- Several surveys have reported that a significant number of people believe a “chemical imbalance” in the brain to be the cause of depression.
- Over time, serotonin started to occupy the pride of place in this “urban myth”, popularised among other reasons to justify the sale of antidepressant drugs.
- The fact is that a one-to-one cause-effect relationship between serotonin and depression is “too simple and not supported by the evidence”.
- A recent review of scientific studies, representing data from more than 100,000 people, reached this conclusion, and hit headlines worldwide.
- At the same time, the review as well as the underlying concepts leave considerable scope to misunderstand an issue that is already a product of miscommunication.
Hyderabad: A review of multiple scientific studies may lay to rest once and for all the ubiquitous yet misguided belief that low levels of serotonin are responsible for depression – the so-called serotonin model. While doctors and other experts have been aware that the model was wrong, most people, including many of those taking antidepressants, have persisted with the belief that the disorder was rooted in a “chemical imbalance”.
The results of the review have already made headlines worldwide as a result of their being at odds with public perception, yet the review as well as the underlying issues leave considerable scope for misunderstanding – a bad thing considering the problem appears to fundamentally be one of miscommunication.
In 1965, psychiatrist and psychopharmacologist Joseph Schildkraut published a paper in which he proposed that depression might be a result of lower levels of a compound in neurons in the brain, called norepinephrine. In 1967, British psychiatrist Alec Coppen proposed that depression originated due to lower levels of another compound, serotonin.
Schildkraut and Coppen thus birthed a new possibility: a disease of the soul or the mind remade as a simple matter of biochemistry. Soon, this serotonin model of depression made way for a simple metaphor: that a “chemical imbalance” in the brain causes depression, and that correcting this imbalance should alleviate its symptoms.
The review, published in the journal Molecular Psychiatry and authored by Joanna Moncrieff and her colleagues at University College London, provides compelling evidence that debunks the causative role of serotonin in depression.
The paper suggests that psychiatrists let go of the ubiquitous but simple metaphors of “chemical imbalance” to explain depression to their patients and allow them the opportunity to make an informed decision about the course of treatment.
Mark Horowitz, a clinical research fellow in psychiatry at University College London and an author of the Moncrieff et al. paper, told The Wire Science that the team pursued this study to investigate whether low levels of serotonin in the brain cause depression.
While psychiatrists recognise that a one-to-one cause-effect relationship between serotonin and depression is, in Horowitz’s words, “too simple and not supported by evidence,” there is widespread belief in society that a “chemical imbalance” – i.e. low levels of serotonin – plays a causal role.
“So we wanted to go directly to the sciences and the studies, and check if this idea is supported by the available evidence or not,” he told The Wire Science.
The brain is the organ that produces and processes thoughts, feelings and emotions in the body. It is made up of neurons – nerve cells – along with other kinds of cells that nourish and assist neurons in their activities.
Neurons connect and communicate with each other at junctions called synapses. Neuroscientists are aware of two broad types of synapses: electrical and chemical. In electrical synapses, a neuron transmits information to a neighbouring neuron through electrical signals.
In the more common chemical synapse, a neuron secretes substances called neurotransmitters. When they bind to receptors on the neighbouring neuron’s membrane, they trigger a cascade of reactions that translate the chemical message into an electrical signal.
Researchers have identified several neurotransmitters in the human body. Three of them have been associated with depression: dopamine, norepinephrine and serotonin. Of these, serotonin is often deemed the most important and has had its status elevated for its putative reputation as the “feel good” chemical.
According to Sanjeev Jain, a professor of psychiatry at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, the roots of the serotonin hypothesis of depression can actually be traced back to the Indian subcontinent.
In 1931, Gananath Sen, an Ayurveda practitioner, and Karthick Chandra Bose, a graduate of the Calcutta Medical College, published a paper that reported the use of a milkweed flower called sarpagandha (Rauwolfia serpentina) to treat hypertension and “insanity with violent maniacal symptoms”.
Around the same time, the noted chemist Salimuzzaman Siddiqui and a colleague were trying to isolate medically useful compounds from the Rauwolfia plant.
Siddiqui could isolate several compounds but failed to isolate the active compound that made Rauwolfia a viable treatment for hypertension and mania.
It was only two decades later that chemists working at Ciba Pharmaceutical Products, Basel isolated the active compound: reserpine. Soon after, in 1955, American psychiatrists Nathan Kline and Alfred Stanley published data from a clinical trial that proved the efficacy of reserpine vis-à-vis several psychiatric disorders, including psychosis and “manic depressive disorder”1.
