Cognitive behavior therapy significantly reduced depression and anxiety in chronic pain patients

The results of a study presented today at the Annual European Congress of Rheumatology (EULAR) 2017 has shown that Acceptance and Commitment Therapy, a form of cognitive behavioural therapy (CBT) that focuses on psychological flexibility and behaviour change, provided a significant reduction in self-reported depression and anxiety among patients participating in a pain rehabilitation programme.

This treatment also resulted in significant increases in self-efficacy, activity engagement and pain acceptance.

To assess the potential benefits of an 8-week programme of group Acceptance and Commitment Therapy (ACT) in people with persistent pain, measures of pain acceptance and activity engagement were taken using the Chronic Pain Acceptance Questionnaire. Measures of psychological distress using the Hospital Anxiety and Depression Scale and self-efficacy were also taken at assessment, on the final day of the programme, and at the follow up six-month review.

For those chronic pain patients with scores at all three time points, there were statistically significant improvements in all parameters between baseline and at six-months follow-up, including the change in mean score of depression, anxiety, self-efficacy, activity engagement and pain willingness (p<0.001).

“To further validate the role of ACT in the treatment of chronic pain, specifically in a rheumatology context, a randomised controlled clinical trial that includes measures of physical and social functioning within a Rheumatology service would be desirable,” said lead author Dr. Noirin Nealon Lennox from Ulster University in Northern Ireland.

ACT is a form of CBT that includes a specific therapeutic process referred to as “psychological flexibility.” ACT focuses on behaviour change consistent with patients’ core values rather than targeting symptom reduction alone. Evidence for this approach to the treatment of chronic pain has been mounting since the mid 2000’s. A previous systematic review had concluded that ACT is efficacious for enhancing physical function and decreasing distress among adults with chronic pain attending a pain rehabilitation programme.

In this study, patients were referred into the ACT programme by three consultant rheumatologists over a five-year period. Over one hundred patients’ outcome measures were available for a retrospective analysis.

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Meditation and yoga can ‘reverse’ DNA reactions which cause stress, new study suggests

Mind-body interventions (MBIs) such as meditation, yoga and Tai Chi don’t simply relax us; they can ‘reverse’ the molecular reactions in our DNA which cause ill-health and depression, according to a study by the universities of Coventry and Radboud.

The research, published in the journal Frontiers in Immunology, reviews over a decade of studies analysing how the behaviour of our genes is affected by different MBIs including mindfulness and yoga.

Experts from the universities conclude that, when examined together, the 18 studies — featuring 846 participants over 11 years — reveal a pattern in the molecular changes which happen to the body as a result of MBIs, and how those changes benefit our mental and physical health.

The researchers focus on how gene expression is affected; in other words the way that genes activate to produce proteins which influence the biological make-up of the body, the brain and the immune system.

When a person is exposed to a stressful event, their sympathetic nervous system (SNS) — the system responsible for the ‘fight-or-flight’ response — is triggered, in turn increasing production of a molecule called nuclear factor kappa B (NF-kB) which regulates how our genes are expressed.

NF-kB translates stress by activating genes to produce proteins called cytokines that cause inflammation at cellular level — a reaction that is useful as a short-lived fight-or-flight reaction, but if persistent leads to a higher risk of cancer, accelerated aging and psychiatric disorders like depression.

According to the study, however, people who practise MBIs exhibit the opposite effect — namely a decrease in production of NF-kB and cytokines, leading to a reversal of the pro-inflammatory gene expression pattern and a reduction in the risk of inflammation-related diseases and conditions.

The study’s authors say the inflammatory effect of the fight-or-flight response — which also serves to temporarily bolster the immune system — would have played an important role in humankind’s hunter-gatherer prehistory, when there was a higher risk of infection from wounds.

In today’s society, however, where stress is increasingly psychological and often longer-term, pro-inflammatory gene expression can be persistent and therefore more likely to cause psychiatric and medical problems.

Lead investigator Ivana Buric from the Brain, Belief and Behaviour Lab in Coventry University’s Centre for Psychology, Behaviour and Achievement said:

“Millions of people around the world already enjoy the health benefits of mind-body interventions like yoga or meditation, but what they perhaps don’t realise is that these benefits begin at a molecular level and can change the way our genetic code goes about its business.

“These activities are leaving what we call a molecular signature in our cells, which reverses the effect that stress or anxiety would have on the body by changing how our genes are expressed. Put simply, MBIs cause the brain to steer our DNA processes along a path which improves our wellbeing.

“More needs to be done to understand these effects in greater depth, for example how they compare with other healthy interventions like exercise or nutrition. But this is an important foundation to build on to help future researchers explore the benefits of increasingly popular mind-body activities.”

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State medical licensing boards’ practices may hurt physician mental health

Sharing a history of mental health issues with an employer is difficult for anyone.

It’s that much harder if reporting an old or well-controlled condition could lead to restrictions on your professional license — as some physicians well know.

A new study found state medical boards ask physicians much more extensive and intrusive questions about mental health conditions than for physical health conditions. Despite national concern about physician suicide and well-being, research shows that even if physicians struggle with depression, they are reluctant to disclose and seek treatment because it could have serious consequences when they apply for their medical license.

