Vive la différence: brain cells of males and females respond differently to chronic stress

8 Female Autism Traits Explained By An Autistic Woman

Scientific excellence requires diversity – research conducted by men and women, by people from different backgrounds and with varied worldviews. The need for diversity extends to scientific experiments themselves, but even today the vast majority of studies in the life sciences are done on male mice only, which could harm the findings, as well as our ability to extrapolate from them to humans. A new study by researchers from the Weizmann Institute of Science addresses this challenge, revealing in unprecedented detail how the brains of male and female mice respond differently to stress. In the study, published in Cell Reports, researchers from Prof. Alon Chen’s joint laboratory at the Weizmann Institute and the Max Planck Institute of Psychiatry in Munich discovered that a subcategory of brain cells responds to stress in a totally different manner in males and females. The findings could lead to a better understanding of health conditions affected by chronic stress, such as anxiety, depression and even obesity and diabetes, and they could pave the way toward personalized therapies for these disorders.

Mental and physical disorders caused by chronic stress are constantly on the rise, putting a significant strain on society. They affect both men and women, but not necessarily in the same way. Although plenty of evidence suggests that men and women deal differently with stress, the causes of these differences are not yet fully understood, and in any event, personalized treatments for men and women are still beyond the reach of medicine. But researchers from Chen’s laboratory, which specializes in studying the response to stress, hypothesized that innovative research methods could help to change the picture. Previous studies in other labs had uncovered certain sex differences in the response to stress, but those findings were obtained using research methods that could mask significant differences in the responses of specific cells or even entirely erase the roles played by relatively rare cells. Chen’s laboratory, in contrast, uses advanced methods that allow scientists to analyze brain activity at an unprecedented resolution – on the level of the individual cell – and could therefore shed new light on the differences between the sexes.

“We turned the most sensitive research lens possible onto the area of the brain that acts as a central hub of the stress response in mammals, the paraventricular nucleus (PVN) of the hypothalamus,” says Dr. Elena Brivio, who led the study. “By sequencing the RNA molecules in that part of the brain on the level of the individual cell, we were able to map the stress response in male and female mice along three main axes: how each cell type in that part of the brain responds to stress, how each cell type previously exposed to chronic stress responds to a new stress experience and how these responses differ between males and females.”

The researchers mapped out gene expression in more than 35,000 individual cells, generating a huge amount of data that provides a picture of stress response that’s unprecedented in its scope and in highlighting the differences between how males and females perceive and process stress. As part of the study, and in keeping with the principles of open-access science, the researchers decided to make the entire detailed mapping publicly available on a dedicated interactive website, which went live at the same time the study was published, providing other researchers with convenient, user-friendly access to the data. “The website will, for example, allow researchers who are focusing on a specific gene to see how that gene’s expression changes in a certain cell type in response to stress, in males as well as females,” Brivio explains.

The comprehensive mapping has already allowed the researchers to identify a long list of differences in gene expression – between males and females, and between chronic and acute stress. The data showed, inter alia, that certain brain cells respond differently to stress in males and females: Some cells are more susceptible to stress in females and some to stress in males. The most significant difference was found in a type of brain cell called the oligodendrocyte – a subtype of glial cell that provides support to nerve cells and plays an important role in regulating brain activity. In males, exposure to stress conditions, especially chronic stress, changed not only the gene expression in these cells and their interactions with surrounding nerve cells but also their very structure. In females, however, no significant change was observed in these cells, and they were not susceptible to stress exposure. “Neurons attract most of the scientific attention, but they only make up approximately a third of all cells in the brain. The method we implemented allows us to see a much richer and fuller picture, including all the cell types and their interactions in the part of the brain under study,” says Dr. Juan Pablo Lopez, a former postdoctoral fellow in Chen’s group and now the head of a research group at the Department of Neuroscience of the Karolinska Institute in Sweden.

Ketamine effective for treatment-resistant depression: clinical trial

A low-cost version of ketamine to treat severe depression has performed strongly in a double-blind trial that compared it with placebo.

