For decades people have been told that depression is caused by a serotonin deficiency. This was the rationale behind the introduction of the SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants in the 1990s, which were thought to work by boosting low levels of serotonin. Our research shows no evidence of low serotonin in depression, which suggests that antidepressants do not work in the way they were originally thought to work.
There are other explanations for how antidepressants affect people, and why they can be helpful that are not to do with reversing underlying brain abnormalities and have different implications. Drugs like antidepressants change normal brain chemistry and this affects people’s moods and behaviour. SSRI’s blunt both negative and positive emotions, for example, and this may provide relief for people who are acutely distressed or unhappy. Antidepressants also act through inducing hope and optimism (the placebo effect). In the long-term these effects may not be so helpful, however, and there are also harmful effects of long-term use such as dependence and withdrawal. People need this information in order to make properly informed decisions about whether to take antidepressants. If people do decide they would like to stop them, they should discuss this with their doctor and do it slowly and gradually following recent guidelines.
The serotonin research paper
Last week we published a systematic review in a journal called Molecular Psychiatry which brought together the evidence from all the main areas of research into connections between serotonin and depression (you can find the paper here). We found that none of these areas of research showed convincing evidence that depression is caused by low serotonin. In fact, there was little evidence of any abnormality of serotonin in people with depression.
The fact that this research has had such wide coverage shows just how shocking this finding is to many, many people. One TV presenter said it ‘blows your mind’. This is because the message that depression is caused by a chemical imbalance, and more specifically a lack of serotonin, has been widely publicised for many years.
Before I go further, for those who have not come across me before, I am a Professor at University College London and my longstanding interest is in understanding the nature and action of psychiatric drugs. I also work in the National Health Service as a consultant psychiatrist and have done so for 30 years or thereabouts. I see people with depression and occasionally prescribe drugs after careful consideration.
What people have been told about serotonin and depression
The idea that serotonin might be involved in depression was first proposed in the 1960s, and became known as the serotonin theory of depression. The public messaging started in the 1990s when the pharmaceutical industry was marketing its new range of antidepressant drugs, the SSRIs (Selective Serotonin Reuptake Inhibitors) such as Prozac. Serotonin is what is called a neurotransmitter- that is a chemical that helps transmit electrical impulses in the nervous system. As well as the brain, it is present in the gut and in blood platelets (tiny cell fragments involved in clotting). SSRI antidepressants increase the availability of serotonin in the brain’s synapses (the gaps between adjacent nerve cells where the impulses are transferred from one nerve to another) in the short-term by inhibiting the action of the serotonin transporter protein which transports serotonin out of the synapse.
So people were told in TV commercials (in countries like the US that have ‘direct to consumer’ advertising), and on internet sites set up by drug companies that are available worldwide, that depression was, or may be, caused by low levels of serotonin, and that antidepressants could help to normalise these. Typically, no other explanations were provided . There was also a huge promotional campaign targeted at doctors. Doctors were given free merchandise such as pens and mugs that kept the drug’s name in the forefront of their minds, and they were treated to lavish hospitality, sometimes including free trips to conferences in appealing and exotic locations. This level of blatant bribery decreased in the 2000s, but the marketing had succeeded in establishing the idea that depression is caused by a chemical imbalance as a fact in the minds of much of the medical profession and the general population.
People started to question the serotonin theory in the early 2000s, however. In 2005, two academics published a piece of research in which they compared the information on pharmaceutical websites with the pronouncements of certain researchers, and found a ‘disconnect’ between the marketing and the experts’ views (paper available here). In response to the publicity surrounding this piece, several leading psychiatrists claimed that psychiatrists had never actually believed in the chemical imbalance ‘myth’ anyway. However, when we investigated this, we found that the idea that serotonin is the cause or part of the causes of depression was widely endorsed in the scientific literature in the 1990s and 2000s (paper available here).
Crucially, though, even if leading psychiatrists were beginning to doubt the evidence for depression being related to low serotonin, no one told the public. Although the pharmaceutical industry has lost interest in antidepressants since they are no longer on patent and are thus less profitable, to this day people continue to be told by the media and some in the medical profession that depression is due to a chemical imbalance. In the last few months, at least two doctors have said this on primetime British TV and radio programmes (in one case on the BBC just a few days ago).
So although some of the commentators who traditionally defend antidepressants might say this doesn’t change anything (see some of the comments from the Science Media Centre) – the idea that there is, in fact, no convincing evidence to support the idea that depression is caused by low serotonin is big news to a lot of people. After this rather long introduction, I want to offer some thoughts about what people should make of this finding and, in particular, what people who are taking antidepressants might do about it.
