Could a discovery in scanning enable psychiatrists to spot the neurological causes of depression in patients’ brains and treat them, just as doctors can identify broken bones with an X-ray? That’s the suggestion raised by recent research published in the journal Nature by psychiatrists at Weill Cornell University in New York. Functional magnetic resonance imaging (fMRI) scanners were used to compare the brain activities of clinically depressed and healthy people. By analysing both sets of scans, the researchers discovered people with depression have a particular brain network which appears to be nearly twice as big as their psychologically healthy counterparts. They suggested depression may be linked to this network and could be a new target for treatment or a way to prevent it entirely. The identified brain network is called the frontostriatal salience network and it plays a role in processing rewards and deciding what merits attention. ‘Having a larger salience network appears to increase the risk for depression,’ said Conor Liston, a professor of psychiatry and neuroscience who co-authored the research. Crucially, this study highlights a seismic shift in mainstream medical belief about what causes depressive feelings. This is thought to be because one of the main symptoms of depression is anhedonia – the inability to feel pleasure and enjoy everyday activities. Since the 1980s, psychiatrists have commonly blamed a ‘chemical imbalance’ in the brain – specifically, a lack of serotonin – and drug companies launched a generation of antidepressants that promised to correct this imbalance: namely, the selective serotonin re-uptake inhibitors (SSRIs), such as Prozac and Zoloft. But these pills are increasingly shadowed by serious concerns about their usefulness, and their debilitating potential side-effects, including weight gain, sexual dysfunction, and an increased risk of suicidal thoughts. Two years ago, the Beyond Pills All-Party Parliamentary Group, which included nine professors of medicine and psychology, published an open letter in the BMJ claiming that rigorous analyses show SSRIs ‘have no clinically meaningful benefit beyond placebo for all but the most severely depressed patients’. What’s more, studies show the drugs can cause serious dependency and crippling withdrawal symptoms. But the serotonin theory is becoming old hat, not least as it still hasn’t been scientifically proven – and instead, the psychiatric research community is embracing the idea that structural defects in the brain are the primary cause. Indeed, the news story that accompanied the recent Nature study also claimed ‘the disease has a consistent mark in the brain, even when symptoms are absent’. This implies that being depressed involves a physical defect, rather than a set of emotional symptoms, such as deep sadness and loss of motivation. Perhaps not surprisingly, pharmaceutical companies appear keen to adopt this new theory. For example, Johnson & Johnson has already launched a new drug that claims to fix ‘errant’ brain structures for tackling depression: esketamine (trade name Spravato). The company claims esketamine can trigger patients’ brains to grow new connections between neurons (nerve cells), which in turn improves brain networks and mood states. However, last year the National Institute for Health and Care Excellence, which evaluates treatments for use in the NHS, refused to approve esketamine. It concluded that the latest evidence on the drug ‘did not show a greater relative benefit compared with current treatments’ – and that esketamine’s potential side-effects (risks of heart attack and stroke) are sufficiently dangerous. So that, if the drug is used in clinical trials or private clinics, it should ‘only be administered by, or under the direct supervision of, personnel experienced in its use… and when resuscitation equipment is available’, it said. Johnson & Johnson is now developing two new drugs that target specific brain-structure features linked to depressive mood problems. But as with the serotonin theory of depression, fundamental scientific doubts cloud the new brain-structure theory, too. The Weill Cornell University study is only the latest of many attempts to find physical causes of depression in the brain, using scans such as fMRI. And the research has been contradictory. This is particularly evident in the fact that different research teams blame completely different brain regions for causing depressive symptoms. For example, while the Cornell researchers blame the salience network, a 2021 paper by Huazhong University of Science and Technology in Wuhan, China, used fMRI technology to conclude that the culprit areas are the frontostriatal-limbic network (involved in regulating motor, cognitive and emotional processes) and the fronto-parietal network (involved in the execution of moment-by-moment subliminal decisions). Another study in the journal Molecular Psychiatry, published in 2016, declared the symptoms were caused by shortages of neurons in four regions of the brain – the orbitofrontal cortex (involved in conscious decision-making), the anterior and posterior cingulate (involved in reward and memory), the insula (self-awareness) and the temporal lobes (which process sensory information and form memories). Meanwhile, other studies have disputed these kinds of structural differences: research published in the journal JAMA Psychiatry in 2022, for instance, analysed existing fMRI scans and concluded that ‘the differences between patients with major depression and healthy people were remarkably small’. There are also serious questions over the reliability of fMRI scans. A US study in 2020, for instance, analysed repeated fMRI scans involving 90 people and showed that the results were vastly different from test to test, even if the tests were repeated within a few days or weeks. This lack of consistency means that the scans can’t give reliable data on people’s mental functioning or health, reported the journal Psychological Science. Such concerns were reinforced in 2022 in Nature, which argued fMRI studies produce such highly complex and variable results even large projects involving thousands of patients are too small to reliably detect links between people’s brain function and the way they behave. Karl Friston, a professor of neuroscience at University College London, and a global authority on brain imaging, told Good Health that the study results reveal the huge complexity involved in getting any reliable information from MRI-based research. This is essentially because if there is lots of data, it is easier to ‘see’ patterns and links – even though they may be coincidental. It’s rather like seeing faces in randomly patterned carpets. So, among all this confusion and conflict, should we put any trust in the latest study by Weill Cornell University? Stella Chan, a professor of evidence-based psychological treatment at the University of Reading, told Good Health: ‘It’s a very well-conducted study [but] the results are still not conclusive. ‘It shows an association rather than any proof of causation.’ Paul Keedwell, a consultant psychiatrist and Fellow of the Royal College of Psychiatrists, agrees that ‘this study is robust in its methodology. But does it tell us anything about what causes depression? No.’ One problem, Dr Keedwell says, is that the study fails to answer a chicken-and-egg question: are people born with this enlarged brain network and therefore naturally at risk of depression – or might suffering early-life trauma and stress (which may later lead to depression) cause this network to become enlarged? Nevertheless, he says, if the scientists could show a consistently reliable link between this enlarged brain network and people being vulnerable to depression, ‘it could be groundbreaking diagnostically for preventing the illness’. Far less impressed is Joanna Moncrieff, a professor of critical and social psychiatry at University College London. She is openly opposed to the idea that depressive feelings are caused by brain structure. Instead, she is convinced that depressive feelings are typically the product of the difficult circumstances that a person finds around them and the adverse experiences they may have previously endured. Thus, she says our psychologies are shaped by our lives, not by our brain circuits. However, brain-structure studies keep being published, complains Professor Moncrieff: ‘There are so many scientists and clinicians who desperately want to believe that depression is caused by the brain. ‘You show one such theory to be groundless, and then they pop up with another, and another and another. It’s exhausting.’ Professor Moncrieff argues that rather than us swallowing a new generation of psychiatric drugs marketed to fix ‘structural problems’ in depressed patients’ brains, ‘we need to find more non-medical ways of supporting people through crises, such as better social support’.