Depression is widely reported to be more common in women than in men, with women twice as likely to receive a diagnosis than men. A new study published in Nature has found that there are differences between male and female genes and how they relate to depression.
In a genome-wide association(GWA} study, the McGill University researchers analysed the genomes of more than 270 000 individuals. They found that sex-specific prediction methods were more accurate in forecasting an individual’s genetic risk of developing depression than prediction methods that did not specify sex. The researchers found 11 areas of DNA that were linked to depression in females, and only one area in males.
In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males.
Despite the biological processes involved in depression being similar in males and females, researchers found that different genes were involved for each sex. This information can be useful to identify future sex-specific treatments for depression. “This is the first study to describe sex-specific genetic variants associated with depression, which is a very prevalent disease in both males and females. These findings are important to inform the development of specific therapies that will benefit both men and women while accounting for their differences,” says Dr Patricia Pelufo Silveira, lead author and Associate Professor in the Department of Psychiatry. “In the clinic, the presentation of depression is very different for men and women, as well as their response to treatment, but we have very little understanding of why this happens at the moment.”
University of South Australia researchers are calling for exercise to be a mainstay approach for managing depression as a new study shows that physical activity is 1.5 times more effective than counselling or the leading medications.
Published in the British Journal of Sports Medicine, the review is the most comprehensive to date, encompassing 97 reviews, 1039 trials and 128 119 participants. It shows that physical activity is extremely beneficial for improving symptoms of depression, anxiety, and distress.
Specifically, the review showed that exercise interventions that were 12 weeks or shorter were the most effective at reducing mental health symptoms, highlighting the speed at which physical activity can make a change.
The largest benefits were seen among people with depression, pregnant and postpartum women, healthy individuals, and people diagnosed with HIV or kidney disease.
Lead UniSA researcher, Dr Ben Singh, says physical activity must be prioritised to better manage the growing cases of mental health conditions.
“Physical activity is known to help improve mental health. Yet despite the evidence, it has not been widely adopted as a first-choice treatment,” Dr Singh says.
“Our review shows that physical activity interventions can significantly reduce symptoms of depression and anxiety in all clinical populations, with some groups showing even greater signs of improvement.
“Higher intensity exercise had greater improvements for depression and anxiety, while longer durations had smaller effects when compared to short and mid-duration bursts.
“We also found that all types of physical activity and exercise were beneficial, including aerobic exercise such as walking, resistance training, Pilates, and yoga.
“Importantly, the research shows that it doesn’t take much for exercise to make a positive change to your mental health.”
Senior researcher, UniSA’s Prof Carol Maher, says the study is the first to evaluate the effects of all types of physical activity on depression, anxiety, and psychological distress in all adult populations.
“Examining these studies as a whole is an effective way for clinicians to easily understand the body of evidence that supports physical activity in managing mental health disorders.
“We hope this review will underscore the need for physical activity, including structured exercise interventions, as a mainstay approach for managing depression and anxiety.”
In a recent study published in The Journal of Advanced Nursing that included pregnant Black women from multiple US states, feeling upset by experiences of racism in the 12 months prior to delivery was associated with significantly higher odds of depression during pregnancy.
Perinatal depression is defined as major or minor depressive episodes that occur during pregnancy or in the first 12 months after birth. Mothers with perinatal depression often report symptoms including depressed mood; loss of interest or pleasure in daily activities; changes in weight, appetite and sleep; poor concentration; feelings of hopelessness; and suicidal ideations. Non-Hispanic Black women are twice as likely to experience symptoms of depression and suicidal ideations during the perinatal period than White women.
For this study, 7328 women answered survey questions. The findings showed that 11.4% of respondents reported feeling upset due to experiences of racism, and 11.4% reported experiencing depression during pregnancy. After adjusting for confounding factors, respondents who reported feeling upset due to the experience of racism had over two-fold higher odds of experiencing depression during pregnancy compared with respondents who did not report feeling upset due to the experience of racism.
“Our findings reinforce the importance of respectful maternity care, given the mental health impacts of experiences of racism during the perinatal period,” the authors wrote. “Racism is a powerful structural determinant of health with roots in a historical system of oppression that persists today in health care practices and policies. Perinatal health care providers, in collaboration with public health and other health disciplines, are ideally positioned to address inequities in maternal and child health that are rooted in racism.”
Most people remember emotional events, like their wedding day, very clearly, but researchers are not sure how the human brain prioritises emotional events in memory. In a study published in Nature Human Behaviour, Joshua Jacobs, associate professor of biomedical engineering at Columbia Engineering, and his team identified a specific neural mechanism in the human brain that tags information with emotional associations for enhanced memory.
