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A review paper published in Molecular Psychiatry looks at the ‘serotonin theory of depression’.
Prof Gitte Moos Knudsen, Professor of Neurobiology and Chair of Department of Neurology and Neurobiology Research Unit, Copenhagen University Hospital, Denmark, said:
“The authors justify the need for such a review by saying that it is a public misconception that depression is caused by low brain serotonin. The main misconception is, however, that depression is a single disease with a single biochemical deficit. Today, it is largely accepted that depression is a heterogeneous disorder with potentially multiple underlying causes. The review aims to uncover existing evidence for a serotonergic deficit, but the studies included in the review use methodologies that only generate proxies for the real question which is if synaptic 5-HT concentration and release are altered in (subsets) of patients with major depression.”
Dr Michael Bloomfield, Consultant Psychiatrist and UKRI Principal Clinical Research Fellow, Translational Psychiatry Research Group Head, UCL, said:
“The hypothesis that depression was caused by a chemical imbalance in serotonin was a really important step forward in the middle of the 20th century. Since then, there is a huge of amount of research which tells us that the brain’s serotonin systems plays very important roles in how our brains process different emotions.
“The findings from this umbrella review are really unsurprising. Depression has lots of different symptoms and I don’t think I’ve met any serious scientists or psychiatrists who think that all causes of depression are caused by a simple chemical imbalance in serotonin. What remains possible is that for some people with certain types of depression, that changes in the serotonin system may be contributing to their symptoms. The problem with this review is that it isn’t able to answer that question because it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense.
“Many of us know that taking paracetamol can be helpful for headaches and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression. There is consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving. Antidepressant medicines are one type of treatment alongside other types of treatment like psychotherapy (talking therapy). Patients must have access to evidence-based treatments for depression and anyone taking any treatment for depression who is contemplating stopping treatment should discuss this with their doctor first.”
Prof David Nutt, Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Imperial College London, said:
“This meta review covers much of the work done over the past 50 years to explore the relationship of the serotonin system to depression. Unfortunately, all of these variables are indirect measures of serotonin function or even worse (as in the case if the gene-linkage studies) merely proxies for serotonin activity. It is only recently that we have developed the technology to measure serotonin release in the living human brain and in the first study of this type (currently under review) we did find decreased serotonin release capacity in people with depression. So, to dismiss the serotonin hypothesis of depression at this point is premature.”
Prof Phil Cowen, Professor of Psychopharmacology, University of Oxford, said:
“I studied the role of serotonin in people with depression for three decades and I’m broadly in agreement with the authors’ conclusions about our current efforts, though I lack their adamantine certainty. No mental health professional would currently endorse the view that a complex heterogenous condition like depression stems from a deficiency in a single neurotransmitter, though in my opinion (and from my own work) the evidence that tryptophan depletion results in depressive symptoms in some remitted depressed patients is quite good. A similar comment applies to PET studies which show lowered serotonin transporter binding, particularly in the midbrain; this is consistent with diminished activity of serotonin neurons. In fact, it would be surprising if a such a widely distributed brain neuromodulatory system was completely uninvolved in the complex experiences that make up clinical depression.
“The article shows that systematic umbrella reviews leave significant room for interpretation. Also, what you leave out can be as important as what you put in. The authors did not include a meta-analysis published in the same journal (Molecular Psychiatry) in 2021, the abstract of which concluded: ‘…our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased L-tryptophan…’.
“The possible role of serotonin in depression is a separate question from the antidepressant effects of selective serotonin re-uptake inhibitors. I was puzzled by the press release which implies that antidepressant drugs could work only by correction of a prior corresponding chemical imbalance. No current theory of antidepressant action derived from either human or animal studies makes this assertion.”
Dr Livia de Picker, Postdoctoral researcher, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, said:
“While umbrella reviews can provide an interesting wide-angle overview of a research field, they are ultimately bound by the design and quality of the summarized studies and the original studies they rely on, and therefore do not allow us to draw new conclusions. Studying changes in brain functioning is very complicated, and this review paper mostly shows that depending on the methods used, it is not always possible to easily detect such changes just by drawing a blood sample for example. Nevertheless, it is important to point out that this study did not in fact look into the effectiveness of antidepressants directly. Antidepressants with serotonergic activity were already being used effectively for patients with depression prior to the theory of serotonin changes of depression. Since this original theory, newer research has also indicated that antidepressants affect several pathways and receptors in the brain, not just limited to serotonin. There is really no reason to question the effectiveness of current antidepressants even if our understanding of the biological causes of depression moves away from theories focused solely on serotonin.”
Prof Allan Young, Director, Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said:
“This is a review of reviews about aspects of the “Serotonin theory of depression”. Many might question the assertion that this is as important as the paper suggests as most psychiatrists adhere to the biopsychosocial model with very few people subscribing to a simple “chemical imbalance” theory.