By 1960, researchers had found that reserpine reduced serotonin and norepinephrine levels in the brain. Around the same time, researchers also found that a class of drugs effective at treating depression, called monoamine oxidase inhibitors (MAOIs), also increased the amount of neurotransmitters in the brain.
Serotonin, dopamine and norepinephrine are monoamines. This means their molecular structure has one amino group (–NH2). After a neurotransmitter has relayed a signal from one neuron to the next, it has to be degraded or recycled. Enzymes called monoamine oxidases do this. Specifically, they degrade the neurotransmitter using oxygen to metabolise it and reduce its level in the synapse. The process also effectively terminates communication between the neurons.
MAOIs, like the name suggests, inhibit the action of monoamine oxidases. So the neurotransmitters are not degraded, allowing their levels in the synapse to increase.
In 1965, Schildkraut put two observations together: that reserpine, a drug that induces a depressive effect (and thus treats mania), reduces the levels of serotonin and norepinephrine, and that drugs that treat depression increase the levels of these neurotransmitters in synapses.
Thus a hypothesis was born: that depression is the result of the low levels of certain neurotransmitters in the brain.
Over time, serotonin started to occupy the pride of place in this hypothesis, for two reasons. One: MAOIs, while effective for treating depression, came with undesirable side effects like nausea and dizziness. So pharmaceutical companies were on the lookout for safer drugs. Two: scientists found evidence in postmortem studies that serotonin levels are lower in the brains of people who have died due to depression-related suicides.
In 1974, the pharmaceutical company Eli Lilly developed fluoxetine, a selective serotonin reuptake inhibitor (SSRI) – the first of a class of drugs that would quickly come to dominate treatment options for people with depression.
Instead of acting on enzymes that degrade neurotransmitters, SSRIs act on the proteins required to recycle them. These proteins, called monoamine transporters, are present in the synaptic membrane and transport neurotransmitters like dopamine, serotonin and norepinephrine from the synapse to the interior of the neuron. SSRIs in particular inhibit the activity of monoamine transporters responsible for recycling serotonin.
“When the drug companies were promoting their drugs that increase serotonin, they emphasised this hypothesis,” Horowitz explained. “It was always a hypothesis, but the messaging from drug companies and advertisements – and through academic psychiatrists – was so effective that most of the population has been convinced that low serotonin is the cause of depression.”
To test whether the available evidence supported this serotonin hypothesis of depression, Moncrieff & co. decided to perform a systematic ‘umbrella’ review. Here, researchers analyse pre-existing reviews and meta-analyses 2 to answer a research question.
The team identified five groups of studies for the review:
- Studies that measure levels of serotonin and serotonin metabolites in body fluids, including blood and the cerebrospinal fluid 3,
- Studies that examine the binding between serotonin and its receptor,
- Studies that examine serotonin transporter levels,
- Studies that deplete serotonin in the body by depleting tryptophan, an amino acid that is the precursor to Serotonin, in the diet, and
- Studies that examine serotonin transporter genes and their association with depression.
Notably, the team excluded studies of animal models, those that addressed specific kinds of depression (e.g. bipolar depression), and those that tracked depression resulting from other physical conditions, like Parkinson’s disease or stroke.
Finally, the team had 17 studies to work with, representing data from more than 100,000 people.
“In every one of those five areas, we found no difference between people with depression and healthy controls,” Horowitz said. So the team concluded that the evidence available doesn’t support the claim that low serotonin levels are responsible for depression.
“We shouldn’t be telling patients that their depression is caused by low serotonin or a chemical imbalance.”
Vidita Vaidya, a neurobiologist at the Tata Institute of Fundamental Research, Mumbai, has worked extensively on the role of serotonin and SSRIs in the neurobiology of emotion. She told The Wire Science that the Moncrieff et al. study reiterates facts that researchers and practitioners already knew.
Horowitz agreed – but added that their study was important to resolve the “disconnect between what academic psychiatrists think and what the public has been led to believe.”
According to him, practising doctors continue to lead their patients to believe that their depression is a result of “chemical imbalance” in the brain. He agreed this might be a useful metaphor to convince people with depression to take their medicines, but Horowitz said he believes doing so deprives patients of their right to informed consent.
Jain, of NIMHANS, said he believes the study provides useful insights that “correct the ‘simplistic’ impressions” and that “‘chemical imbalance’ as a cause of depression may be true, but at a scale not detectable by available methods.”
