Bethan Finighan

In recent weeks, chaos has ensued in the scientific Twittersphere. A new study has brought a debate that has long been had behind the scenes to centre stage – and doubts have been cast over a scientific theory that was widely accepted by the public for decades. The belief that depression is caused by a chemical imbalance in the brain may just have been debunked. The upshot of the study’s findings is a wave of controversy and misleading claims about antidepressants, where the media are drawing their own conclusions about the effectiveness of SSRIs and the future of depression treatment. The serotonin myth A new umbrella review, published in Molecular Psychiatry this July, says there is “no convincing evidence” that depression is caused by low serotonin levels. The study analysed seventeen existing meta-analyses and systematic reviews, pooling data from hundreds of thousands of participants. The researchers concluded that there is no support for the chemical imbalance theory of depression, which has been widely accepted by the public for decades. The findings have sparked considerable debate in the scientific community about the function of antidepressants, namely selective serotonin reuptake inhibitors (SSRIs), the primary function of which is to rectify insufficient levels of serotonin. Here, the chemicals in question are neurotransmitters. They act as chemical messengers in the brain, carrying signals across the gap between two nerve cells. Serotonin is the neurotransmitter involved in regulating our mood, development, perception, cognition, memory, and much more; for this reason, it is often referred to as our “happy hormone”. SSRIs prevent serotonin from being taken back up into nerve cells, therefore making it more widely available in the brain. According to University College London (UCL), there is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression. The study’s authors found no difference in both blood and brain serotonin levels between people diagnosed with depression and healthy participants. Similarly, they concluded that artificially lowering serotonin does not produce depression in healthy volunteers. There was also no evidence for serotonin transporter gene variation between people with depression and healthy controls. “It is always difficult to prove a negative,” says Joanna Moncrieff, a professor of psychiatry at UCL and the paper’s lead author, “but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.” I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities The paper has since led many to question how SSRIs really work in the brain, and whether these findings indicate there is a better pharmacological option out there. What the experts say The paper’s authors highlight the chemical imbalance theory is still widely believed by the public, citing surveys that suggest 85% to 90% of people think depression is caused by low serotonin. Despite this, it seems that their findings have not shocked many experts in the field, with most agreeing that the review does not change the current scientific understanding of depression. “No mental health professional would currently endorse the view that a complex heterogeneous condition like depression stems from a deficiency in a single neurotransmitter,” explains Phil Cowen, professor of psychopharmacology at the University of Oxford. According to Prof David Curtis, honorary professor at UCL Genetics Institute, the chemical imbalance theory is “outmoded” and he claims “it is certainly not news that depression is not caused by low serotonin levels.” Some researchers, however, have opinions on the merit of the study itself. “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 original studies they rely on, and therefore do not allow us to draw new conclusions,” says Dr Livia de Picker, a postdoctoral researcher at the University of Antwerp. Prof David Nutt, Head of the Centre for Neuropsychopharmacology at Imperial College London, also adds that the review exclusively analyses “indirect measures of serotonin function or, even worse, merely proxies for serotonin activity,” so “to dismiss the serotonin hypothesis of depression at this point is premature.” Though what the paper– or, more specifically, the media’s response to it – does highlight is the gap between the expert and public understanding of depression. This is made abundantly clear by the many misleading claims made about antidepressants in the wake of these findings. SSRI scepticism One important thing to address is the Molecular Psychiatry paper did not specifically review the effects of antidepressants, yet some major media outlets are now feeding the public a narrative that this new evidence pokes holes in their effectiveness. As the headline of the Daily Mail reads, “Study casts doubt over widespread use of potent drugs designed to treat chemical imbalance in brain.” Similarly, The Guardian writes that “scientists have called into question the widespread use of antidepressants” in light of the study’s findings. Not only is this an exaggeration, but these claims are likely to spark unnecessary doubt amongst the one in eight UK adults currently taking antidepressants. The reality is, scientists still aren’t entirely sure how antidepressants work, but an abundance of clinical data shows that they do for many patients. The study in question doesn’t change what researchers already know about these drugs. For a start, if depression was purely a result of a chemical imbalance then antidepressants would work immediately – but, as any SSRI users will know, it takes about 2-3 weeks to start feeling their effects. In a thread of tweets, Dr Dean Burnett, neuroscientist and honorary research associate at Cardiff Psychology School, uses the analogy that the outdated chemical imbalance theory is comparable to stating headaches are caused by “not enough paracetamol”. The lack of paracetamol isn’t what causes the pain, but taking the drug still induces a positive effect. As Burnett explains, the exact mechanisms of SSRIs aren’t fully understood, but “a lot of evidence suggests is a big part of mood regulation,” and increasing its availability in the brain “should make the brain more capable of changing mood.” In keeping with this, much of the newer research into SSRIs suggests they influence neuroplasticity, a fundamental process that underlies learning and memory through the brain’s ability to modify its structure and function. It is generally believed that this increased brain plasticity makes the depressed individual more inclined to experience changes in emotional and social processing. What causes depression – and how do we treat it? Depression does not have one single cause; more recent theories suggest that mood disorders are a result of numerous dysfunctional brain circuits and neurotransmitter systems. There is also evidence to suggest early life stress triggers neurobiological changes that influence a person’s development, making them more vulnerable to depression. Why the serotonin-depression theory was the one that both the public and medical professionals latched onto, however, is likely because it reduces such complex emotions to a simple biological mechanism – “something tangible and blame-free,” as Dean Burnett suggests. Prof Joanna Moncrieff implies the oversimplification of the science behind depression has caused more confusion than clarity. “ should not be led to believe that antidepressants work by targeting these hypothetical and unproven abnormalities,” she says. “Giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.” So whilst SSRIs do have immeasurable value in psychiatry – they have, and will continue to save lives – antidepressants reflect a medical model that isn’t necessarily how mental health issues should be treated, and moving beyond this one-size-fits-all approach to psychiatry should be a priority. Interventions “that combine the precision, potency and cost-effectiveness of biomedicine with the depth of insight and roundedness of psychology,” such as taking SSRIs in combination with talking therapy, have shown to be superior, according to Prof Carhart-Harris, former Head of the Imperial Centre for Psychedelic Research, in a 2018 World Psychiatry paper. Newer interventions – psychedelic-assisted psychotherapy, for instance – also adopt this hybrid approach and, so far, results have been hugely promising. Psychedelics have, too, shown to influence the serotonin neurotransmitter system, which Carhart-Harris claims “opens a door to heightened sensitivity to context, an ideal pre-condition for effective change.” The widespread use of antidepressants has long been a divisive issue. With many unpleasant side effects and potentially severe withdrawal symptoms, SSRIs are certainly not the perfect pill they were once marketed to be. But whatever your stance, experts at the Royal College of Psychiatrists urge SSRI users not to stop taking their antidepressants in light of this new research, and they encourage anyone with concerns about their medication to contact their GP.