More than a chemical imbalance: rethinking serotonin and depression

Part 1: The chemical imbalance story

1Depression affects around 280 million people worldwide, and antidepressants are among the most widely prescribed medicines. For decades, patients were often told that depression is caused by a "chemical imbalance" in the brain, a shortage of the neurotransmitter serotonin that the tablets correct. The real picture turns out to be more complicated and more interesting. Antidepressants do help many people, but how they help is still being worked out. This document follows the serotonin story from an accidental discovery in the 1950s to brain imaging and genetic studies today.

2Depression is more than feeling sad for a few days. People with depression have a low mood or lose interest and pleasure in almost everything for at least two weeks, and they often sleep badly, lose their appetite, find it hard to concentrate and feel worthless or hopeless. Depression has no single cause. Inherited factors, stressful events, long-term illness and the way a person has learned to think about problems can all play a part. It is diagnosed from a person’s symptoms, because there is no blood test or brain scan that can detect it.

3Serotonin is made from the amino acid tryptophan. Most of the serotonin in the brain is released by a small group of neurones in the brain stem, called the raphe nuclei. Their axons branch many times and reach almost every part of the brain, including the cerebral cortex, the hippocampus and the hypothalamus. Serotonin is involved in the control of mood, sleep, appetite and how strongly we respond to threats and rewards.

4The serotonin story began by accident in the 1950s. Doctors treating patients for tuberculosis with a drug called iproniazid noticed that many patients became unusually cheerful. Iproniazid turned out to inhibit monoamine oxidase, or MAO, an enzyme that breaks down serotonin and similar neurotransmitters. At about the same time, a drug used to lower blood pressure, which depletes these neurotransmitters, was found to cause depression in some patients. Together, these observations led to the monoamine hypothesis of depression.

5At a serotonin synapse, an action potential arriving at the presynaptic neurone causes vesicles to release serotonin into the synaptic cleft by exocytosis. Serotonin diffuses across the cleft and binds to receptors on the postsynaptic membrane. The signal is ended mainly by a transporter protein in the presynaptic membrane, which takes serotonin back into the presynaptic neurone. Some of the serotonin taken back in is stored again, and some is broken down by MAO.

6In 1987, the first selective serotonin reuptake inhibitor, or SSRI, went on sale. SSRIs bind to the serotonin transporter protein and block it, so less serotonin is taken back into the presynaptic neurone. Older antidepressants also affected other neurotransmitters and receptors, which caused side effects such as a dry mouth and drowsiness. Because SSRIs act mainly on serotonin, they are usually easier to take, although they can still cause nausea, sleep problems and other side effects.

7In an illustrative trial, 300 adults with moderate depression were randomly divided into two groups of 150. One group took an SSRI and the other took a placebo tablet that looked identical, for eight weeks. Neither the patients nor the doctors knew who received which tablet. A patient was said to have responded if their score on a depression rating scale had at least halved. In the SSRI group, 81 patients responded. In the placebo group, 57 patients responded.

8One puzzle has never fitted the simple chemical imbalance story. An SSRI increases the concentration of serotonin in synaptic clefts within hours of the first tablet, but most patients do not feel better for two to six weeks. At first, the presynaptic neurones detect the extra serotonin using receptors on their own membranes, called autoreceptors, and they release less. Over several weeks these autoreceptors become less sensitive. In animals, long-term SSRI treatment also increases the production of new neurones in the hippocampus and the formation of new synapses.

9Several brain regions are affected in depression. The frontal lobe of the cerebral cortex is involved in planning, making decisions and controlling emotional responses. The hippocampus is needed to form new memories, and the hypothalamus helps to control sleep, appetite and the release of hormones. Deep inside each temporal lobe, a small region called the amygdala is involved in detecting threats and producing fear. These regions are linked by bundles of axons, and serotonin neurones from the raphe nuclei release serotonin in all of them, which helps to explain why one neurotransmitter can affect so many different behaviours.