Instead, Jain called the serotonin model an “urban myth” popularised to justify the big rise in antidepressant sales. According to one estimate, the worldwide sale of antidepressants could be worth $18.29 billion4 by 2027.
This said, Vaidya cautioned that the authors of the review might be making too strong a statement when they indicate that serotonin is not related to depression at all. “They are equally oversimplifying the relationship by suggesting that serotonin has nothing to do with depression,” she told The Wire Science. This is important, Vaidya said, because the authors set out to counter the oversimplified claim that low levels of serotonin cause depression.
Jain also said that while the Moncrieff et al. paper correctly observes that genes related to serotonin are not necessarily associated with genes that have been implicated in depression, “that is true for all non-communicable diseases”.
He used the example of diabetes: the genes implicated in this condition aren’t necessarily associated with the insulin gene. “But does that mean insulin biology is not related to diabetes?”
Jain also questioned the authors’ decision to not consider bipolar depression in their study – “which was the kind of depression that the 1965 theory was trying to explain”.
Horowitz said in turn that serotonin might be involved in depression in a “complex but poorly understood” way – as might be several other neurotransmitters and other substances in the brain. However, he added, “that is extremely different from telling people you have low serotonin and that this medication will fix it in the same way as insulin will fix diabetes.”
Whence depression, then?
It’s clear that low serotonin levels can’t be ascribed a causal role in the aetiology5 of depression, yet two elephants still stand in the room. What causes depression, if not low levels of certain neurotransmitters like serotonin? And how do antidepressants, especially SSRIs, work?
Most mental health practitioners recognise that depression is a complex and heterogeneous disorder – that is, it is difficult to pinpoint one factor that causes depression.
A widely accepted model that explains the aetiology of depression is the biopsychosocial model. It encourages mental health practitioners to contextualise depression in biological as well as psychological (patterns of thought, ability to perceive, express and cope with emotions, etc.) and social factors (poverty, racism, sexism, etc.).
Horowitz said that stressful life events like “relationship breakdown, poverty, job insecurity, racism and sexism” correlate “incredibly well” with occurrences of depression in an individual. The Wire has also reported previously, in the context of India, that people from marginalised castes and low-income groups are at higher risk of depression.
Horowitz added that looking for a neurochemical explanation of all these correlations might be “missing the forest for the trees”.
How do antidepressants work?
Vaidya said that “antidepressants can improve mood along with a combination of psychotherapy and cognitive behavioural therapy.”
She pointed to one hypothesis that purports to explain, for example, the antidepressant effect of SSRIs.
Neuroplasticity refers to the phenomenon of neuronal networks adapting to stimuli. This includes both structural – e.g. change in the number of connections that one neuron has with other neurons – and functional changes – e.g. change in how a neuron responds to a particular amount of neurotransmitter.
“Serotonin is a regulator of plasticity in the brain,” Vaidya explained – suggesting that SSRIs could lead to changes in neuroplasticity, which in turn alleviates depressive symptoms in ways that are not clearly understood. This is the neuroplasticity hypothesis.
Jain said that SSRIs could also alter the distribution of receptors in the brain, which could in turn ease one’s path “out from the state of depression”.
Yet other studies have suggested that antidepressants may not be as effective as researchers once believed. In a 2008 study, for example, researchers independently analysed data submitted to the US Food and Drug Administration from the clinical trials of four antidepressants.
They concluded that differences in the mood-elevating effects as a result of the antidepressants versus placebo were “relatively small even for severely depressed patients”.
On July 20, a spokesperson for the Royal College of Psychiatrists, London, cautioned people against stopping their antidepressants regimens based on the Moncrieff et al. review:
“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 [general practitioner].”
Horowitz agreed with the guidance. “Nobody should stop their medication suddenly. It can be dangerous to stop… If people want to stop their medication after discussing with their doctor and a sensible reflection, they should do it gradually under the supervision of a doctor,” he said.
At the same time, Horowitz and Vaidya agreed that it is important that clinicians discard simplistic metaphors to explain depression to their patients and instead allow people with depression to make informed choices about the course of treatment.
“One should share the information with the honesty it deserves. Patients need to be participants in decisions regarding what they take for their depression,” Vaidya said.
Sayantan Datta (they/them) are a queer-trans science writer, communicator and journalist. They currently work with the feminist multimedia science collective TheLifeofScience.com, and tweet at @queersprings.