Seidman, SN, Sysko, R, Gould, M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002; 287(14): 1840–7.
12 Medical Research Council. Clinical trial of the treatment of depressive illness. Br Med J 1965; 1: 881–6.
13 Zhang, Y, Yang, H, Yang, S, Liang, W, Dai, P, Wang, C, et al. Antidepressants for bipolar disorder: a meta-analysis of randomized, double-blind, controlled trials. Neural Regen Res 2013; 8(31): 2962–74.
14 Moncrieff, J, Cohen, D. Rethinking models of psychotropic drug action. Psychother Psychosom 2005; 74(3): 145–53.
15 Moncrieff, J, Cohen, D. Do antidepressants cure or create abnormal brain states? PLoS Med 2006; 3(7): e240.
16 Lacasse, JR, Leo, J. Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS Med 2005; 2(12): e392.
17 Dumont, GJ, de Visser, SJ, Cohen, AF, van Gerven, JM. Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 2005; 59(5): 495510.
18 Goldsmith, L, Moncrieff, J. The psychoactive effects of antidepressants and their association with suicidality. Curr Drug Saf 2011; 6(2): 115–21.
19 Sharma, T, Guski, LS, Freund, N, Gotzsche, PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ 2016; 352: i65.
20 Reefhuis, J, Devine, O, Friedman, JM, Louik, C, Honein, MA. Specific SSRIs and birth defects: Bayesian analysis to interpret new data in the context of previous reports. BMJ 2015; 351: h3190.
21 Fava, GA, Gatti, A, Belaise, C, Guidi, J, Offidani, E. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom 2015; 84(2): 7281.
22 Farnsworth, KD, Dinsmore, WW. Persistent sexual dysfunction in genitourinary medicine clinic attendees induced by selective serotonin reuptake inhibitors. Int J STD AIDS 2009; 20(1): 68–9.
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Against the stream: Antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants

  • Joanna Moncrieff (a1)
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eLetters

Ideology over evidence?

Sameer Jauhar, Senior Research Fellow , Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College
Allan H Young, Director, Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College, London
16 March 2018

Ideology versus evidence?

In her narrative, Dr Moncrieff makes assertions about depressive illness, antidepressants, and psychotropic medication (1).

Her main points are that they are not clinically effective when using rating scales, and that models proposed for antidepressant action are erroneous.

We would suggest the narrative reflects ideology, as opposed to evidence, and should be interpreted accordingly.

Firstly, a 1969 narrative supplementary review is given as an example of lack of efficacy of tricyclic and older antidepressants. A more recent (and comprehensive) review found significant benefits for MAOIS over placebo, which were surpassed by tricyclics (2). The argument is then made that change in Hamilton Depression Rating Scale (HDRS) is minimal, in comparison to placebo, and differences are clinically insignificant, when the clinical global impression (CGI) scale is used, citing amongst other reviews, the Kirsch meta-analysis (where the effect size was 0.31 (3)). A similar effect size was seen in a recent analysis of over 500 studies, that showed odds ratios of between 1.37 and 2.13 for response, compared to placebo (4).

In focusing argument on change in total HDRS Dr Moncrieff appears unaware the scale was never intended to measure change. A more robust way of analysing it was recently demonstrated, using the rating of subjective mood (Item 1 on HDRS), which would be akin to the CGI. This avoided the influence of antidepressant side-effects on the scale, and found clear benefits for paroxetine and citalopram over placebo (5).

A study cited to indicate severity of depression does not predict outcome evaluated short-term efficacy of antidepressants, and was not intended to test the hypothesis of severity, the authors reporting significant benefits of fluoxetine over placebo in adults (improvement of approximately 35%) (6). The 1964 MRC trial (which showed efficacy of ECT) is given as evidence of lack of effect of severity on response, and the statement that antidepressants did not outperform placebo is not surprising, given that the dose of imipramine was 50mg and phenelzine 15mg. A more recent, and influential publicly funded study (cited over 3000 times in google scholar) found effectiveness of imipramine (at therapeutic dose of around 185mg) in people with severe depression, in comparison to psychological therapies (CBT and IPT). These therapies showed little benefit over placebo in this group (7).