What antidepressants do
Many people, including many doctors and researchers, assume that the only way drugs can ‘work’ or affect people with mental health problems is by correcting an underlying abnormality- whether that abnormality is a chemical imbalance or something more complex. But there are other explanations for how drugs affect people.
First, it’s important to remember that the majority of the effect of an antidepressant is due to a combination of the natural course of our moods and placebo (a pill that contains no active ingredient) effects. Randomised controlled trials that compare antidepressants and placebo are the basis for the use of antidepressants. It is evidence from these trials that regulating bodies like the United States FDA (Food and Drug Administration) and the United Kingdom’s MHRA (Medicines and Healthcare products Regulatory Agency) look at when they licence a drug. It is what institutions like NICE (the National Institute for health and social Care Excellence) considers when it produces its guidelines and recommendations about how to treat depression. When you get all these trials together (as in this meta-analysis paper) they show that antidepressants are a little bit better than a placebo (an inactive sugar pill), but not much. People who take the placebo do almost as well. In fact, it is not certain that there is much difference at all, because there are methodological problems with these studies that may explain this small difference between drugs and placebo. These include the possibility that people on antidepressants have an enhanced placebo effect because some of them identify that they got the real drug due to side effects or other subtle changes, and this induces optimism, which helps with recovery. Read more about these concerns with antidepressant trials in this paper and this one. Other important points are that these trials are almost all conducted by drug companies, and the vast majority of them last only a few weeks. Many people end up taking antidepressants for months and frequently years, however, but there are very few studies of long-term use. .
So what else could be producing this small difference between antidepressants and placebos, assuming it is not an artefact of the trial methods? Could antidepressants be working on some other brain chemical or pathway that produces depression? Theoretically they could be, but there is no agreement about what this might be and no consistent evidence to support alternative theories.
How antidepressants affect people
We know that SSRIs modify serotonin, therefore, if they are not correcting an underlying deficiency, we have to conclude that they are actually changing our normal brain chemistry. Drugs that change brain chemistry affect our mental states and emotions. Alcohol, for example, changes our brain chemistry and affects our moods. It can reputedly help us to ‘drown our sorrows’ temporarily. Antidepressants do not have the same chemical or behavioural effects as alcohol, but they have been reported to numb emotions in a general sense. They make both negative and positive emotions less intense. This effect may be linked with their well-recognised ability to produce sexual dysfunction, including reduced sexual desire.
The proposal that drugs like antidepressants work by changing normal brain chemistry and changing normal mental activity and emotions is what I have called the ‘drug centred model of drug action’. I call it this to distinguish it from the ‘disease centred model of drug action’, which is the idea that medications work by reversing a hypothetical underlying abnormality, like low serotonin, that is assumed to give rise to symptoms. I have been writing about these alternate ways of understanding how drugs might affect people with mental health problems of all sorts for a long time now. My first paper on the topic published in 2005 is here, and here is a paper about it published in the British Medical Journal in 2009. People might also like to read a previous blog which summarises the ideas quite briefly and if people are really interested I have published several books, my first being The Myth of the Chemical Cure, and most recent A Straight Talking Introduction to Psychiatric Drugs, revised edition, 2020.
The drug-centred model helps us to understand that drugs that affect the brain change our mental state by changing the way our brain normally works. In the short-term, some drugs may produce effects that are experienced as useful for people who in a state of acute distress or anxiety. Taking a drug that numbs emotions may provide short-term relief for someone who is deeply unhappy, fearful or confused, but in the long-term, taking a drug that alters normal brain chemistry may have harmful effects. In fact we know that antidepressants cause physical dependence. The brain alters to try and counteract the effects of the drug, and then when people miss a dose or stop taking the drug they experience withdrawal effects which are a consequence of the brain changes no longer being opposed by the drug. These can be severe and prolonged, especially if people have used the drugs for a long time and are of course well known in society in connection with alcohol use and other recreational drugs.
Long-term use of drugs that numb emotions may also have harmful psychological consequences because it may prevent people from finding other, potentially more lasting ways of managing their emotions. It may also prevent people from identifying and addressing the problems that made them depressed in the first place.
So what causes depression?
So if depression is not caused by low serotonin, what is it caused by? I have been asked this question by TV and radio presenters on several occasions over the last few days. Many psychiatrists assume that there must be some brain processes that cause depression that we haven’t fully discovered yet. This might be the case, but at the moment, it is merely speculation. A paper from 2019 reviewed research on all the main biological theories of depression, and concluded that ‘there is a lack of evidence for leading biological theories for onset and maintenance of depression.’
