Almost half of patients diagnosed with depression classify as being ‘treatment-resistant’ as new research suggests that many don’t respond to multiple antidepressant options.
The new study, published in the British Journal of Psychiatry was led by academics from the University of Birmingham and Birmingham and Solihull Mental Health NHS Foundation Trust. The study found that 48% of patients whose electronic healthcare records reported a diagnosis of depression had tried at least two antidepressants, and 37% had tried four or more different options.
Treatment-resistant depression (TRD) is typically defined as a form of depression that isn’t effectively managed after a patient tries two different antidepressants. There are currently few guidelines for treating TRD.
Patients who experience TRD were also invited to take part in interviews to share their experiences. Patients talked about a “sense of hopelessness” after trying multiple treatment options for the condition, and many shared their frustrations with a “one size fits all” approach to what works with treatment.
PhD researcher Kiranpreet Gill from the School of Psychology at the University of Birmingham and corresponding author of the study said:
“This paper highlights how widespread treatment-resistant depression is among those who are diagnosed with depression. With nearly half of all patients not responding to multiple drug options, we need better treatment options to be able to support patients for whom first line antidepressant medications don’t make a difference.
“Furthermore, the experiences of patients who took part in this study shows that more awareness and options for treating depression when first line antidepressant medications don’t work well is urgently needed.
“There is an irony that the experience of struggling to treat depression is in itself a risk factor for a worsening sense of ‘hopelessness’ as one patient described it. This should be a clarion call to recognise that treatment-resistant depression needs to be factored into clinical decision making and the ongoing support that patients are offered.”
There are increased risks of other psychiatric disorders among those with TRD such as anxiety, self-harm, and personality disorders, and physical health issues such as heart disease. Data analysis suggests that patients with TRD have 35% higher odds of having a personality disorder and 46% higher odds of cardiovascular disease and the combination with qualitative data suggests that patients have multiple and considerable barriers to achieving good health.
Professor Steven Marwaha, Clinical Professorial Fellow at the Institute for Mental Health at the University of Birmingham, a Consultant Psychiatrist at Birmingham and Solihull Mental Health NHS Foundation Trust, and co-author of the study said:
“This study is important as the data demonstrates people with TRD are at a higher risk of a range of poorer outcomes, and that we need better defined care pathways for helping this population, and are in urgent need of developing and testing new treatments for this group.”
Photo by Inzmam Khan: https://www.pexels.com/photo/man-in-black-shirt-and-gray-denim-pants-sitting-on-gray-padded-bench-1134204/
A study by researchers at the University of Helsinki and HUS Helsinki University Hospital found a significant association among adolescents between having psychotic-like experiences and depressive symptoms, as well as with self-destructive behaviours.
Psychotic-like experiences resemble symptoms of psychosis, but are milder, less frequent and much more common than psychotic disorders. While these symptoms do not constitute a disorder diagnosed as psychosis, they can still be disruptive, distressing or detrimental to functional capacity. Typical psychotic-like experiences include perceptual distortions and hallucinations, suspicious paranoid thinking, delusions and bizarre, unusual thoughts.
Psychotic-like experiences are abundant among adolescents referred to care, but are generally considered fairly neutral, with only some of the adolescents reporting them as frightening, worrisome or harmful. In the study, published in the journal Psychosis, the correlation between psychotic-like experiences and depressive symptoms turned out to be strong. This link was not explained by connections between individual psychotic-like experiences and depressive symptoms, but by factors that more broadly measure paranoia and unusual thoughts. In addition to depressive symptoms, paranoid thoughts and unusual thought content were also associated with self-destructive thinking.
Making questions about psychotic-like experiences part of care
The findings show that psychotic-like experiences should be systematically surveyed in all adolescents seeking psychiatric care. It should also be assessed how frightening, worrisome or harmful they are considered to be. Particularly in the case of responses emphasising bizarre thinking and exaggerated suspiciousness, attention should also be paid to assessing mood and self-destructive thinking, as these factors can remain hidden without further enquiry.
“Our findings provide a clear recommendation for treatment practices: psychotic-like experiences should be assessed as part of routine procedures, but it is also important to determine how they are perceived. These phenomena cannot be uncovered unless separately and systematically asked,” says the principal investigator, Docent Niklas Granö.