Seeing the depressed brain

10Functional magnetic resonance imaging, or fMRI, allows researchers to see which regions of the brain are most active while a person carries out a task. Active neurones use more oxygen, so the flow of blood to an active region increases. Oxyhaemoglobin and deoxyhaemoglobin respond differently to a magnetic field, and the scanner detects the change in the proportion of oxyhaemoglobin. A computer then produces images that show the regions where activity has increased.

11In an illustrative fMRI study, people with depression and a control group were shown photographs of fearful faces while they were in the scanner. The amygdala of the people with depression responded more strongly than that of the control group. After only two weeks of taking an SSRI, before their mood had improved, the response of the amygdala had fallen to almost the same level as in the control group.

12Structural MRI scans, which show the size and shape of brain regions rather than their activity, have found that the hippocampus is often slightly smaller in people who have had depression for many years. One explanation is that long periods of stress increase the concentration of the hormone cortisol, which can reduce the growth of new neurones in the hippocampus. Some studies have found that the difference becomes smaller after successful treatment, although other researchers have not been able to repeat this finding.

13"I think the drugs change how the brain processes emotional information first, and mood follows later," says Dr Tomás Ribeiro, a psychiatrist who studies brain imaging. "A person starts to notice a friendly face rather than a hostile one, and over weeks of living with that slightly different view of the world, their mood begins to lift. That is a very different story from simply topping up a missing chemical."

Part 2: Beyond serotonin

14In 2022, a large review of earlier studies concluded that there was no consistent evidence that people with depression have lower serotonin activity than other people. The review was widely reported, and some people stopped taking their tablets suddenly as a result, which can be harmful. Most researchers argued that the review did not show that antidepressants do not work, only that the simple chemical imbalance explanation of how they work is not correct.

15The recreational drug MDMA, or ecstasy, has the opposite effect on the serotonin transporter to an SSRI. MDMA enters the presynaptic neurone and causes the transporter to work in reverse, so it pumps serotonin out into the synaptic cleft. MDMA also blocks the reuptake of serotonin. The result is a large release of serotonin, which produces feelings of happiness and closeness to other people. Many users feel low for several days afterwards. High doses can also cause dangerous overheating.

16Scientists are investigating whether MDMA could be used, under careful supervision, alongside talking therapy for post-traumatic stress disorder. Some early trials gave promising results, but in 2024 the medicines regulator in the United States decided that more evidence about its safety and effectiveness was needed before the treatment could be approved. Critics had pointed out that it is very difficult to run a blind trial of a drug whose effects are so obvious, because most patients can tell whether they have been given MDMA or a placebo.

17Studies of twins suggest that about 35 per cent of the variation in the risk of depression between people is due to differences in their genes. Depression is polygenic, which means that many genes are involved, each with a very small effect. Early studies claimed that a particular allele of the gene for the serotonin transporter greatly increased the risk of depression after stressful events, but much larger studies have not found this effect.

18The environment can also change how genes are expressed. In experiments with rats, pups whose mothers licked and groomed them less often had more methyl groups attached to the DNA of a gene for a cortisol receptor in the hippocampus. As adults, these rats produced fewer receptors and had a stronger response to stress. Such epigenetic changes alter the transcription of genes without changing the base sequence of the DNA, and they can last for a lifetime.

19Antidepressants are not the only treatment. Talking therapies such as cognitive behavioural therapy can be as effective as medicines for mild and moderate depression, and regular exercise also helps. For people whose depression has not responded to other treatments, a nasal spray containing a drug related to ketamine can improve mood within hours. It acts mainly on receptors for a different neurotransmitter, glutamate, rather than on serotonin. Many people benefit most from a combination of medicine and talking therapy, and doctors often try more than one antidepressant before finding one that suits a patient.

20"Depression is not one disease with one cause, and serotonin is only one part of the story," says Dr Ribeiro. "That is not bad news. It means there are many different ways in, through medicines, therapy, exercise and changing the situations that people live in. The most important message is still the oldest one: depression is common, it is treatable, and it is always worth asking for help." "Research over the next decade should tell us which treatment is most likely to work for which person."