The rest of the narrative dwells on "disease centred" models of psychiatric illness, as an alternative to the current "targeting a brain abnormality" approach. We are unaware of modern psychiatry relying on the neurotransmitter models she discusses; the field has moved on significantly, and most neuroscientists would point to more nuanced models, involving effects on neural networks and plasticity (8). The predominant reference cited here is Dr Moncrieff's own hypotheses.

In summary, we would suggest Dr Moncrieff's narrative is selective at best, and on cursory examination there is little effort to appraise literature in a scientifically objective manner. One cannot help but assume that this opinion piece represents ideology over evidence, and therefore any interpretation should be cautious.

References

1. Moncrieff J. Against the stream: Antidepressants are not antidepressants - an alternative approach to drug action and implications for the use of antidepressants. BJPsych Bulletin. 2018 Feb;42(1):42-4.

2. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995 May;12(3):185-219.

3. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008 Feb;5(2):e45.

4. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet 2018 Feb 20. pii: S0140-6736(17)32802-7.

5. Hieronymus F, Lisinski A, Nilsson S, Eriksson E. Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry 2017 (epub aheads of Print)

6. Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012 Jun;69(6):572-9.

7. Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program: General Effectiveness of Treatments. Arch Gen Psychiatry. 1989 Nov 1;46(11):971-82.

8. Morrison PD, Murray RM. The antipsychotic landscape: dopamine and beyond. Th
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Conflict of interest: Dr Young reported receiving payment for lectures from or serving on advisory boards for AstraZeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, and LivaNova; reported serving as the lead investigator for the Embolden Study (AstraZeneca), Brain Cells Incorporated Neuroplasticity Study, and Arip

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Psychiatrists use an outcome centered prescribing model

Adam Moreton, ST5 Old Age Psychiatry Specialty Registrar, Health Education North West
Mawada Adam, ST5 General Adult Psychiatry Specialty Registrar, Health Education North West
Ahmed S Huda, Consultant Psychiatrist, Early Intervention Team, Pennine Care NHS Foundation Trust
08 March 2018

Dear Editor,



We read Dr Moncrieff’s article[1] in the February edition with interest. Dr Moncreiff is co-chair of the Critical Psychiatry Network, a group which argues that utilising a medical framework for the treatment of mental disorder is not appropriate[2]. Members of this group (and this article) have suggested two conceptual models of prescribing: drug- and disease-centered [3]. Of concern to us was Dr Moncrieff’s unreferenced assertion in her article that a diseased-centred model is “the accepted view of drug action in psychiatry”[1].



A disease-centered model presumes medications correct the hypothesised underlying causative mechanism and that medications are beneficial. In the drug-centered model, psychiatric medications have several psychoactive effects some of which can be perceived as beneficial in some patients, whilst in others they can be harmful.



However, there are also other conceptual models. In an outcome-centered model, medication may be chosen as research has shown it to be effective for certain clinical indications but how that effect is achieved is uncertain. Psychiatrists may also use different prescribing models across different conditions due to variations in the evidence-base.



A literature review failed to identify any studies measuring the frequency of psychiatrists’ use of the various conceptual models of prescribing. Therefore a survey of psychiatrists’ prescribing rationale would provide useful data to add to this debate.



We conducted an online survey of consultant psychiatrists within a North West England NHS Mental Health Trust. They were presented with eight common clinical scenarios - including the use of antidepressants in depression - for which respondents could choose one of four options corresponding to disease-centred, drug-centred, outcome-centred, and ‘no medication’ models.



A 64% (n=56) response rate was achieved covering a range of psychiatric subspecialties. All respondents had worked in psychiatry for a minimum of six years. Five declared six to 10 years experience, 37 between 10 and 25 years, and 14 had worked for 25 years or more.



Using Clopper-Pearson method with two-sided p-values reported an outcome-centred model was chosen (by 71 - 96% of respondents, p<0.01) in seven out of eight scenarios. An exception was thiamine to prevent Wernicke-Korsakoff syndrome in alcohol withdrawal where a disease-centred model was commonest (70% of respondents, p=0.009). No statistical difference was seen in the most popular choice of model between psychiatrists of different experience levels.