It should be clearly explained to adolescents and their families that these symptoms are common and often manageable. In addition, applications of cognitive psychotherapy, even brief interventions, can help adolescents understand their symptoms and alleviate the strain they cause.
A type of therapy that involves applying a magnetic field to both sides of the brain has been shown to be effective at rapidly treating depression in patients for whom standard treatments have been ineffective.
Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depression
Valerie Voon
The treatment – known as repetitive transcranial magnetic stimulation (TMS) – involves placing an electromagnetic coil against the scalp to relay a high-frequency magnetic field to the brain.
Around one in 20 adults is estimated to suffer from depression. Although treatments exist, such as anti-depressant medication and cognitive behavioural therapy (‘talking therapy’), they are ineffective for just under one in three patients.
One of the key characteristics of depression is under-activity of some regions (such as the dorsolateral prefrontal cortex) and over-activity of others (such as the orbitofrontal cortex (OFC)).
Repetitive transcranial magnetic stimulation applied to the left side of the dorsolateral prefrontal cortex (an area at the upper front area of the brain) is approved for treatment of depression in the UK by NICE and in the US by the FDA. It has previously been shown to lead to considerable improvements among patients after a course of 20 sessions, but because the sessions usually take place over 20-30 days, the treatment is not ideal for everyone, particularly in acute cases or where a person is suicidal.
In research published in Psychological Medicine, scientists from Cambridge, UK, and Guiyang, China, tested how effective an accelerated form of TMS is. In this approach, the treatment is given over 20 sessions, but with four sessions per day over a period of five consecutive days.
The researchers also tested a ‘dual’ approach, whereby a magnetic field was additionally applied to the right-hand side of the OFC (which sits below the dorsolateral prefrontal cortex).
Seventy-five patients were recruited to the trial from the Second People’s Hospital of Guizhou Province in China. The severity of their depression was measured on a scale known as the Hamilton Rating Scale of Depression.
Participants were split randomly into three groups: a ‘dual’ group receiving TMS applied first to the right- and then to the left-hand sides of the brain; a ‘single’ group receiving sham TMS to the right-side followed by active TMS applied to the left-side; and a control group receiving a sham treatment to both sides. Each session lasted in total 22 minutes.
There was a significant improvement in scores assessed immediately after the final treatment in the dual treatment group compared to the other two groups. When the researchers looked for clinically-relevant responses – that is, where an individual’s score fell by at least 50% – they found that almost half (48%) of the patients in the dual treatment group saw such a reduction, compared to just under one in five (18%) in the single treatment group and fewer than one in 20 (4%) in the control group.
Four weeks later, around six in 10 participants in both the dual and single treatment groups (61% and 59% respectively) showed clinically relevant responses, compared to just over one in five (22%) in the control group.
Professor Valerie Voon from the Department of Psychiatry at the University of Cambridge, who led the UK side of the study, said: “Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depression. This means it could be particularly useful in severe cases of depression, including when someone is experiencing suicidal thoughts. It may also help people be discharged from hospital more rapidly or even avoid admission in the first place.
“The treatment works faster because, by targeting two areas of the brain implicated in depression, we’re effectively correcting imbalances in two import processes, getting brain regions ‘talking’ to each other correctly.”
The treatment was most effective in those patients who at the start of the trial showed greater connectivity between the OFC and the thalamus (an area in the middle of the brain responsible for, among other things, regulation of consciousness, sleep, and alertness). The OFC is important for helping us make decisions, particularly in choosing rewards and avoiding punishment. Its over-activity in depression, particularly in relation to its role in anti-reward or punishment, might help explain why people with depression show a bias towards negative expectations and ruminations.
Dr Yanping Shu from the Guizhou Mental Health Centre, Guiyang, China, said: “This new treatment has demonstrated a more pronounced – and faster – improvement in response rates for patients with major depressive disorder. It represents a significant step forward in improving outcomes, enabling rapid discharge from hospitals for individuals with treatment-resistant depression, and we are hopeful it will lead to new possibilities in mental health care.”
Dr Hailun Cui from Fudan University, a PhD student in Professor Voon’s lab at the time of the study, added: “The management of treatment-resistant depression remains one of the most challenging areas in mental health care. These patients often fail to respond to standard treatments, including medication and psychotherapy, leaving them in a prolonged state of severe distress, functional impairment, and increased risk of suicide.
