Why it is important to discuss what antidepressants do
Dear Editor
We would like to respond to the suggestion that we over-stepped the data in discussion of the relevance of our serotonin paper to the use of antidepressants.[1] The serotonin hypothesis is intimately connected to the rationale presented to patients for why they should take antidepressants and is still widely disseminated.[2]
The serotonin hypothesis is one of the most researched biological hypotheses of depression and antidepressant action, and it turns out the evidence is not convincing. No other biological hypotheses are proven or accepted.[3] If there is no conclusive evidence that antidepressants work by reversing an underlying abnormality, we cannot dismiss other, equally plausible explanations for how they might work. We know antidepressants, like other drugs prescribed for mental health problems, produce more or less subtle mental changes [4] including mental numbing.[5] These are likely to impact depressive symptoms and may also, along with other mental and physical effects, produce amplified placebo effects (which are not refuted by the paper cited, since there is good evidence of unblinding[6] and expectation effects in antidepressant studies).[7] Currently, we suspect few patients are given this information.
The RCTs referred to as evidence supporting prescription routinely demonstrate a drug-placebo difference of less than 2 points on the 52-point HAM-D scale [8], a difference thought to be clinically unimportant by NICE [9] and large analyses.[10] The recent FDA modelling exercise was exploratory and probabilistic and does not exclude amplified placebo effects as an explanation for the slightly different, though substantially overlapping distributions of antidepressant and placebo response.[11]
A review of tryptophan levels was not missed by our review which specified inclusion criteria of studies which measured serotonin or its metabolites. We do not know how precursors like tryptophan relate to serotonin levels and they are influenced by diet. Neuroimaging and post-mortem examination of central serotonin receptors are not peripheral markers of serotonin as claimed, and their levels will reflect cumulative serotonergic activity over time, arguably more informative than momentary sampling.
Understanding that antidepressants produce mental and physical alterations that may account for their effects has quite different implications from the idea that they work by reversing an underlying abnormality, which makes the use of drugs seem necessary and reassuring. Many people might have made different decisions about using antidepressants if they had not been led to believe this narrative. The situation is reminiscent of the false claims made about OxyContin (that it was not addictive for people in pain) that resulted in escalating rates of opioid use. We need to recognise the effect of drug companies on medical discourse and the hiring of academics as drug advocates to avoid repeating the same mistakes. Indeed, Janssen, manufacturer of esketamine, has links to authors of articles on the ‘glutamate hypothesis of depression’.[12]
As Kendrick and Collison argue patients should be made aware of what is known about antidepressants – that they show marginal differences from placebo, there are a variety of adverse effects, we have no long-term data on safety or efficacy and we do not know what are the effects of drugs that modify neurotransmitters when taken for long periods. There is no evidence they reverse an underlying abnormality, and the most obvious explanations for what they do are inspire hope (the placebo effect) or cause numbing of emotions (both positive and negative). If patients are not made aware of all this information, they are not able to make fully informed choices. Given widespread medical consensus that the chemical imbalance theory of depression is not supported, while vast numbers of the public still believe it, a public education campaign seems necessary, similar to campaigns about the cause of upper respiratory tract symptoms.
References
1 Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 2022; published online July 20. DOI:10.1038/s41380-022-01661-0.
2 The truth about antidepressants - What you need to know? ITV. 2022; published online Oct 11. https://www.itv.com/thismorning/articles/the-truth-about-antidepressants... (accessed Aug 17, 2022).
3 Kennis M, Gerritsen L, van Dalen M, Williams A, Cuijpers P, Bockting C. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry 2020; 25: 321–38.
4 Moncrieff J, Cohen D. How do psychiatric drugs work? BMJ 2009; 338: b1963.
5 Sansone RA, Sansone LA. SSRI-Induced Indifference. Psychiatry 2010; 7: 14–8.
6 Scott AJ, Sharpe L, Colagiuri B. A systematic review and meta-analysis of the success of blinding in antidepressant RCTs. Psychiatry Res 2022; 307: 114297.
7 Faria V, Gingnell M, Hoppe JM, et al. Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial. EBioMedicine 2017; 24: 179–88.
8 Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open 2019; 9: e024886.
9 National Institute of Clinical Excellence (NICE). Depression in adults: treatment and management | Guidance | NICE. 2022; published online June. https://www.nice.org.uk/guidance/ng222 (accessed July 16, 2022).
10 Leucht S, Fennema H, Engel R, Kaspers-Janssen M, Lepping P, Szegedi A. What does the HAMD mean? J Affect Disord 2013; 148: 243–8.
11 Horowitz M, Naudet F, Jakobsen J, Plöderl M, Moncrieff J. Data modelling in search of meaning. BMJ. 2022; published online Aug 14. https://www.bmj.com/content/378/bmj-2021-067606/rr (accessed Aug 16, 2022).
12 Moriguchi S, Takamiya A, Noda Y, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry 2019; 24: 952–64.
Competing interests:
JM is a co-applicant on the NIHR-funded REDUCE trial testing internet and telephone support for people wanting to come off long term antidepressants. She receives royalties from books she has written about psychiatric drugs. MH is co-founder of Outro Health which aims to provide digital support for people wanting to come off long term antidepressants in Canada.
