As experts cast doubt on the “chemical imbalance” theory, new research suggests treatment should be tailored to specific symptoms.
Antidepressants don’t work, we often hear these days – except for roughly half of patients, for whom they provide significant relief. Others argue that exercise, fresh air, and a good diet are all that’s needed to lift a low mood, but this approach works in only about 60% of cases. You might think, then, that we need to address the deep-rooted causes on a therapist’s couch, but even that doesn’t work for everyone, and different therapeutic techniques have varying levels of efficacy.
If depression affects a quarter of the population and has been studied for centuries, why is it still so difficult to treat?
New research suggests we may have been approaching it the wrong way. Just as doctors now recognise that physical symptoms such as swelling and fatigue can stem from a range of underlying health problems, it appears that depression “has many different causes, subtypes or dimensions”, says Jonathan Roiser, professor of neuroscience and mental health at University College London and an expert in the brain changes that underlie mental health conditions.
As a neuroscientist, Professor Roiser uses functional magnetic resonance imaging (fMRI) scans to get up close and personal with the brain, examining what actually happens when someone experiences depression. The findings are rewriting what mental health professionals understand about the condition, and could have significant implications for how it is managed and treated.
What is depression?
Depression is defined by the NHS as a mental health condition involving persistent low mood or a loss of interest or pleasure in life. Confusingly, this means “you don’t actually need to have low mood to be diagnosed with depression”, explains Prof Roiser.
Although not essential for diagnosis, low mood is the most common symptom of depression, Roiser says, appearing in “over 90% of people with depression”. Anhedonia, or a lack of enjoyment or interest in activities, affects around two-thirds of those with the condition. In reality, depression is “rather a fuzzy concept”, Roiser explains.
The ICD-10, a diagnostic manual used in Britain and elsewhere, lists nine symptoms of depression, and “you only need five to receive a diagnosis”, says Roiser. Some symptoms, such as sleep disturbance, can manifest as either an increase or a decrease. “This means there are potentially hundreds of different combinations of symptoms in people with depression.”
Crucially, “there is no particular reason to believe that those symptoms share the same cause”, Roiser argues. The serotonin theory of depression, which suggests this complex condition is caused by a chemical imbalance, is “a very outdated idea from the 1960s, and even then it was understood to be a massive oversimplification”.
Instead, it appears there are several different “dimensions in brain function”, changes in which may lead to different symptoms.
The three key types of depression
A new study from Washington University School of Medicine in St Louis, published in June, identified three main types of depression experienced in the general population and explored how they manifest in patients’ brains and daily lives.
Though the study was conducted in the US, it used data from the UK Biobank, which tracks the health of half a million British volunteers over their lifetimes. Low mood without low motivation, low motivation without low mood and a combination of both are all common.
1. Low mood (without low motivation)
People who primarily struggle with low mood might experience:
- A persistent feeling of sadness, tearfulness, numbness or emptiness lasting at least two weeks.
- Becoming easily frustrated, irritated, or angry over things that never used to bother them (a symptom of anxiety, which often co-occurs with low mood).
- Excessive or inappropriate feelings of guilt or shame over things they didn’t do or weren’t responsible for.
- A consistent and extreme negative view of themselves and their abilities, or feelings of worthlessness.
2. Low motivation (without low mood)
People who primarily struggle with low motivation might experience:
- Persistent tiredness, despite sleeping well.
- Cognitive impairment (brain fog), which can appear as difficulty concentrating or making decisions.
- Trouble completing everyday tasks like work, housework or admin.
- A sharp decrease in sex drive.
- A loss of interest in other people, as well as activities and hobbies they once enjoyed.
3. Low mood and low motivation
People who struggle with a mix of low mood and low motivation may experience a combination of these symptoms.
The inflammation theory
The study’s participants differed not only in their symptoms but also “in their neurobiology”, says Dr Janine Bijsterbosch, the lead scientist, in a press release.
In other words, different symptoms correlated with different changes in the brain. At the same time, however, people with similar symptom profiles sometimes showed different underlying brain patterns. This is part of why most neuroscientists “have lost faith in the idea that there is a single explanation for depression at the level of the brain”, says Roiser.
“It is a condition defined by its symptoms, so there is an inherent circularity there.”
Despite its complexity, these findings align with Roiser’s own decades of experience studying depression as a neuroscientist. He explains there appears to be “a set of different brain circuits that underlie motivation, linked to symptoms like loss of energy as well as brain fog”.
Meanwhile, “another circuit in the brain deals with negative emotions”. Both can “interact with and affect each other”, but the fact that there are some general trends in people with different clusters of symptoms “means that we might soon be able to target them with different types of intervention”.
It’s also difficult to determine whether these brain changes are a cause or a consequence of depression. Scientists currently estimate that the heritability of depression is between 40 and 50%, suggesting a strong genetic component, alongside life experiences that can increase vulnerability to the condition.