“This new TMS approach offers a beacon of hope in this difficult landscape. Patients frequently reported experiencing ‘lighter and brighter’ feelings as early as the second day of treatment. The rapid improvements, coupled with a higher response rate that could benefit a broader depressed population, mark a significant breakthrough in the field.”
Just under a half (48%) of participants in the dual treatment group reported local pain where the dual treatment was applied, compared to just under one in 10 (9%) of participants in the single treatment group. However, despite this, there were no dropouts.
For some individuals, this treatment may be sufficient, but for others ‘maintenance therapy’ may be necessary, with an additional day session if their symptoms appear to be worsening over time. It may also be possible to re-administer standard therapy as patients can then become more able to engage in psychotherapy. Other options include using transcranial direct current stimulation, a non-invasive form of stimulation using weak electrical impulses that can be delivered at home.
The researchers are now exploring exactly which part of the orbitofrontal cortex is most effective to target and for which types of depression.
The research was supported by in the UK by the Medical Research Council and by the National Institute for Health and Care Research Cambridge Biomedical Research Centre.*
Research using animal models has shown that the diabetes drug dulaglutide, which is a glucagon-like peptide-1 (GLP-1) receptor agonist, may reduce symptoms of depression. A new study published in Brain and Behavior reveals the mechanisms that are likely involved.
By conducting a range of tests in mice treated with and without dulaglutide, investigators confirmed the effects of dulaglutide on depressive-like behaviours, and they identified 64 different metabolites and four major pathways in the brain associated with these effects.
Markers of depression and the antidepressant effects of dulaglutide were linked to lipid metabolism, amino acid metabolism, energy metabolism, and tryptophan metabolism.
“These primary data provide a new perspective for understanding the antidepressant-like effects of dulaglutide and may facilitate the use of dulaglutide as a potential therapeutic strategy for depression,” the authors wrote.
World Mental Health Day, celebrated internationally on 10 October, is not just another commemorative day, but in fact, a time to truly reflect on the need to break the stigma associated with seeking mental health support.
Today, many may acknowledge that mental health issues are common and can adversely affect a significant portion of the population. “In fact, according to the fourth annual Mental State of the World Report 2023, published in March 2024 by Sapien Labs, Brazil, South Africa and the United Kingdom all show the greatest proportion of respondents who are distressed or struggling with their mental health, which indicates that there is still a dire need for more open conversations about mental health in families, workplaces and communities,” says Madelein O’Connell,Executive: Marketing, Sales and Corporate Relations at Bestmed Medical Scheme.
“We already know that our mental wellbeing can affect emotions, physical health, relationships and overall quality of life,” adds O’Connell. “Beyond this, neglecting your mental health can also lead to burnout, anxiety, and an array of serious health conditions. However, prioritising your mental health can be daunting, with so many not knowing where to start. It’s important to remember that it starts with, and is built on, small, consistent steps, which can make a significant difference.”
From a medical scheme perspective, there is often a range of mental health services covered as supplementary benefits by the medical scheme, such as access to psychologists, psychiatrists, counsellors, and support for conditions like anxiety, depression, and trauma. It’s important for members to understand what their medical scheme provides.
“At Bestmed, we offer a free Tempo wellness programme for our members, which can be accessed via the Bestmed App or online Member portal. As part of the Tempo wellness programme, members have access to free Tempo Wellness Webinars, hosted by mental healthcare experts, who discuss and give advice on various relevant topics,” says O’Connell.
“We really want to support the integration of mental, nutritional, and physical health in overall wellbeing for our members, as we recognise that mental health covers a wide array of aspects. In fact, the World Health Organisation (WHO), defines mental health as ‘a state of mental well-being that enables people to cope with the stresses of life, realise their abilities, learn well and work well, and contribute to their community’, so giving people the support and skills to navigate their life is vital, particularly those more vulnerable to mental health challenges, such as adolescents, the elderly, or individuals dealing with long-term physical illness.”
Madelein O’Connell concludes, “of course, we also recognise that limited mental health service availability, a shortage of mental health professionals and financial constraints can impact a person’s ability to find the right support they need, when they need it. However, there are also some incredible mental health support organisations, locally, that can assist. LifeLine and The South African Depression and Anxiety Group (SADAG), for example, are confidential, free, and offer a starting point for anyone in need.”