In contradiction to the assertion that a disease-centered model is most prevalent amongst psychiatrists including for the use of antidepressants in depression, an outcome-centered model was overwhelmingly chosen in this survey. In most clinical scenarios respondents’ prescribing models used empirical evidence of effectiveness with an awareness of uncertainty around mechanism of effect.The preference for a disease-centered model for thiamine in Wernicke-Korsakoff syndrome demonstrated that respondents did not have a fixed model of prescribing for all situations but varied based on the available knowledge base.



We acknowledge that this is a very small study limited by its response rate and within a single NHS trust. However, it is the first survey we are aware of that measures psychiatrists’ prescribing models as opposed to assertions that psychiatrists believe they are reversing disease with prescriptions of medications such as antidepressants. In most clinical scenarios respondent’s prescribing models used empirical evidence of effectiveness but with an awareness of the uncertainty around mechanism of effect. The exception was where clear knowledge of disease mechanism reversal by medication was known.



REFERENCES



[1] Moncrieff J. Against the stream: Antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants. BJPsych Bulletin 2018; 41: 42-44.https://doi.org/10.1192/bjb.2017.11

[2] Moncrieff J, Huws R. About Us. The Critical Psychiatry Network. Available from: http://www.criticalpsychiatry.co.uk/index.php/36-info/info/226-about-us

[3] Yeomans D, Moncrieff J, Huws R. Drug-Centred Psychopharmacology: a Non-Diagnostic Framework for Drug Treatment. BJPsych Advances 2015; 21: 229-36.
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Conflict of interest: None declared

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Assessing the evidence for antidepressants.

Caoimhe Cooney, Registrar in Psychiatry, Cluain Mhuire Mental Health Services, Dublin , Ireland.
Elizabeth Cummings, Consultant Psychiatrist, Cluain Mhuire Mental Health Services, Dublin, Ireland.
03 March 2018

Dr Moncrieff presents some persuasive arguments, which we are willing at the outset to concede; that the “chemical imbalance theory” is not supported by the evidence, that the diagnosis of depression has obvious limitations and that the choices we have in the treatment of an operationally defined diagnosis of depression are imperfect ones.(1) There is a risk in any polemic, of oversimplifying the opposing side.

The assertion that depression is currently regarded as a “discrete and universal disorder” and that the public continue to be informed by the psychiatric profession that depression is a “chemical imbalance” that antidepressants can help reverse is not supported by a review of literature by public-facing organisations such as the Royal College of Psychiatrists (2) or diagnostic manuals used by professionals.

There is demonstrable evidence for the efficacy of antidepressants. Placebo controlled antidepressant clinical trials have consistently demonstrated placebo response rates of 30%-50%, drug response rated of 45%-70%, and drug placebo differences of 18%-25% (3).

Placebo response is an interesting, complex phenomenon. The wider medical literature reflects a strong placebo response in a variety of medical conditions. For most situations and conditions, placebo contributes 30% to 40% to the benefit of an intervention. Likely, 35% to 50%, if not more, of a response to an analgesic or opiate can be attributed to placebo (4). Meta-analyses of antidepressant trials suggest that high placebo response rather than low medication response explains most of the variability in drug-placebo differences and that placebo response has been increasing over the past 20 years (5). The contention that there is little difference between placebo and antidepressant therapy in terms of efficacy has the potential to alienate patients from effective therapy.

While our widely acknowledged limitations in the understanding of the nature of depression are frustrating, and current treatment options imperfect, it is often not possible, desirable or safe for patients to endure the suffering associated with depression and it is in their interests that all evidence be considered.

Caoimhe Cooney, Registrar in Psychiatry, and Elizabeth Cummings, Consultant Psychiatrist, Cluain Mhuire Community Mental Health Service, Dublin, Ireland. Email caoimhe.cooney@sjog.ie

1. Moncrieff, J. (2018) “Against the stream: Antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants,” BJPsych Bulletin. Cambridge University Press, 42(1), pp. 42–44. doi: 10.1192/bjb.2017.11

2. Royal College of Psychiatrists. Depression. Royal College of Psychiatrists, 2015.

3. Khan A; Warner H A; Brown W A. Symptom Reduction and Suicide Risk in Patients Treated with Placebo in Antidepressant Clinical Trials. An Analysis of the Food and Drug Administration Database. Arch Gen Psychiatry/Vol 57, Apr 2000, 57(4):311-7

4. Olshanky B, Placebo and Nocebo in Cardiovascular Health: Implications for Healthcare,Research, and the Doctor-Patient Relationship. J Am Coll Cardiol. Volume 49, Issue 4, January 2007. Pages 415-421 DOI: 10.1016/j.jacc.2006.09.036.