In research published today in the British Journal of Psychiatry, researchers led by UNSW Sydney and the affiliated Black Dog Institute found that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50 per cent. The study was a collaboration between six academic clinical mood disorder units in Australia and one in New Zealand and was funded by the Australian National Health and Medical Research Council (NHMRC).

“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20 per cent remission is actually quite good,” lead researcher Professor Colleen Loo says.

“We found that in this trial, ketamine was clearly better than the placebo – with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo.”

How the trial worked

The researchers recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation – or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off – usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.

As a double-blind trial, neither participants nor researchers administering the drug were aware which patients received generic ketamine or placebo, to ensure psychological biases were minimised. Importantly, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.

“Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” Prof. Loo says.

“In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”

Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).

“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Prof. Loo says.

“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”

Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.

Much more affordable

Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about $800 per dose, the generic ketamine is a mere fraction of that, costing as little as $5, depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe – which at Black Dog Institute clinics, comes to $350 per session.

“With the S-ketamine nasal spray, you are out of pocket by about $1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you’re paying around $300-350 for the treatment including the drug cost,” Prof. Loo says.

She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone’s clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most Australians.

“This is why we’re applying for a Medicare item number to fund this treatment now, because it’s such a powerful treatment.

“And if you consider that many of these people might spend many months in hospital, or be unable to work and are often quite suicidal, it’s quite cost effective when you see how incredibly quickly and powerfully it works. We’ve seen people go back to work, or study, or leave hospital because of this treatment in a matter of weeks.”

The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.

From Promise to practice: A Dose of reality for psychedelic therapies

Psychedelics stand at a pivotal crossroad in mental health, offering the prospect of novel therapeutic avenues to address multiple mental conditions, from treatment-resistant depression to post-traumatic stress disorder (PTSD). However, their mind-altering properties present unique ethical and clinical challenges. In a newly published article in Nature Medicine, leading psychiatrists, psychologists and psychotherapists highlight the importance of protecting patients during these vulnerable states of altered consciousness and the imperative for regulatory frameworks and collaborative efforts to fully realise the potential benefits of this emerging treatment paradigm.

The exploration of alternative therapeutics for hard-to-treat mental health disorders has brought into focus an array of psychedelics such as psilocybin, present in ‘magic mushrooms’, and LSD, substances once associated more with counterculture than clinical practice. Alongside ‘atypical’ psychedelics like ketamine and MDMA, these substances are increasingly being recognised for their potential therapeutic attributes. For example, synthetic psilocybin has shown promising results in alleviating symptoms of depression and anxiety associated with cancer diagnosis, while its efficacy is being investigated in relation to conditions such as obsessive-compulsive disorder, eating disorders, and substance use disorders.

Moreover, while the subjective experiences they elicit may differ, both typical and atypical psychedelics are generally deemed safe with limited potential for abuse. However, a seamless transition from clinical trials to regular clinical practice is by no means guaranteed. As Albino Oliveira-Maia, senior author of the article and head of the Champalimaud Foundation’s Neuropsychiatry Unit, notes, “up until now, psychedelic therapies have largely been confined to the realm of research and clinical studies. But this looks set to change. We’re already witnessing off-label use of ketamine, once solely viewed as an anaesthetic, in treating depression and substance use disorders, despite the lack of clear guidelines, formal approval from regulatory agencies, and recommendations regarding psychological support”.

Unlike most drug treatments, psychedelics are typically coupled with psychotherapy to safeguard patients and potentially enhance clinical effectiveness through shaping the drug-induced subjective experiences. The authors emphasise the necessity of assessing the clinical effectiveness of the accompanying therapy. “If psychotherapy during the psychedelic experience offers substantial additional benefits to the patient, defining and standardising optimal therapeutic procedures for these dosing sessions becomes essential”, says Oliveira-Maia. “Our goal is also to ensure that the promise of psychedelics does not come at the expense of patient safety”. Psychedelics can provoke heightened suggestibility or feelings of intimacy, which may increase vulnerability to potential abuse and boundary transgressions in the therapist-patient relationship.