So maybe thinking about depression as a brain disease is the wrong way to think about it. Maybe we need a different sort of framework. Maybe our common-sense understanding of depression is more helpful than a medical one. Although our brain is involved in everything we think and do, of course, our moods and emotions are almost always reactions to events in our lives. We feel good when things go well, and sad, anxious, angry or frustrated when things go badly. Our large human brain is what gives us the capacity to reflect on our circumstances and to evaluate whether we like them or not, and it enables us to experience emotions, but the brain is not the cause of these emotions. In contrast, we know that adverse life events such as poverty, debt, divorce, child abuse, loneliness etc strongly predict whether someone will get depressed or not. This is not to suggest that depression cannot sometimes be very severe and the events that may have caused it hard to identify.
The British Psychological Society’s report on depression published in 2020 argues that ‘depression is best thought of as an experience, or a set of experiences, rather than as a disease. The experience we call depression is a form of distress. The depth of distress itself, as well as the contributing events and circumstances, can be life-changing, and even life-threatening. However, calling it an illness is only one way of thinking about it, with advantages and disadvantages.’
International bodies such as the United Nations and WHO (World Health Organisation) have also expressed concern that thinking about depression and anxiety as medical problems is not appropriate or useful and is leading to ‘an over-reliance on psychotropic drugs to the detriment of psychosocial interventions’ (WHO, 2021).
Of course, doctors don’t think depression only has biological causes, even those who tell you that depression is caused by a chemical imbalance. They always acknowledge that personal and social circumstances and life events are important as well. Some refer to this idea that depression has mixed causes as the ‘biopsychosocial’ model. But the bio bit is necessarily and inevitably the most important bit in this mix. If there is a biological cause or component to the causation of a condition, then this is what has to be dealt with. If your low mood is a consequence of your thyroid gland not working properly, or of an infectious disease like glandular fever, you have to treat the disease. The things going on in your life are only indirectly relevant. So telling people that depression is caused by a chemical imbalance logically implies that other causes are not as important, which means in practice they may be downplayed or ignored.
How should we help people with depression?
If we understand depression as a reaction to things going wrong in life, then treating depression means helping people to fix those things. Obviously the circumstances that make people depressed are individual, so the solutions will be individual too. Some people will need support to address family or relationship problems, others will require advice and support with employment issues; some may need help sorting out debt or financial or housing problems.
There are also some general things that people can do to improve their mood. The NICE depression guideline lists nine treatments for ‘less severe’ depression and eight treatments for ‘more severe’ depression (the new term for moderate and severe depression) that people can pursue as an alternative to taking medication that have been shown to be helpful in randomised trials. These include various forms of psychotherapy including cognitive behavioural therapy (CBT) and problem-solving therapy as well as exercise and mindfulness or meditation. Sometimes people are not quite sure why they are depressed, and therapy can help them explore what it is that might need changing to make them feel better.
Some people get very severely depressed. They might lose touch with reality and think everyone is against them (this is sometimes called ‘psychotic depression’) and some even try to take their own lives. It is tempting to think that in these cases medication is more effective, but this has not been shown to be the case. The severity of depression has no effect or a small effect on people’s response to antidepressants in placebo-controlled trials and an analysis found that studies involving people in hospital who have the most severe forms of depression did not show antidepressants to be very effective. It is important to keep people safe in these situations, and to remember that the vast majority of people do recover from depression eventually – although it may take months and for some even a few years.
What to do if you are taking antidepressants
Many people taking antidepressants today have been told by their doctor that they have a chemical imbalance and that the antidepressant will help put that right. If that is you, you might well feel shocked and upset by the news that the suggested links between depression and low serotonin have not in fact been demonstrated. You might wonder what the antidepressant is doing to your brain if it is not correcting an underlying imbalance.
If you are re-assessing the use of antidepressants in the light of this new information, I would encourage you to take time to reflect on how exactly antidepressants might be affecting you. What ‘side effects’ are you experiencing? Do you experience emotional numbing and if so do you find that useful or do you find it unpleasant? It will be useful to discuss this new information with your family and friends, and also with your doctor or prescriber. You might also want to read my blog about what you should think about before starting a drug for a mental health problem.
IT IS REALLY IMPORTANT THAT YOU DO NOT STOP YOUR ANTIDEPRESSANTS SUDDENLY OR TOO FAST.
We know that many people suffer from withdrawal symptoms when they try and stop their antidepressant and these can be severe and prolonged for some people, especially people who have used antidepressants for a long time.
If you are considering stopping your antidepressants, you should make a list of what you think are the positive and negative effects of being on them. If you feel the negatives outweigh the positives, and you want to stop them, you should do this very gradually with the support of a doctor or knowledgeable health professional. There is useful guidance on how to do this on the Royal College of Psychiatrists website here.