Emerging evidence suggests that lycopene—a natural plant extract—may have antidepressant properties. New research in Food Science & Nutrition reveals the mechanisms behind its antidepressant effects.
Lycopene is a carotenoid, related to beta-carotene and gives some vegetables and fruits (eg, tomatoes, grapefruit) a red colour. Lycopene is a powerful antioxidant that might help protect cells from damage.
In mice with depressive-like behaviours, brain analyses revealed impairments in the hippocampus. Lycopene treatment lessened these impairments and reversed the animals’ depressive-like traits.
Lycopene treatment boosted the expression of brain-derived neurotrophic factor (BDNF), a protein with roles in many aspects of brain function. Experiments indicated that a signalling pathway involving BDNF (called the BDNF-TrkB pathway, which helps regulate learning, memory, and communication between neurons) is inhibited in mice with depression, and that lycopene treatment alleviates this inhibition.
The study “offers an effective avenue for the development of novel antidepressant therapies,” the authors wrote. “We plan to conduct further verification in future studies and include multiple brain regions in our research.”
About 75% of a sample of nearly 20 000 people who have taken selective serotonin reuptake inhibitors (SSRIs) report they found them helpful, according to new research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London.
Published in Psychological Medicine, the study explored different factors that could explain why SSRIs work for some people with major depressive disorder, but not others.
Researchers analysed data from UK Biobank on 19 516 participants who had tried at least one SSRI, such as citalopram, fluoxetine, paroxetine or sertraline, for at least two weeks. Participants reported whether the SSRI helped them “feel better” using a single item questionnaire with possible responses “yes, at least a little”, “no”, “do not know”, or “prefer not to answer”. This is the first detailed analysis of this large-scale study which assesses SSRIs using self-reported experiences rather than clinician-reported remission from symptoms.
Overall, 74.9% felt SSRIs helped them feel better. 18.8% said the prescribed drug was not helpful.
Using a range of data collected by UK Biobank, the study analysed what factors might influence whether people found SSRIs helpful.
It found that sociodemographic factors such as age, gender and household income were linked to differences in how people perceived the effectiveness of SSRIs. Those participants who were older, male, had lower incomes, and reported alcohol or illicit drug use were more likely to say that they did not find antidepressants helpful.
Participants who had experienced no mood improvement even when positive events occurred or whose worst episode of depression lasted more than two years, were also less likely to report that SSRIs were helpful. Lastly those who had a greater genetic risk for depression, calculated using polygenic risk scores, were less likely to report that SSRIs were helpful.
The use of antidepressants, and the rate at which they are prescribed in the UK, has been the source of much debate both in the public and media. While antidepressants don’t work for every user, this research provides reassuring evidence that many people report that this common type of medication is helping them manage what can be a severe illness.
Dr Michelle Kamp, Postdoctoral Research Associate at King’s IoPPN and first author on the study
We know that not all people respond to antidepressants prescribed, but most studies have focussed on clinician’s perspectives of response. Using participant reports, we found a strong support for antidepressants, with three quarters of people saying the drugs had helped them. The factors that make people more likely to respond to antidepressants mirror findings in clinical trials which use measures reported by clinicians. This suggests that patient-focussed responses can capture valuable insights into the effectiveness of antidepressants.
Professor Cathryn Lewis, Professor of Genetic Epidemiology & Statistics at King’s IoPPN and senior author on the study
Professor Andrew McIntosh, Professor of Biological Psychiatry at the University of Edinburgh’s Centre for Clinical Brain Sciences and co-investigator on the study, said: “The findings from this large study show that nearly three-quarters of people in UK Biobank who were treated with antidepressants found them helpful. There is already excellent evidence from clinical trials that antidepressants work for people with depression. However those studies focus on addressing only whether they are more effective than placebos, and not why they are more effective in some people than others. We must now focus on developing a better understanding of how antidepressants work and how we can predict which people are most likely to benefit from these treatments.”
The study offers key insights into antidepressant response, however the sample may not fully represent the general population and reliance on retrospective self-reports can lead to inaccurate recollection.
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.