An alleged example of such a transgression occurred in a Canadian clinical trial of MDMA-assisted therapy for PTSD, where a participant and her unlicensed therapist were involved in an out-of-court settlement for a sexual assault claim. Such incidents underscore the necessity for certified and professionally trained practitioners, regulatory oversight, and enhanced informed consent procedures to address possible use of touch and patient susceptibility during altered states of mind.

“This will demand a collective effort”, elucidates co-author Ana Matos Pires, Director of the Mental Health Department at Unidade Local de Saúde do Baixo Alentejo and Member of the Board of Psychiatrists at the Portuguese Medical Association. “Not only will it involve the physicians who prescribe the treatment and the psychologists who administer it, but also a range of other stakeholders at national and international levels, from regulatory bodies like the US Food and Drug Administration and European Medicines Agency, to policy makers, ethics boards, pharmacists, nurses, and of course, the patients themselves”.

In Portugal, researchers working with psychedelics are already engaging with professional societies of psychiatrists and clinical psychologists, as well as ethical authorities, to preemptively address the regulatory challenges that may surface if these psychedelic treatments become mainstream. “We see our proactive approach serving as a blueprint for other countries preparing for the potential incorporation of psychedelic treatments into clinical practice”, asserts Matos Pires. “Health literacy is also critical in this area. It’s crucial that we clearly inform the public about this kind of treatment. Psychedelic therapies are not a panacea but another tool with which to treat mental illness”.

Many aspects remain to be clarified, from determining appropriate dosages and antipsychotics to counter adverse effects, to identifying the ideal settings for treatment, whether within traditional hospital environments or alternative therapeutic spaces. Time, though, is of the essence. Recently, Australia declared its intent to authorise the therapeutic use of MDMA and psilocybin starting July 2023, while the FDA could approve the use of MDMA for treating PTSD as early as 2024.

“We agree on the potential benefits of psychedelics”, says co-author Luís Madeira, President-elect of the Portuguese Society of Psychiatry and Mental Health, and Counsellor  of the National Council of Ethics for the Life Sciences. “Nevertheless, it’s vital to acknowledge the associated challenges and avoid rushing the process. Given that trials typically pair psychedelics with therapy, further research will be needed to better understand the individual effects of both the drug and the therapy. It’s plausible that one may prove more efficacious than the other”.

One notable challenge Madeira brings up is the difficulty of conducting unbiased double-blind studies, as the distinct psychoactive effects make it obvious to both participant and researcher who has received the treatment or placebo. Additionally, the question of accessibility in the public health system arises, given that each psychedelic experience can last 8 hours and usually involves two trained therapists. “A potential solution”, explains Madeira, “might be group therapy, allowing therapists to treat multiple patients simultaneously, thereby reducing costs and making the treatment more feasible within public health systems”.

The article’s first author Carolina Seybert, Clinical Psychologist at the Champalimaud Clinical Centre, stresses the need for an agile process. “These protocols need to be flexible and dynamic as our understanding of these therapies evolves. In a rapidly changing field like this, in which our knowledge base is constantly updating, it’s key that our guidelines and regulations are not just robust, but also adaptable. We need a uniform framework in place that can be modified as new information comes in. If we leave this process to the self-regulation of individuals, the patient’s experience may vary substantially from one case to the next”. In a sense, our exploration of psychedelics in mental health mirrors the very nature of the treatment itself, a venture into uncharted territory and new possibilities. The authors’ article provides a timely compass and a lucid appreciation of the ethical and regulatory realities ahead.

Light It Up: How Your Lighting Could Affect Your Mental Health

Light It Up: How Your Lighting Could Affect Your Mental Health
Light It Up: How Your Lighting Could Affect Your Mental Health

In recent years, the way people respond to light has been something of a hot topic. From the growing numbers of people dealing with Seasonal Affective Disorder (SAD) to the rise of blue light glasses, we’re learning more and more about how lighting can affect our moods, life patterns and behaviours.