In a review of 27 different studies, a Johns Hopkins Children’s Center team concludes that some video games created as mental health interventions can be helpful – if modest – tools in improving the mental well-being of children and teens with depression and attention-deficit/hyperactivity disorder (ADHD). They did not significantly help with anxiety, however.
A report on the review of studies from peer-reviewed journals between 2011 and March 20, 2024, was published in JAMA Pediatrics.
“We found literature that suggests that even doubling the number of paediatric mental health providers still wouldn’t meet the need,” says Barry Bryant, MD, a resident in the Department of Psychiatry and Behavioral Sciences in the Johns Hopkins University School of Medicine and first author of the new study.
In a bid to determine if so-called “gamified digital mental health interventions,” or video games designed to treat mental health conditions, benefited those with anxiety, depression and ADHD, the research team analysed their use in randomised clinical trials for children and adolescents.
Bryant and child and adolescent psychologist Joseph McGuire, PhD, identified 27 such trials from the US and around the world. The studies overall included 2911 participants with about half being boys and half being girls, ages six to 17 years old.
The digital mental health interventions varied in content, but were all created with the intent of treating ADHD, depression and anxiety. For example, for ADHD, some of the games involved racing or splitting attention, which required the user to pay attention to more than one activity to be successful in gameplay. For depression and anxiety, some of the interventions taught psychotherapy-oriented concepts in a game format. All games were conducted on technology platforms, such as computers, tablets, video game consoles and smartphones. The video games are available to users in a variety of ways. Some are available online, while others required access through specific research teams involved in the studies.
The research team’s analysis found that video games designed for patients with ADHD and depression provided a modest reduction (both with an effect size of .28) in symptoms related to ADHD and depression, such as improved ability to sustain attention and decreased sadness, based on participant and family feedback from the studies. (An effect size of .28 is consistent with a smaller effect size, where as in-person interventions often produce moderate [.50] to large [.80] effects.) By contrast, video games designed for anxiety did not show meaningful benefits (effect size of .07) for reducing anxiety symptoms for participants, based on participant and family feedback.
Researchers also examined factors that led to improved benefit from digital mental health interventions. Specific factors related to video game delivery (i.e., interventions on computers and those with preset time limits) and participants (i.e., studies that involved more boys) were found to positively influence therapeutic effects. Researchers say these findings suggest potential ways to improve upon the current modest symptom benefit.
“While the benefits are still modest, our research shows that we have some novel tools to help improve children’s mental health – particularly for ADHD and depression – that can be relatively accessible to families,” says Joseph McGuire, Ph.D., an author of the study and an associate professor of psychiatry and behavioural sciences in the school of medicine. “So if you are a paediatrician and you’re having trouble getting your paediatric patient into individual mental health care, there could be some gamified mental health interventions that could be nice first steps for children while waiting to start individual therapy.”
The team cautioned that their review did not indicate why certain video game interventions performed better than others. They also note that some of the trials included in the study used reported outcome measures, and the studies did not uniformly examine the same factors which could have influenced the effects of the treatment. Some of the video games included in the studies are not easily accessible to play.
The researchers also noted that while video game addiction and the amount of screen time can be concerns, those children who played the games studied in a structured, time-limited format tended to do best.
Myocardial infarction, stroke, neuropathy: when a person has any of these chronic diabetes complications, they are more likely to have a mental health disorder, and vice versa, according to a University of Michigan-led study.
“We wanted to see if chronic diabetes complications led to mental health disorders or if mental health disorders led to those diabetes complications – but we found that both relationships are true,” said Brian Callaghan, MD, MS, senior author of the study published in Diabetes Care.
“The findings highlight a need for clinicians to actively screen for mental health disorders in patients with diabetes in addition to screening for chronic complications, which is the recommended standard of care in diabetes.”
Three-times greater risk
The research team, led by Michigan Medicine and the Department of Biostatistics at the U-M School of Public Health, examined insurance claims data from over 500 000 individuals with type 1 or type 2 diabetes and 350 000 people without diabetes.
The results reveal that people with chronic diabetes complications had up to a three-times greater risk of having a mental health condition, such as anxiety or depression. This effect increased as adults got older.