5. Bret R. Rutherford, M.D., and Steven P. Roose, M.D. A Model of Placebo Response in Antidepressant Clinical Trials. Am J Psych. Volume 170, Issue 7, July 2013, pp. 723-733

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Conflict of interest: None declared

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Rational Antidepressant Use

Daniel Dunleavy, MSW, Doctoral Candidate, Florida State University College of Social Work
08 February 2018

To the Editor:

In her contribution to the "Against the Stream" series, Dr. Moncrieff [1] articulates the case for the drug-centered model of antidepressant action. She notes that antidepressants: do not typically outperform placebo in well-designed studies (particularly in rare instances where an active placebo is used as a control [2]); have little clinical impact; and can cause serious adverse effects. Having made the case that antidepressants are not "specific" antidepressant agents, she makes some comments about their use in clinical practice. I would like to offer a few remarks about these issues, including some musings about what "rational antidepressant use" might look like.

Modern psychiatric practice has seen the rise and fall of several promising antidepressant agents (the Monoamine Oxidase inhibitors, the Tricyclic Antidepressants, and Selective Serotonin Reuptake Inihibitors). Recent efforts include testing the possible antidepressant properties of ketamine. But are these efforts futile? Perhaps yes, perhaps no. A truly specific antidepressant drug (if one is ontologically possible) appears to be a pipedream, in light of current diagnostic limitations. Our categorisaztion of Major Depressive Disorder is highly heterogenous [3], creating a disjunctive category of cognitive, behavioral, and biological symptoms that do not reliably cluster together. Even if any of our current drugs had specificity for "depression", it would be extremely difficult to uncover in clinical practice or research settings. As a result, drug development will be prone to ideological, as opposed to scientific, revolutions [4]

Should we therefore abandon antidepressants as a treatment modality? As long as we are honest with our patients about our current state of knowledge, I think not. Drug use has always been an integral part of human life (see generally [5]), helping to alleviate life's various physical, emotional, and existential pains. Antidepressants are no different in this respect. While researchers continue the search for a discrete condition called "depression", drugs like the SSRIs can be exploited for particular patient complaints. Antidepressants can cause emotional blunting, sedation, activation, and decreased libido, among other things. Some have a proclivity toward one effect more than others These effects can be exploited to relieve particular problems (e.g. sedation to alleviate insomnia; emotional numbing to transcend an episode of intense anxiety or distress), without pretense toward a yet-to-be disovered condition. A rational provider would match a drug's effects to the patient's complaints, irrespective of diagnosis (or drug class); and remain vigilant to the development of any adverse effects or of deterioration of condition, will start at the lowest recommended dose, and will withdrawal the patient from the drug as soon as possible. Psychosocial interventions can remain an important part of treatment, in many cases being the first treatment of choice. Antidepressants, like all drugs, are neither angels nor demons. They should be used selectively and thoughtfully, when used at all.

1. Moncrieff, J. Antidepressants are not antidepressants-An alternative approach to drug action and implications for the use of antidepressants. BJPsych Bulletin 2018; 42(1): 42-44.

2. Jensen, JS, Bielefeldt, AS, Hróbjartsson, A. Active placebo control groups of pharmacological intervention were rarely used but merited serious consideration: A methodological overview. Journal of Clinical Epidemiology 2017; 87: 35-46.

3. Paris, J. The mistreatment of major depression. Canadian Journal of Psychiatry 2014; 59(3): 148-151.

4. Healy, DT. The structure of psychopharmacological revolutions. Psychiatric Developments 1987; 4: 349-376.

5. Chast, F. A history of drug discovery. In: Wermuth, CG, ed. The practice of medicinal chemistry. 3rd ed. Cambridge, MA: Academic Press; 2008.

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Conflict of interest: None declared

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