In defence of the Serotonin hypothesis

This week saw the publication of an important paper by Professor of Psychiatry Dr Joanna Moncrieff and her colleagues. The conclusions of the paper were as follows; that approximately 80% of the British public believe that depression is due to a “chemical imbalance in the brain” and that the neurotransmitter that is implicated in depression is Serotonin (also called 5-HT) however Moncrieff argues that further to a meta-analysis, there is no convincing evidence that Serotonin deficiency is the root cause of depression.

What do I make of this as a practising psychiatrist and as someone with a special interest in treating depression and suicidal people? First, I would say that the results of the Moncrieff paper need to be interpreted with caution. The researchers conducted a broad search to identify research papers about depression and Serotonin. They found 361 relevant papers yet excluded the majority of these based on a set of inclusion criteria and included only 17 papers in their meta-analysis. A number of the research papers included were systematic reviews or meta-analyses themselves rather than randomised controlled trials; the former do not generally lend themselves to meta-analysis although one particular study had many thousand participants. Another limitation of the study was the fact that some of the participating studies included patients who had been treated with antidepressant drugs. One would expect brain differences in Serotonin levels to be less marked in these subjects, hence introducing bias. I believe that the Moncrieff paper should rightly open up a dialogue about the nature and treatment of depression however it would be dangerous for public opinion to do an “about turn” and for the lay person to now conclude that they have been misled by psychiatrists and that antidepressant medication has no place in the treatment of depression.

I would like to redress the balance. I would like to inform the public about my own naturalistic research on depressed patients, many hundreds, possibly thousands of patients over the last 30 years of my clinical career. I want to reinforce the message that depression is a serious mental illness (not an issue or a struggle or ordinary human distress), that more severe forms of the illness require drug treatment as well as psychological treatment and most importantly that antidepressants save lives. My patients tell me this again and again. They tell me how they felt before antidepressant treatment. They tell me how differently they feel if and when a specific antidepressant drug works for them. They tell me which drugs have made them feel different and which drugs have not. They are not there to please me, they are there to get better and sometimes many drug trials are needed before the individual finds a drug that they know they are responding to.

I am not here to report that antidepressants are problem-free or side-effect free, no they are not. However, my patients who make a good response to antidepressant treatment are usually willing to continue to take them for at least 12 months as the benefits far outweigh the risks and negatives. At a time when more people than ever across the globe are suffering from depression and at a time when we still need to find a way to reduce suicides in the general population, it is not right for one research group to instil such confusion and mistrust when it comes to antidepressants.

I will outline some of the historical research findings that I still believe are relevant in an understanding of the causes of depression. The Serotonin hypothesis of depression is necessarily simplistic. It always has been. But it is relatively easy to understand, and it has stuck. Psychiatrists refer more specifically to the monoamine hypothesis of depression. This is because monoamine neurotransmitters other than Serotonin have been shown to play a part in depression and certain antidepressants target Norepinephrine and Dopamine. For example, SNRIs increase the availability of both Serotonin and Noradrenaline in the brain. Agomelatin a relatively new antidepressant only targets Dopamine receptors.
NICE guidance for the treatment of depression (a set of national guidelines) recommend that an SSRI is first-line treatment for moderate and severe depressive illnesses and they can also be prescribed for mild depressive illnesses where patients have not responded to other measures such as CBT and exercise therapy. Treatment with an SSRI involves choosing the right drug for the individual based on previous response and side effect profile. Dose escalation is OFTEN necessary to achieve a good response. Many patients in primary care are under treated for their depressive illness leading to partial recovery and re-enforcing some doctors’ views that antidepressants do not really work. My experience as a clinical psychiatrist is that antidepressants DO work when prescribed and taken correctly.

Where a patient does not respond to an SSRI, algorithms exist which guide GPs and psychiatrists in the next stages of treatment. An SNRI (such as Venlafaxine or Duloxetine) should be tried next followed by either an MAOI or a tetracyclic antidepressant such as Mirtazapine if the patient still does not respond or has unacceptable side effects. For the most severe or treatment-resistant forms of depression, drugs such as Lithium or antipsychotics are often added to an antidepressant to enhance its effect. Electroconvulsive therapy (ECT) can be and is still used in treatment-resistant and/or life-threatening depression.

What does all this mean? The honest answer is that we don’t fully understand all the neurochemical processes that underly mood, behaviour, suicidal thoughts and the treatment of depression. We need to continue to carry out high quality research in this area. My own belief is that there are likely to be many subtypes of depression with slightly different aetiologies, some of which are likely to be genetically determined. We already know for example that particular algorithms apply in the treatment of psychotic depression and bipolar depression and that these patients do not fully respond to an antidepressant drug alone although they are all displaying common symptoms of depression.

To return to Serotonin, which is the subject of the current debate, there is already ample evidence that Serotonin is involved in many depressive illnesses. The evidence for this is millions of patients who respond to first line treatment with an antidepressant called an SSRI. An SSRI is a Selective Serotonin Reuptake Inhibitor. It increases the amount of Serotonin between nerve cells in the brain and it makes Serotonin receptors in the brain more sensitive to its effects. Many patients with depression DO respond to an SSRI.

I hope that readers of this article will be reassured to some extent that depression was never as simple as “low Serotonin”, but this is a hypothesis that has stuck because it is readily explainable and backed up by certain research papers AND more importantly by millions of case studies, namely real patients who have got better from their depression with an SSRI.

If a team of researchers suddenly announced that extrinsic insulin does not help diabetics, as doctors we would not conclude that insulin should no longer be given to diabetics. We would want to examine the research findings carefully and carry out original research on a much larger scale to help to find a definitive answer to the insulin question. I hope that doctors and researchers will respond in the same way when it comes to the Serotonin question. Let us not forget our responsibilities to our patients and to the public at large who deserve a balanced appraisal of the evidence.

Janet Meehan

28th July 2022

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