Those with mental health disorders were up to 2.5 times more likely to experience sustained diabetes complications.
In adults younger than 60 years old, having type 1 diabetes was more associated with chronic complications. People with the more common type 2 diabetes were more likely to experience mental health difficulties.
A possible reason for this bi-directional relationship, researchers say, may be that having a diabetes complication or mental health condition has direct effects on developing the other complication.
“For instance, a stroke causes detrimental effects on the brain, which may directly lead to depression,” Callaghan said.
“And having a mental health condition and diabetes may affect a person’s self-management of their condition – like poor glycaemic control or not taking medications – which, in turn, may increase their risk of diabetes complications.”
Common risk factors
The relationship may also be less direct. Diabetes complications and mental health conditions share common risk factors; obesity, issues with glycaemic control and social determinants of health can all increase the likelihood of developing both comorbidities.
“Most likely, a combination of direct and indirect effects and shared risk factors drive the association we are seeing,” said first author Maya Watanabe, MS, a biostatistician at the Harvard T.H. Chan School of Public Health and former graduate student research assistant at U-M.
“Diabetes care providers may be able to simultaneously prevent the risk of multiple complications by providing interventions to treat these shared risk factors.”
While physical activity, especially aerobic exercise, is known to reduce depressive symptoms, the processes behind this have been poorly understood – until now. In a new review article published in Translational Psychiatry, researchers propose a novel hypothesis to understand the antidepressant effects of exercise. They believe that the process may hinge on motivation, which is very important for alleviating a number of symptoms of depression, such as anhedonia (a lack of interest or joy in life’s experiences), low energy and ‘brain fog’.
The team summarised research papers that explored the mechanisms of depression in both humans and animals and concluded that depression, especially anhedonia, is associated with elevated inflammation (caused by the body’s immune response). Importantly, inflammation is also linked to disrupted dopamine transmission. These biological changes may represent key processes leading to changes in motivation, and in particular a lower willingness to exert physical or mental effort.
Meanwhile, exercise reduces inflammation, boosts dopamine function, and enhances motivation. The researchers believe that this could be an important reason as to why exercise exerts an antidepressant effect.
Lead author, Dr Emily Hird (UCL Institute of Cognitive Neuroscience) said: “The antidepressant effect of aerobic exercise has been convincingly demonstrated through randomised controlled trials, but its mechanism is not well understood. This is, in part, because it likely involves a variety of biological and psychological processes.
“For example, alongside its positive effect on inflammation, dopamine and reward processing, exercise also reduces oxidative stress and improves self-esteem and self-efficacy.
“However, we are proposing that exercise – particularly aerobic activities that make you sweaty and out of breath – decreases inflammation and boosts dopamine transmission, which in turn increases the desire to exert effort, and therefore boosts motivation generally.”
The team hope that this understanding of how exercise reduces symptoms of depression will help to inform the development of new treatment strategies – such as personalised exercise programmes.
Dr Hird said: “Understanding the mechanisms that underly the antidepressant effects of physical activity in depression could also inform our understanding of the mechanisms causing depression and the development of novel intervention strategies, in particular personalised intervention, and social prescribing.”
To further test their hypothesis, the researchers advise that large randomised controlled trials need to be conducted that assess the antidepressant effects of exercise, whilst also measuring the effect on variables including inflammation, dopamine transmission and motivation.
It would also be important to investigate any potential barriers to exercise.
Dr Hird said: “Addressing barriers to exercise – particularly in people with depression – is crucial, as regular physical activity may be able to alleviate symptoms, enhance mood and empower individuals on their path to recovery. As part of this, finding strategies to encourage exercise is key.”
The team are now running a trial based on the hypothesis proposed in the review, which will involve 250 participants aged 18 to 60 and is funded by a Wellcome Mental Health Award.
Since I was young, I have been intrigued by altered states of consciousness, such as out-of-body experiences, paranormal phenomena and religious visions. I studied psychology and neuroscience to gain a better understanding of how these experiences come about. And in my scientific career, I have focused on the question of why some people are more prone to having these experiences than others.
Naturally, when I came across psychedelic science a couple of years ago, this field also sparked my academic interest. Here was an opportunity to study people who had a psychedelic experience and who claimed to have had a glimpse of ultimate reality. I started to research psychedelic experiences at Leiden University and founded the PRSM lab – a group of scientists from different academic backgrounds who study psychedelic, religious, spiritual and mystical experiences.