“The authors get some details wrong, particularly with regards to the 5-HT1A receptor. The 5-HT1A receptor is present both pre and post-synaptically in the brain and researchers have hypothesised that it may be up or down regulated in mood disorders. Indeed, one of the best neuroimaging studies (https://pubmed.ncbi.nlm.nih.gov/15042104/) showed a persistent reduction in brain 5-HT1A receptors in recovered depressed men. The (undiscussed) elephant in the room is the good evidence of the efficacy and acceptability of serotonergic antidepressants.
“The use of these medicines is based on clinical trial evidence which informs their use for patients. This review does not change that.”
Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:
“This paper does not present any new findings but just reports results which have been published elsewhere and it is certainly not news that depression is not caused by “low serotonin levels”. The notion of depression being due to a “chemical imbalance” is outmoded, and the Royal College of Psychiatrists wrote that this was an over-simplification in a position statement published in 2019. Nor is it the case that SSRI antidepressants increase serotonin levels. Their immediate action is to alter the balance between serotonin concentrations inside and outside neurons but their antidepressant effect is likely due to more complex changes in neuronal functioning which occur later as a consequence of this. It is very clear that people suffering from depressive illness do have some abnormality of brain function, even if we do not yet know what this is, and that antidepressants are effective treatments for severe depression whereas interventions such as exercise and mindfulness are not. It is important that people with severe depression are not discouraged from receiving appropriate treatments, which can make a huge difference to them and those around them.”
A spokesperson for the Royal College of Psychiatrists said:
“Antidepressants are an effective, NICE-recommended treatment for depression that can also be prescribed for a range of physical and mental health conditions.
“Treatment options such as medication and talking therapy play an important role in helping many people with depression and can significantly improve people’s lives. Antidepressants will vary in effectiveness for different people, and the reasons for this are complex, which is why it’s important that patient care is based on each individual’s needs and reviewed regularly.
“Continued research into treatments for depression is important to help us better understand how medications work as well as their effectiveness. Medication should be available for anyone who needs it. We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their GP.”
Additional notes to the above comment:
The primary mode of action for most antidepressants is to target monoamine neurotransmitter function, increasing serotonin or noradrenaline availability, or both, at least initially (Harmer et al, 2017). While these changes start to happen relatively quickly, clinical improvement and therapeutic effects can take a few weeks. The original idea that antidepressants ‘correct a chemical imbalance in the brain’ is an over-simplification, but they do have early physiological effects and effects on some aspects of psychological function.
They can induce changes in the function of brain areas that are associated with the improvement in depressive symptoms. In animal studies they have been shown to increase the number and function of brain cells and the connections between them (ibid). They also exert effects on the processing of emotional information within a few hours of drug administration. Depression is often associated with a ‘negative bias’ in the way a person looks at the world and processes information: cognitive–behavioural therapy works in part through challenging automatic negative thoughts, and the cognitive bias in depression can also be ameliorated by antidepressant drugs.
It is important to recognise that antidepressants can treat the symptoms of depression but do not directly address any underlying psychosocial causes, which is why their use is often combined with psychological therapies that can improve patients’ ability to cope with difficult life situations.
3) NICE have also very recently updated their guidance on depression, which we have commented on. The new guidance has looked at the evidence on the treatment of new depressive episodes, chronic depression, preventing relapse, patient choice, and the organisation of, and access to, mental health services. Anti-depressants can be an important tool in a suite of treatment options and research into the mechanisms of how they work is vast and ongoing.
‘The serotonin theory of depression: a systematic umbrella review of the evidence’ by Joanna Moncrieff et al. was published in Molecular Psychiatry at 01:00 UK time on Wednesday 20th July.
DOI: 10.1038/s41380-022-01661-0
Declared interests
Dr Michael Bloomfield: “No declarations of interest.”
Prof David Nutt: “No declarations of interest.”
Prof Phil Cowen: “I have no COI to declare.”
Dr Livia de Picker: “I have no conflicts of interest to declare in relation to the current work. Outside this work:
– Performed paid consultancy for Boehringer-Ingelheim
– Received research grants for Boehringer-Ingelheim and Janssen R&D”
Prof Allan Young: “Employed by King’s College London; Honorary Consultant SLaM (NHS UK)
Deputy Editor, BJPsych Open
Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage
Consultant to Johnson & Johnson
Consultant to Livanova
Received honoraria for attending advisory boards and presenting talks at meetings organised by LivaNova. Principal Investigator in the Restore-Life VNS registry study funded by LivaNova.
Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.”
Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”
Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)”
UK Chief Investigator for Novartis MDD study MIJ821A12201
Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK)
No shareholdings in pharmaceutical companies.”
Prof David Curtis: “I have no conflict of interest to declare.”
For all other experts, no reply to our request for DOIs was received.