If you have paid attention to the science of mental health, you will have heard the theory that depression is caused by a chemical imbalance in the brain. Since the 1990s, the common symptoms – low mood, loss of interest and pleasure, changed sleep and appetite – have been said to arise from a lack of a neurotransmitter called serotonin. By raising levels of this “happy hormone”, certain antidepressant pills such as Prozac could relieve our inner torment and return our minds to equanimity.
The truth, as ever, has turned out to be more complicated. Last year, an influential review of the available data concluded that there was no clear evidence to support the theory, and the ensuing headlines left many bewildered about who or what to believe.
Two new books may help us to cut through the confusion. The first, Breaking Through Depression, comes from Philip Gold, a senior investigator at the US National Institute of Mental Health who has spent a lifetime investigating the illness. Gold performed some of the trials of the very first antidepressants and he continues to work at the cutting edge today.
Many sections of Breaking Through Depression read like a medical memoir, intercutting stories from the frontline of this research with detailed scientific explanations. I found his descriptions of the condition to be painfully precise. Gold dismisses the common idea that depression is medicalised sadness, noting that “true sadness is often associated with cherished, loving memories of, for instance, a lost loved one, combined with grief over their loss, and, at times, a bittersweet feeling encompassing both the bounties of life and the harsh reality that all relationships must come to an end”. Such feelings, he says, are typically unavailable to seriously depressed individuals, whose emotional repertoire is constricted to “a deadening litany of self-excoriation and hopelessness”.
The condition is often accompanied by physiological changes, leading Gold to call it a “total-body illness”. He notes that it is associated with premature coronary artery disease, diabetes, stroke and osteoporosis – an underacknowledged burden for the one in five people who develop depression. On average, depression knocks about 10 years from someone’s life expectancy. It is, Gold concludes, a “cancer of the self” that “erodes our dignity and self-respect while it erodes our bodies”.
Gold argues that many cases of depression result from “a stress response that has run awry”. When a healthy person faces a dangerous situation – a forest fire, say – it makes sense to focus on the threat itself, and how to deal with the immediate risk until you have found safety. The brain starts to prepare the body for action, which includes increasing inflammation and blood clotting to reduce the risk of infection and haemorrhage after injury.
For many people with depression, however, the brain’s alarm bells keep ringing long after a real threat has passed. It continues to look for potential signs of danger or hostility while ignoring things that might bring reward. As Gold writes, “it’s one thing to maintain a singular focus when there is a wildfire raging nearby, but in normal life the inability to appreciate any pleasurable stimulus is a great burden”. This results in the profound dread and lack of pleasure and motivation that characterise the disease, and severely disrupt normal routines of eating and sleeping. Living in a state of permanent stress can result in brain-cell death and a reduced ability to form new neural networks, which leaves the person locked in their doom-laden thinking. For this reason, Gold describes depression as a neurodegenerative disease, and says that any effective treatments will need to undo this damage and prevent it from occurring again.
Gold makes a convincing argument for his theory, but Camilla Nord’s The Balanced Brain offers many alternative viewpoints. Nord leads the Mental Health Neuroscience Lab at the University of Cambridge, and her writing is masterfully nuanced in its treatment of depression, without sacrificing the clarity of her argument. Throughout, she is careful to explain how experiences can vary widely from person to person. Rather than opting for a simplistic narrative, she acknowledges the ambiguities in the academic research on mental illness.
There has been a lot of excitement about the potential role of bodily inflammation as a potential cause of depression, rather than a consequence. But only a subset of patients show higher-than-average inflammation, while others have normal levels. And even among those with heightened inflammation, the underlying source may be found in different parts of the immune system. “Targeting the immune system might represent a new route to treat or improve mental health but it would require carefully finding the right immunological targets and tailoring treatments for each individual on the basis of their particular immune system,” Nord writes.
The cognitive causes of depression can be similarly varied. One compelling explanation of depression concerns the basic ways that the brain learns from its experiences and predicts the future, but the exact nature of the problem will vary from patient to patient. Some people’s brains may place too much focus on negative outcomes; another person’s brain may fail to predict potential rewards. Either way, the overall outcome may be a more pessimistic and frightening view of the world that throws someone’s life into disarray.
For some commentators, the recent downfall of the chemical imbalance theory has cast doubt on the use of existing antidepressant drugs, which were meant to restore the lost serotonin. Yet the data certainly suggests that they work better than placebos – and the authors of these two new books can explain why. For Nord, it is because antidepressant drugs help to correct the fundamental biases in someone’s perceptions of the world. This change occurs incredibly quickly. People with depression are more likely to see anger, and less likely to see happiness, in neutral facial expressions – but in many patients, this tendency begins to disappear after they have taken just one antidepressant pill. Gold, meanwhile, points to studies showing that our current antidepressant pills encourage the birth of new brain cells and neural connections, which would help people to break free of the hyperactive stress response.
The same goes for the new generation of treatments, such as the psychedelic drug psilocybin, which has recently shown great promise in clinical trials, and which can bring serious relief after a single dose. Nord suggests that throwing open the doors of perception may help to reset the brain’s predictions, immediately breaking someone out of their bleak worldview. For Gold, it’s all about restoring connectivity between different brain regions and undoing neurological damage; he points to studies showing that psilocybin docks into the same receptors as brain-derived neurotrophic factor, a protein that promotes the growth and rewiring of neurons. Perhaps both explanations are correct – or are simply different ways of expressing the same experience. What’s most exciting is that the drug seems to work well for many people, with apparently few undesirable side effects.
Nord and Gold suggest a constellation of promising options for treatment, including other psychedelic drugs and various forms of brain stimulation. Through brain imaging and genetic testing, it may even be possible to predict which treatments will work best for each person. Without offering false hope, both these books are ultimately optimistic about our future understanding of depression. The chemical imbalance theory may have been extinguished, but there are now many more flashes of light in the darkness.
David Robson is an award-winning science writer and author of The Expectation Effect: How Your Mindset Can Transform Your Life
Breaking Through Depression: New Treatments and Discoveries for Healing by Philip Gold is published by Allen Lane (£25). To support the Guardian and Observer, order your copy at guardianbookshop.com. Delivery charges may apply
The Balanced Brain: The Science of Mental Health by Camilla Nord is published by Allen Lane (£25). To support the Guardian and Observer, order your copy at guardianbookshop.com. Delivery charges may apply