The team demonstrated that high-frequency brain waves in the amygdala, a hub for emotional processes, and the hippocampus, a hub for memory processes, are critical to enhancing memory for emotional stimuli. Disruptions to this neural mechanism, brought on either by electrical brain stimulation or depression, impair memory specifically for emotional stimuli.
Rising prevalence of memory disorders
The rising prevalence of memory disorders such as dementia has highlighted the damaging effects that memory loss has on individuals and society. Disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD) can also feature imbalanced memory processes, especially with the COVID pandemic. Understanding how the brain naturally regulates what information gets prioritised for storage and what fades away could provide critical insight for developing new therapeutic approaches to strengthening memory for those at risk of memory loss, or for normalising memory processes in those at risk of dysregulation.
“It’s easier to remember emotional events, like the birth of your child, than other events from around the same time,” says Salman E. Qasim, lead author of the study, who started this project during his PhD in Jacobs’ lab at Columbia Engineering. “The brain clearly has a natural mechanism for strengthening certain memories, and we wanted to identify it.”
The difficulty of studying neural mechanisms in humans
Most investigations into neural mechanisms take place in animals such as rats, because such studies require direct access to the brain to record brain activity and perform experiments that demonstrate causality, such as careful disruption of neural circuits. But it is difficult to observe or characterise a complex cognitive phenomenon like emotional memory enhancement in animal studies.
To study this process directly in humans. Qasim and Jacobs analysed data from memory experiments conducted with epilepsy patients undergoing direct, intracranial brain recording for seizure localisation and treatment. During these recordings, epilepsy patients memorised lists of words while the electrodes placed in their hippocampus and amygdala recorded the brain’s electrical activity.
Studying brain-wave patterns of emotional words
Qasim found that participants remembered more emotionally rated words, such as “dog” or “knife,” better than more neutral words, such as “chair.” Whenever participants successfully remembered emotional words, high-frequency neural activity (30-128 Hz) would become more prevalent in the amygdala-hippocampal circuit, a pattern which was absent when participants remembered more neutral words, or failed to remember a word altogether. Analysing 147 participant, they found a clear link between participants’ enhanced memory for emotional words and the prevalence in their brains of high-frequency brain waves across the amygdala-hippocampal circuit.
“Finding this pattern of brain activity linking emotions and memory was very exciting to us, because prior research has shown how important high-frequency activity in the hippocampus is to non-emotional memory,” said Jacobs. “It immediately cued us to think about the more general, causal implications – if we elicit high-frequency activity in this circuit, using therapeutic interventions, will we be able to strengthen memories at will?”
Electrical stimulation disrupts memory for emotional words
In order to establish whether this high-frequency activity actually reflected a causal mechanism, Jacobs and his team formulated a unique approach to replicate the kind of experimental disruptions typically reserved for animal research. First, they analysed a subset of these patients who had performed the memory task while direct electrical stimulation was applied to the hippocampus for half of the words that participants had to memorise. They found that electrical stimulation, which has a mixed history of either benefiting or diminishing memory depending on its usage, clearly and consistently impaired memory specifically for emotional words.
Uma Mohan, another PhD student in Jacobs’ lab at the time and co-author on the paper, noted that this stimulation also diminished high-frequency activity in the hippocampus. This provided causal evidence that, by knocking out the brain activity pattern correlating with emotional memory, stimulation was also selectively diminishing emotional memory.
Depression acts similarly to brain stimulation
Qasim further hypothesized that depression, which can involve dysregulated emotional memory, might act similarly to brain stimulation. He analyzed patients’ emotional memory in parallel with mood assessments the patients took to characterize their psychiatric state. And, in fact, in the subset of patients with depression, the team observed a concurrent decrease in emotion-mediated memory and high-frequency activity in the hippocampus and amygdala.
“By combining stimulation, recording, and psychometric assessment, they were able to demonstrate causality to a degree that you don’t always see in studies with human brain recordings,” said Bradley Lega, a neurosurgeon and scientist at the University of Texas Southwestern Medical Center and not an author on the paper. “We know high-frequency activity is associated with neuronal firing, so these findings open new avenues of research in humans and animals about how certain stimuli engage neurons in memory circuits.”
Next steps
Qasim is now investigating how individual neurons in the human brain fire during emotional memory processes. Qasim and Jacobs hope that their work might also inspire animal research exploring how this high-frequency activity is linked to norepinephrine, a neurotransmitter linked to attentional processes that they theorise might be behind the enhanced memory for emotional stimuli. They also hope that future research will target high-frequency activity in the amygdala-hippocampal circuit to protect memory.