17 August 2022
Joanna Moncrieff
Professor of Critical and Social Psychiatry and Consultant Psychiatrist
Mark Abie Horowitz
University College London
Division of Psychiatry, Maple House,149 Tottenham Court Rd, London W1T 7NF
Rapid Response:
Why it is important to discuss what antidepressants do
Dear Editor
We would like to respond to the suggestion that we over-stepped the data in discussion of the relevance of our serotonin paper to the use of antidepressants.[1] The serotonin hypothesis is intimately connected to the rationale presented to patients for why they should take antidepressants and is still widely disseminated.[2]
The serotonin hypothesis is one of the most researched biological hypotheses of depression and antidepressant action, and it turns out the evidence is not convincing. No other biological hypotheses are proven or accepted.[3] If there is no conclusive evidence that antidepressants work by reversing an underlying abnormality, we cannot dismiss other, equally plausible explanations for how they might work. We know antidepressants, like other drugs prescribed for mental health problems, produce more or less subtle mental changes [4] including mental numbing.[5] These are likely to impact depressive symptoms and may also, along with other mental and physical effects, produce amplified placebo effects (which are not refuted by the paper cited, since there is good evidence of unblinding[6] and expectation effects in antidepressant studies).[7] Currently, we suspect few patients are given this information.
The RCTs referred to as evidence supporting prescription routinely demonstrate a drug-placebo difference of less than 2 points on the 52-point HAM-D scale [8], a difference thought to be clinically unimportant by NICE [9] and large analyses.[10] The recent FDA modelling exercise was exploratory and probabilistic and does not exclude amplified placebo effects as an explanation for the slightly different, though substantially overlapping distributions of antidepressant and placebo response.[11]
A review of tryptophan levels was not missed by our review which specified inclusion criteria of studies which measured serotonin or its metabolites. We do not know how precursors like tryptophan relate to serotonin levels and they are influenced by diet. Neuroimaging and post-mortem examination of central serotonin receptors are not peripheral markers of serotonin as claimed, and their levels will reflect cumulative serotonergic activity over time, arguably more informative than momentary sampling.
Understanding that antidepressants produce mental and physical alterations that may account for their effects has quite different implications from the idea that they work by reversing an underlying abnormality, which makes the use of drugs seem necessary and reassuring. Many people might have made different decisions about using antidepressants if they had not been led to believe this narrative. The situation is reminiscent of the false claims made about OxyContin (that it was not addictive for people in pain) that resulted in escalating rates of opioid use. We need to recognise the effect of drug companies on medical discourse and the hiring of academics as drug advocates to avoid repeating the same mistakes. Indeed, Janssen, manufacturer of esketamine, has links to authors of articles on the ‘glutamate hypothesis of depression’.[12]
As Kendrick and Collison argue patients should be made aware of what is known about antidepressants – that they show marginal differences from placebo, there are a variety of adverse effects, we have no long-term data on safety or efficacy and we do not know what are the effects of drugs that modify neurotransmitters when taken for long periods. There is no evidence they reverse an underlying abnormality, and the most obvious explanations for what they do are inspire hope (the placebo effect) or cause numbing of emotions (both positive and negative). If patients are not made aware of all this information, they are not able to make fully informed choices. Given widespread medical consensus that the chemical imbalance theory of depression is not supported, while vast numbers of the public still believe it, a public education campaign seems necessary, similar to campaigns about the cause of upper respiratory tract symptoms.
References
1 Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 2022; published online July 20. DOI:10.1038/s41380-022-01661-0.
2 The truth about antidepressants - What you need to know? ITV. 2022; published online Oct 11. https://www.itv.com/thismorning/articles/the-truth-about-antidepressants... (accessed Aug 17, 2022).
3 Kennis M, Gerritsen L, van Dalen M, Williams A, Cuijpers P, Bockting C. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry 2020; 25: 321–38.
4 Moncrieff J, Cohen D. How do psychiatric drugs work? BMJ 2009; 338: b1963.
5 Sansone RA, Sansone LA. SSRI-Induced Indifference. Psychiatry 2010; 7: 14–8.
6 Scott AJ, Sharpe L, Colagiuri B. A systematic review and meta-analysis of the success of blinding in antidepressant RCTs. Psychiatry Res 2022; 307: 114297.
7 Faria V, Gingnell M, Hoppe JM, et al. Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial. EBioMedicine 2017; 24: 179–88.
8 Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open 2019; 9: e024886.
9 National Institute of Clinical Excellence (NICE). Depression in adults: treatment and management | Guidance | NICE. 2022; published online June. https://www.nice.org.uk/guidance/ng222 (accessed July 16, 2022).
10 Leucht S, Fennema H, Engel R, Kaspers-Janssen M, Lepping P, Szegedi A. What does the HAMD mean? J Affect Disord 2013; 148: 243–8.
11 Horowitz M, Naudet F, Jakobsen J, Plöderl M, Moncrieff J. Data modelling in search of meaning. BMJ. 2022; published online Aug 14. https://www.bmj.com/content/378/bmj-2021-067606/rr (accessed Aug 16, 2022).
12 Moriguchi S, Takamiya A, Noda Y, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry 2019; 24: 952–64.
Competing interests: JM is a co-applicant on the NIHR-funded REDUCE trial testing internet and telephone support for people wanting to come off long term antidepressants. She receives royalties from books she has written about psychiatric drugs. MH is co-founder of Outro Health which aims to provide digital support for people wanting to come off long term antidepressants in Canada.