Often, people don’t realise the impact that lighting can have upon their sleep and wellbeing. The simplest of changes could help you enjoy a new lease of life. Here, the lighting and smart home system experts at Wandsworth Electrical take a look at how you can use lighting in your home to feel better, sleep deeper and unwind in style.

Key findings

  • Seasonal Affective Disorder (SAD) usually occurs during winter, when days are darker and there’s less light. Light therapy, using a lightbox, can help combat this.
  • Blue light limits the amount of melatonin your body produces, making it more difficult for you to sleep at night.
  • Certain colours of light can affect your mood in different ways – yellow can relieve feelings of irritation and green can reduce feelings of pleasure.
  • Studies suggest that lighting can even affect your appetite, the speed at which you eat, and your overall decision-making.

Lighting and mental health

Your home’s lighting can be used to combat Seasonal Affective Disorder (SAD). Sometimes known as winter depression, SAD predominantly occurs during the winter months, since the bad weather and short daylight hours are thought to negatively affect your mood.

According to the NHS website, some people who suffer from SAD find light therapy helpful. This involves sitting in front of a specialised light box for 30-60 minutes a day. The lightbox simulates the sunlight that’s missing during the winter months, encouraging your brain to produce serotonin.

Sweet dreams

If your body is exposed to bright light before bed, it can negatively affect your sleep. Your circadian rhythm (a.k.a. your body clock) responds primarily to lighting. Your body responds to light as a sign that it needs to be awake, and darkness as a signal to fall asleep. This doesn’t just mean the sun, however. Sitting in a brightly lit room just before going to bed will make it harder for you to go sleep.

The backlight on your phone screen and other devices can also prevent you from sleeping and is one of the main reasons most smartphones have a night mode. Blue light, which is present in white light, reduces your body’s ability to produce melatonin, thereby making it more difficult for you to get to sleep.

Colour Me Excited

The colour of your lighting can also have a huge impact on your mental health – and your mood. Studies show that certain lighting colours can affect your mood in different ways; yellow light can help relieve feelings of irritation, whilst green light can reduce feelings of pleasure and negatively impact your mood.

Warm colours like yellow and red can trick your brain, triggering some of the same responses as if you were actually sat in a warm room. Meanwhile, colder colours like blues and greens can have the opposite effect, and can make you feel colder. Warming light can make all the difference in winter!

Feeling hungry?

Research in the International Journal of Environmental Research and Public Health showed that lighting is not only important for visual performance and safety, but also plays a vital role in regulating human physiological functions.

In fact, lighting can have an effect on everything, from your appetite to the speed that you eat at Research shows that dining in bright interiors will make you eat faster, whilst dim lighting will make you eat slower. Even your perception of flavour can be altered by the lighting you choose in your home.

Clearly, lighting has a noticeable effect on people’s moods. But how can you implement these changes at home?

Dimmer switches

Installing dimmer switches in your home gives you more flexibility to tailor your lighting to your mood – it’s called mood lighting for a reason! Dimmer lighting allows your eyes to relax, and can help your entire body feel more comfortable. Some studies even suggest dimmer lighting calms our body down, improving our decision-making skills.

Daylight harvesting

Daylight harvesting, also known as constant light levels, can be used to help offset some of the effects of SAD. Daylight harvesting uses a Passive Infrared (PIR) sensor to detect the level of light you’ve set and maintain it constantly all day, adjusting in line with how much natural light comes into the room.

If you’re working from home, you can set your light levels to a specific brightness at the start of the day. The PIR sensor will then take over, dimming your light up or down depending on the time of day. Eventually, you’ll end up with 100% artificial light inside and darkness outside. This way, you can maintain the perfect light level, whilst cutting your energy costs.

Timing your lights

It’s easy to lose track of time, particularly if you’re having a busy day! If you’re working late or even just unwinding at home, you might forget to dim the lights to prep your body for bed. Try having your lighting on a timer to make sure you don’t strain your eyes – if you’ve got a smart home, you can set your lighting to change at certain times to ease you into the morning, or wind down at night.