“Our emotional memories are one of the most critical aspects of the human experience, informing everything from our decisions to our entire personality,” Qasim added. “Any steps we can take to mitigate their loss in memory disorders or prevent their hijacking in psychiatric disorders is hugely exciting.”
Scientists have worked out why selective serotonin reuptake inhibitors (SSRIs), a common antidepressant class, cause around a half of users to feel emotionally ‘blunted’. In a study published in Neuropsychopharmacology, they show that the drugs interfere with reinforcement learning, which allows humans to adapt to their environment.
As their name implies, SSRIs target the neurotransmitter serotonin, and are commonly used to treat more resistant depression and anxiety. One of their widely-reported side effects is ‘blunting’, where patients report feeling emotionally dull and no longer finding things as pleasurable as they used to. Between 40–60% of patients taking SSRIs are believed to experience this side effect.
To date, most studies of SSRIs have only examined their short term use, but, for clinical use in depression these drugs are taken chronically, over a longer period of time. Researchers sought to address this by recruiting healthy volunteers and administering one of the best tolerated SSRIs, escitalopram, over several weeks and assessing the impact the drug had on their performance on a suite of cognitive tests.
In total, 66 volunteers took part in the experiment, 32 of whom were given escitalopram while the other 34 were given a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and were given a series of tests to assess cognitive functions including learning, inhibition, executive function, reinforcement behaviour, and decision-making.
No differences were found in ‘cold’ cognition – such as attention and memory, nor any differences found in most tests of ‘hot’ cognition – cognitive functions that involve our emotions.
However, the key novel finding was that there was reduced reinforcement sensitivity on two tasks for the escitalopram group compared to those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment.
In order to assess reinforcement sensitivity, the researchers used a ‘probabilistic reversal test’. In this task, a participant would typically be shown two stimuli, A and B. If they chose A, then four out of five times, they would receive a reward; if they chose B, they would only receive a reward one time out of five. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would switch and participants would need to learn the new rule.
The team found that the escitalopram group was less likely to use the positive and negative feedback to guide their learning of the task compared to the placebo group. This suggests that the drug affected their sensitivity to the rewards and their ability to respond accordingly.
The finding may also explain the one difference the team found in the self-reported questionnaires, that volunteers taking escitalopram had more trouble reaching orgasm when having sex, a side effect often reported by patients.
Professor Barbara Sahakian, senior author, from the Department of Psychiatry at the University of Cambridge and a Fellow at Clare Hall, said: “Emotional blunting is a common side effect of SSRI antidepressants. In a way, this may be in part how they work – they take away some of the emotional pain that people who experience depression feel, but, unfortunately, it seems that they also take away some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provide important feedback.”
Dr Christelle Langley, joint first author also from the Department of Psychiatry, added: “Our findings provide important evidence for the role of serotonin in reinforcement learning. We are following this work up with a study examining neuroimaging data to understand how escitalopram affects the brain during reward learning.”
Antidepressants and psychotherapy typically are the preferred treatment options for anxiety and depression, although benzodiazepines can be helpful in treating acute or persistent anxiety that does not respond to first-line therapy. In “Walking the Benzodiazepine High Wire,” published in Psychiatric Services, two experts advocate advocate a multipronged strategy for the cautious prescribing of this class of anxiety medications rather than a stringent and exclusively regulatory approach to their use.
Kurt Kroenke, MD, of the Regenstrief Institute and Indiana University School of Medicine, and Matthew E. Hirschtritt, MD, MPH, of Kaiser Permanente Northern California and University of California, San Francisco,
Noting that the number of benzodiazepine prescriptions in the US has substantially increased over the past decade, leading to a parallel rise in rates of misuse and overdose, Dr Kroenke and Dr Hirschtritt counsel that to stem this disquieting tide, provider and patient education, coupled with prescribing surveillance, may be preferable to overly strict governmental regulation of benzodiazepines.
“Benzodiazepines should not be tried first or probably even second, but as with opiates which can be appropriate for acute pain at end of life or following a severe injury or major surgery, there are appropriate reasons for prescribing benzodiazepines for severe anxiety,” said Dr Kroenke.
He is a pioneer in the field of medical symptomology and international leader in the interpretation and treatment of psychological and physical symptoms. He has co-developed brief survey measures in worldwide clinical use to track symptoms of anxiety (GAD-7); depression (PHQ-9); suicide risk (P-4); and other conditions. These tools have been translated into more than 100 languages and assist clinicians around the world in selecting treatments and evaluating their effectiveness.