Initially, I was enthusiastic about the mind-transforming potential of psychedelics. These substances, when administered correctly, appear to be capable of enhancing people’s mental and physical wellbeing. They also increase feelings of connectedness to and concern for the environment.
Psychedelic therapy appeared to offer great potential for treating a wide variety of disorders, including depression, anxiety, addiction and post-traumatic stress disorder. This enthusiasm about the potentially transformative effects of psychedelics was reflected in positive media attention on this topic over the past few years. Michael Pollan, an American author and journalist, has brought psychedelics to an audience of millions with his book and Netflix documentary.
However, my initial optimism about psychedelics and their potential has changed into scepticism about the science behind much of the media hype. This is due to a closer scrutiny of the empirical evidence. Yes, at face value it seems as if psychedelic therapy can cure mental disease. But on closer inspection, the story is not that straightforward.
The main reason? The empirical evidence for the efficacy of and the working mechanisms underlying psychedelic therapy is far from clear.
Two issues
I wrote a critical review paper with my colleague Eiko Fried in which we listed the problems with the current clinical trials on psychedelic therapy. The main concern is called the “breaking blind problem”. In psychedelic studies, patients easily figure out if they have been randomly assigned to the psychedelic or the placebo group, simply because of the profound mind-altering effects of psychedelic substances.
This breaking-of-the-blind can actually result in placebo effect in patients in the psychedelic group: they finally get the treatment they’d been hoping for and they start feeling better. But it can also result in frustration and disappointment in patients assigned to the control group. They were hoping to get a miracle cure but now find out they will have to spend six hours on a placebo pill with their therapist.
As a consequence, any difference in therapeutic outcomes between the psychedelic and the placebo group is largely driven by these placebo and nocebo effects. (A nocebo effect is when a harmless treatment causes side-effects or worsening of symptoms because the person believes they may occur or expects them to occur.)
Knowing who received what also affects the therapists, who may be motivated to get more out of the therapy session if their patient got the “real deal”. And this problem is impossible to control for in so-called randomised controlled trials – still the gold standard in evaluating the effectiveness of drugs and treatments.
Also, non-clinical research on psychedelics faces problems. You may recall the graphic of a brain on psilocybin compared to one on a placebo (see below). Psilocybin increases the connections between different brain areas, which is represented in a colourful array of connecting lines.
This has become known as the “entropic brain hypothesis”. Psychedelics make your brain more flexible such that it returns to a child-like state of openness, novelty and surprise. This mechanism in turn has been hypothesised to underlie psychedelic therapy’s efficacy: by “liberating your brain” psychedelics can change entrenched and maladaptive patterns and behaviour. However, it turns out the picture is much more complicated than that.
Psychedelics constrict the blood vessels in your body and brain and this causes problems in the measurement of brain signals with MRI machines.
The graphic of the entropic brain may simply reflect the fact that the blood flow in the brain is dramatically altered under psilocybin. Also, it is far from clear what entropy exactly means – let alone how it can be measured in the brain.
A recent psilocybin study, which is yet to be peer-reviewed, found that only four out of 12 entropy measures could be replicated, casting further doubt on how applicable this mechanism of action is.
Although the story about psychedelics freeing your mind is compelling, it does not yet square well with the available empirical evidence.
These are just two examples that illustrate why it is important to be really cautious when you evaluate empirical studies in psychedelic science. Don’t trust findings at face value, but ask yourself the question: is the story too good or too simple to be true?
Personally, I have developed a healthy dose of scepticism when it comes to psychedelic science. I am still intrigued by psychedelics’ potential. They offer great tools for studying changes in consciousness. However, it is too early to conclude anything definite about their working mechanisms or their therapeutic potential. For this, we need more research. And I’m excited to contribute to that endeavour.
Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. The discovery, reported on 2 July in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.
Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.
While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.
Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. The mothers also had obesity, but in addition had experienced postnatal depression.
To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).
Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.
Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”
TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.
When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.
Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.
In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.
Professor Sadaf Farooqi from the Institute of Metabolic Science at the University of Cambridge said: “There’s a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”
While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.
The researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.
Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”
There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. The team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.
Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”
This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.