There is one new theory that may underlie depression in all its forms.
“A substantial number of people with depression also seem to have high levels of inflammation in their bodies, which could drive changes in the brain”, says Roiser. This might explain why both exercise and antidepressants, some of which have anti-inflammatory effects, can be effective in treating the various symptoms of depression.
“It’s currently just a hypothesis. There are several rigorous studies currently underway to investigate the role of inflammation in depression, and in five years we may have some answers.”
This is why Roiser’s work on brain imaging is so crucial.
“An MRI scan of neurobiology may have the potential to predict clinical outcomes that depression symptom screening alone cannot capture”, says Dr Yvette Sheline, who also contributed to the Washington University study.
While doctors may not yet fully understand what depression is or why it occurs, brain scans could help tailor treatments to the unique symptoms of different types of depression.
A number of treatments for depression are currently available on the NHS, while others are being explored by researchers as potential therapies. There is limited evidence, however, to indicate which treatments work best for specific types of depression.
“The important thing is not to lose hope”, says Roiser. “There are a number of different treatments that are effective for depression, so if one proves not to work well for you, you should certainly go back to your doctor and ask about different options.” Different treatments are likely to work for different people, due to the different brain circuits driving their depression.
The best treatments for different kinds of depression
Low mood without low motivation
Antidepressants
Antidepressants, such as SSRIs, appear to work best for “negative affect”, in other words, low mood and anxiety, says Professor Roiser. Although their effects on brain chemistry are well understood, “we don’t know exactly how they work in terms of brain circuits. One important idea is that they change the emotional response to the negative thought patterns that characterise depression. We do know that SSRIs are especially effective at blunting the experience of negative emotions.”
CBT and other talking therapies
Cognitive behavioural therapy is designed to interrupt the cycle of thoughts, behaviours, and actions that keep people stuck in depression. Other talking therapies focus on addressing traumatic past events and interpersonal relationships, helping people challenge negative assumptions about themselves.
As a result, these therapies “often tend to be most effective in combating negative emotions rather than improving motivation, though the two do go hand in hand”, says Roiser. He also points out that modern therapies approved for treating depression “are totally different from older Freudian-style psychoanalysis, which is not well supported by evidence from clinical trials”.
Best for low mood with low motivation
Mindfulness
Mindfulness practices, such as regular meditation, have been shown to alleviate both low mood and difficulties with motivation. “But these practices are probably most effective for symptoms of stress or anxiety, which often occur alongside depression and can exacerbate it, though they are not part of the clinical diagnosis,” says Roiser.
Severe low mood
Deep brain stimulation and transcranial magnetic stimulation
Deep-brain stimulation (DBS) is a relatively new treatment. As a surgical procedure, “only those struggling with the most severe depression, for whom nothing else has worked, will ever receive it”, says Roiser. It targets specific brain circuits linked to a person’s depression, stimulating changes that can alleviate symptoms.
Transcranial magnetic stimulation, or TMS, is a more established, non-invasive treatment, explains Roiser. It involves repeatedly exciting a particular brain region using magnetic fields delivered by a machine. Some NHS clinics have TMS machines, “but they aren’t widely available in the UK”.
There is evidence that TMS is “effective in improving emotional experience and regulation”, but, as with antidepressants, “how it works is a bit of an open question”. Both treatments are “very different from old electroconvulsive therapy”.
Low motivation
Exercise
Roiser’s recent research suggests that exercise can be especially effective for people struggling with a lack of motivation or enjoyment of life. “For some people, it’s almost like a miracle cure,” he says. Meeting the NHS recommendation of 150 minutes of exercise per week is enough.
“It doesn’t necessarily make people feel better immediately, but in the long run there is good evidence that exercise is just as powerful as antidepressants and talking therapies, and the results from our latest study suggest a specific impact on anhedonia.”
New psychedelic drug-assisted therapies
The benefits of psilocybin, or “magic” mushroom–assisted therapy for depression, have been widely discussed in recent years. Psilocybin has been decriminalised or approved as a medical treatment for certain mental health conditions in parts of the US and Europe, as well as in Australia and New Zealand, but not yet in Britain.
“The crucial thing is that it always comes with therapy,” says Roiser. “It is thought that using a psychedelic drug might help people to engage with that therapy in new ways.”
Preliminary research suggests that psilocybin therapy might be more effective than SSRI antidepressants in reducing anhedonia. “But there is also a lot of hype,” Roiser cautions, and the potential benefits – and harms – of using psilocybin as a medical treatment are not yet fully understood.
Ketamine is another drug with stronger evidence supporting its use as a treatment for depression.
“In our research, it seems to be very convincing as a treatment for people who have severe motivational problems,” Roiser says. Ketamine can be accessed in the UK via off-label prescription, but only at a limited number of clinics.