The authors conclude: “The tightrope between the benefits and risks of prescribing a medication that may be useful for some patients and harmful for others exists not only for controlled drugs but also for treatments such as antibiotics, which continue to be overprescribed, leading to antibiotic resistance. A multipronged strategy for BZD [benzodiazepine] use that includes ongoing education of providers, patients, and the general population; surveillance to optimise selective and appropriate use; and closer oversight of outlier prescribing patterns is preferable to a stringent and exclusively regulatory approach.”
Ketamine, an established anaesthetic and increasingly popular antidepressant, dramatically reorganises activity in the brain, as if a switch had been flipped on its active circuits, according to a new study published in a Nature Neuroscience paper.
Researchers observed greatly altered patterns of neuronal activity in the cerebral cortex of animal models after ketamine administration – normally active neurons were silenced while another set that were normally quiet suddenly sprang to action.
This ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry.
“Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state,” said the co-lead and co-senior author Joseph Cichon, MD, PhD, an assistant professor at the University of Pennsylvania. “It’s possible that this new network induced by ketamine enables dreams, hypnosis, or some type of unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine’s therapeutic effects take place.”
Anaesthesiologists routinely deliver anesthetic drugs before surgeries to reversibly alter activity in the brain so that it enters its unconscious state. Since its synthesis in the 1960s, ketamine has been a mainstay in anaesthesia practice because of its reliable physiological effects and safety profile. One of ketamine’s signature characteristics is that it maintains some activity states across the surface of the brain (the cortex). This contrasts with most anaesthetics, which work by totally suppressing brain activity. It is these preserved neuronal activities that are thought to be important for ketamine’s antidepressant effects in key brain areas related to depression. But, to date, how ketamine exerts these clinical effects remains mysterious.
In their new study, the researchers analysed mouse behaviours before and after they were administered ketamine, comparing them to control mice who received placebo saline. One key observation was that those given ketamine, within minutes of injection, exhibited behavioural changes consistent with what is seen in humans on the drug, including reduced mobility, impaired responses to sensory stimuli, which are collectively termed “dissociation.”
“We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it’s administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it,” said co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor at Penn.
Two-photon microscopy was used to image cortical brain tissue before and after ketamine treatment. By following individual neurons and their activity, they found that ketamine turned on silent cells and turned off previously active neurons.
The neuronal activity observed was traced to ketamine’s ability to block the activity of synaptic receptors called NMDA receptors and ion channels called HCN channels. The researchers found that they could recreate ketamine’s effects without the medications by simply inhibiting these specific receptors and channels in the cortex. The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally quiet neurons, the ones usually being suppressed when ketamine wasn’t present, to become active.
The study showed that this dropout in inhibition was necessary for the activity switch in excitatory neurons – the neurons forming communication highways, and the main target of commonly prescribed antidepressant medications. More work will need to be undertaken to determine whether the ketamine-driven effects in excitatory and inhibitory neurons are the ones behind ketamine’s rapid antidepressant effects.
“While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications,” said co-author Max Kelz, MD, PhD. “Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses.”
A large-scale study published in JAMA Network has found no link between benzodiazepines use in pregnancy and subsequent autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) diagnoses in offspring. When comparing siblings, benzodiazepines use had no effect on ASD or ADHD risk, indicating that the mother’s genetics partly explained the increased risk.
Some 10–30% of pregnant women experience mental disorders, including mood or anxiety spectrum disorders, for which benzodiazepine agents are sometimes prescribed; this occurs in an estimated 1.9% of pregnancies globally.
The safety of these agents to the developing foetus and newborn has been called into question, since benzodiazepines are able to cross the placenta and have been found to be present in amniotic fluid and breast milk. The US FDA includes in the category of possible harm to the foetus.
While rodents studies have tested benzodiazepine exposure during the first trimester of pregnancy, investigations of neurodevelopmental outcomes in humans, such as ASD and ADHD, have been lacking.
One study found no significantly increased risks of ADHD symptoms or fine or greater motor deficits. Those researchers suggested the disorder resulting in benzodiazepine use might partly explain the increased risks. Maternal depressive and anxiety symptoms in pregnancy have also been linked to increased ADHD risk in children.
From the Taiwanese national health database, of over 1 .5 million children born full term who were younger than 14 years of age and followed up to 2017; 5.0% had been exposed to benzodiazepines in utero.