Switch the big light off

If you’re looking to go for some softer lighting, investing in some smaller, more restrained lighting could be the way to go. Freestanding lights, table lamps or fairy lights are a great way to reduce brightness in your home. Plus, LED bulbs are much better for the planet than traditional filament bulbs, so you can cut down on your electricity bill, too.

Colour carefully

Customising the colour of your lighting is another great way to ensure that your body and mind benefit from your lighting choices. Whether you’re opting for a smart-controlled main light bulb or remote LEDs in your ambient lighting, you can tailor your light to your mood and the time of day, to ensure you’re not getting too much blue light and can properly relax.

Robert Aiken, Technical Director at Wandsworth Electrical, comments: “In many ways, your lighting choices are just as important as your interior design, and the two should go hand-in-hand to maximise the potential of your space. However, it’s not just aesthetics that make lighting a vital consideration – people should understand the consequences of being exposed to bright light or coloured light, and how these can affect their body.”

More depressed patients than previously estimated could have increased activation of their immune system.

New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London has used an assessment of gene expression involved in the immune response to show that there could be more patients with MDD with activated immune systems than research has previously estimated.   

Depression
Depression

By identifying the molecular mechanisms involved in this association, the research could pave the way to better identify those patients with an immune component to their depression which would potentially help to provide more personalised approaches to treatment and management of MDD.

The research, published in Translational Psychiatry and funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC) and a Wellcome Trust strategy award, builds on previous findings that there is an activated immune response in many people with MDD.

However, most of the research in this area has focussed on the levels of inflammation related proteins like C-reactive protein (CRP). Studies using CRP have found that about 21 to 27 % of people with depression have an activated immune responsebut CRP levels do not capture the complete picture of the immune response.  This new study set out to observe broader immune related characteristics that are not captured by CRP levels.

168 participants were sourced from the Biomarkers in Depression Study (BIODEP). 128 of them had a confirmed diagnosis of MDD and they were then divided into three subgroups according to their levels of CRP in the blood.

Researchers analysed the expression of 16 genes whose activation is involved in the immune response. Gene expression is the initial stage of the process by which the information present in our genes influences our features and behaviour. The initial analysis found increased expression of immune-related genes in people with MDD compared to the those without a diagnosis of depression. When comparing MDD patients who did and didn’t have elevated levels of CRP in their blood, there were no differences in the expression of these 16 genes, suggesting this pattern of expression was independent of CRP levels and potentially underlying a different mechanism.

Importantly, researchers then conducted a secondary analysis on all those participants (both with and without a diagnosis of MDD) who had CRP values of less than 1, meaning that they are not considered to have any inflammation. The researchers found that participants with MDD and low levels of CRP still had significantly higher expression of immune genes compared to those without a depression diagnosis.

Professor Carmine Pariante, Professor of Biological Psychiatry at King’s IoPPN and the study’s senior author said, “Previous research into this field has had a significant focus on C-reactive protein (CRP) levels within people with MDD which is a known marker for inflammation but just part of the immune response. Our study has successfully broadened this focus and shown that there is an immune response in the genes of those with MDD that is independent of CRP levels and, crucially, even in those where inflammation is not captured by measuring CRP. This means that increased immune activation is present in many more depressed patients than originally thought.”

“These important findings will allow us to identify the molecular pathways involved in depression and also help to more accurately identify those who have different types of immune responses which could pave the way for more personalised approaches to treatment.”

Dr Luca Sforzini, the study’s first author from King’s IoPPN said, “This evidence contributes to strengthen our knowledge on immune-related depression. Notably, people with depression and immune alterations are less likely to respond to standard antidepressant medications and may benefit from specific interventions targeting the immune system. I am hopeful these findings will aid current and future research in better characterizing individuals with depression based on their immunobiological profiles, offering more effective clinical strategies to a large number of people who are not benefitting from current antidepressants.”

The evidence of an immune related predisposition in people with depression irrespective of their levels of inflammation as routinely measured can extend our concept of immune related depression.