However, no differences were found with unexposed sibling controls during the same time frame for ADHD or ASD.
The researchers concluded that their results “challenge current assumptions of a potential association of neurodevelopmental disorders with maternal benzodiazepine use before or during pregnancy. Better identification of maternal mental health concerns, as well as possible interventions or provisions of guidance to build better nurturing and raising environments for newborns at risk, may be relevant to the prevention of adverse outcomes of neurodevelopmental disorders.”
The largest and most rigorous clinical trial to date of psilocybin (a psychoactive ingredient in magic mushrooms), suggests the possibility that COMP360 psilocybin with psychological support could be a beneficial therapeutic strategy for people with treatment-resistant depression (TRD). The trial results were published in the New England Journal of Medicine.
Prompted by promising preliminary findings, this funded multi-centre, randomised, double-blind, phase 2b clinical trial was launched in 2018 to determine the safety and potential antidepressant effects of a single dose of COMP360 psilocybin (25mg or 10mg), compared to 1mg, with psychological support in people with TRD.
The trial, which included 233 people with TRD across 10 countries who received a single dose of 25mg COMP360 psilocybin experienced a highly statistically and clinically significant rapid reduction in symptoms of depression compared to 1mg at three weeks. This offers hope that COMP360 psilocybin with psychological support could be an effective antidepressant treatment paradigm for some people with TRD, if proven effective and safe in larger studies. COMPASS Pathways, the company that developed the psilocybin formulation., will be running a larger phase 3 programme of COMP360 psilocybin therapy in TRD, which is on schedule to begin in 2022.
KEY RESEARCH FINDINGS
25mg COMP360 psilocybin with psychological support led to a statistically and clinically significantly reduction in symptoms of depression in people with TRD compared to 1mg at week 3.
37% of people with TRD in the 25mg group met criteria for response at week 3 (≥ 50% decrease in depressive symptoms).
Approximately 30% of people with TRD in the 25mg group met criteria for remission at week 3 (29.1%).
20% of people with TRD in the 25mg group met criteria for sustained response at week 12.
COMP360 psilocybin was generally well-tolerated.
Dr John R. Kelly, Psychiatrist and Clinical Senior Lecturer, Trinity College said: “This is the largest and most rigorous clinical trial of psilocybin to date. It shows a promising antidepressant signal for 25mg COMP360 psilocybin with psychological support and has paved the way for phase 3 clinical trials, which will determine whether it translates into a much-needed complementary treatment strategy in the psychiatry clinic.”
As work hours increase, new doctors are at greater risk of depression, according to a study in the New England Journal of Medicine. Working 90 or more hours a week was associated with changes in depression symptom scores three times larger than the change in depression symptoms among those working 40 to 45 hours a week.
Additionally, compared to those working normal hours, those working more hours had greater odds of scores equating to moderate to severe depression.
By means of advanced statistical methods, the researchers emulated a randomised clinical trial using data on more than 17 000 first-year medical residents, accounting for many other factors in the doctors’ personal and professional lives. Less than 5% met the criteria for moderate to severe depression.
They found a “dose response” effect between hours worked and depression symptoms, with an average symptom increase of 1.8 points on a standard scale for those working 40 to 45 hours, ranging up to 5.2 points for those working more than 90 hours. They conclude that, among all the stressors affecting physicians, working a large number of hours is a major contributor to depression.
The data come from the Intern Health Study, based at the Michigan Neuroscience Institute and the Eisenberg Family Depression Center. Each year, the study recruits new medical school graduates to take part in a year of tracking of their depressive symptoms, work hours, sleep and more while they complete the first year of residency, also called the intern year.
The impact of high numbers of work hours
Though the interns in the study reported a wide range of previous-week work hours, the most common work hour levels were between 65 to 80 hours per week.
The authors say their findings point to a clear need to further reduce the number of hours residents work each week on average.
“This analysis suggests strongly that reducing the average number of work hours would make a difference in the degree to which interns’ depressive symptoms increase over time, and reduce the number who develop diagnosable depression,” said Amy Bohnert, PhD, the study’s senior author and a professor at the U-M Medical School. “The key thing is to have people work fewer hours; you can more effectively deal with the stresses or frustrations of your job when you have more time to recover.”
Yu Fang, MSE, the study’s lead author and a research specialist at the Michigan Neuroscience Institute, notes that the number of hours is important, but so are the training opportunities that come from time spent in hospitals and clinics. “It is important to use the time spent at work for supervised learning opportunities, and not low-value clinical service tasks,” she says.