Katherine J. Gold, M.D., M.S.W., M.S., assistant professor in the University of Michigan’s Department of Family Medicine, recently led a study published in the Society of Teachers of Family Medicine that examined how state medical licensing boards across the 50 states and Washington, D.C., evaluated mental illnesses compared to physical illnesses or substance use on state licensing forms.

What she found is cause for alarm.

“The differences were really quite striking,” says Gold. “States were significantly more likely to ask if physicians had been diagnosed, treated or hospitalized for mental health or substance abuse verses for physical health disorders, often asking about many years in the past.”

Many of the questions violated the Americans with Disabilities Act as well, the study finds.

“The problem is that states don’t ask, ‘Do you have a problem right now that affects your ability to provide good care for patients?'” Gold explains. “(Instead) they ask broad questions that intrude on physician privacy and prevent doctors from seeking care, but don’t necessarily pick up on impaired physicians.”

A similar number of states asked about both physical and mental health, but the content and nature of the questions varied. Physical health questions tended to be much more lenient and vague while questions about mental health and substance abuse were much more specific, and at times, even intrusive, Gold says.

Fear and female physicians

Last year Gold led a survey that asked 2,100 female physicians who were also mothers about their mental health history and treatment.

Nearly half said they believed they met the definition for a mental illness at some point in their career, but had not sought treatment. Two-thirds reported that fear of stigma, including fear of reporting to state medical boards, drove them to keep their worries quiet.

Only 6 percent who had ever been diagnosed had reported it to their state licensing board, as most felt their condition didn’t affect the care they gave.

“I actually had a physician email me a month ago, and she was really worried because she had postpartum depression several years ago,” says Gold. “[She] reported this to her state medical board and shared all of her treatment records but was still fearful that they would limit her license, despite the fact that there were no problems with her work and she was now doing much better. She was really terrified.”

How state licensing boards respond to disclosures made by physicians about their mental health cannot be predicted and varies state by state, says Gold.

“It completely depends on the board,” she says. “It could range from the board saying, ‘Just send us a letter from your doctor, to send us all of your medical records from all of your treatment, to come before the board and give us your defense as to why you are fit to practice,’ or even calling for ongoing monitoring and license restrictions.”

Physician and patient safety

There is minimal data examining the impact of physician mental health on patient outcomes, Gold says. But conclusions can be drawn about how this issue affects doctors.

“Asking about prior problems or mental health diagnoses make it less safe for physicians because it creates an enormous pressure not to seek mental health treatment,” says Gold.

“It affects physician identity. If you’ve trained for all these years as a physician and then you can’t practice because back 10 years ago you had postpartum depression, that’s really threatening. A lot of people just don’t get help, and if they do get help, it’s often off the books or informal help, which is not ideal.”

Because of attention on the issue from the American Medical Association, there has been a sharp uptick in media focus on physician burnout and mental health, as well as the willingness of some doctors to tell their stories, and reporting on physician suicides.

A number of hospitals nationwide, including Michigan Medicine, are implementing programs to help residents and physicians individually improve their overall wellness and resilience.

Although health systems should promote healthy lifestyles for doctors, more comprehensive and system-level changes should occur as well, Gold says.

“We’re not going to improve physician health until we can take away some of the barriers to seeking help,” she says. “We know that reporting this level of detail to state licensing boards is a huge barrier for physicians because of self-stigma and fears about their license and not being able to practice.”

As a first step to make changes, Gold suggests making sure all questions about mental health on state medical licensing applications comply with the Americans with Disabilities Act. She also says questions should only ask about current conditions causing impairment. This ensures physicians aren’t punished for disclosing an issue in their past that they’ve correctly addressed.

Gold also indicates the Federation of State Medical Boards must take action.

“I think that’s where change has to come from. It has to come from the group that is advising the state medical boards,” she says. “They don’t have regulatory authority over the boards, but certainly they can recommend best practices for the states.”

 

‘Moral enhancement’ technologies are neither feasible nor wise

A recent study by researchers at North Carolina State University and the Montreal Clinical Research Institute (IRCM) finds that “moral enhancement technologies” — which are discussed as ways of improving human behavior — are neither feasible nor wise, based on an assessment of existing research into these technologies.

The idea behind moral enhancement technologies is to use biomedical techniques to make people more moral. For example, using drugs or surgical techniques to treat criminals who have exhibited moral defects.

“There are existing ways that people have explored to manipulate morality, but the question we address in this paper is whether manipulating morality actually improves it,” says Veljko Dubljevic, lead author of the paper and an assistant professor of philosophy at NC State who studies the ethics of neuroscience and technology.

Dubljevic and co-author Eric Racine of the IRCM reviewed the existing research on moral enhancement technologies that have been used in humans to assess the effects of these technologies and how they may apply in real-world circumstances.

Specifically, the researchers looked at four types of pharmaceutical interventions and three neurostimulation techniques:

  • Oxytocin is a neuropeptide that plays a critical role in social cognition, bonding and affiliative behaviors, sometimes called “the moral molecule”;
  • Selective serotonin reuptake inhibitors (SSRIs) are often prescribed for depression, but have also been found to make people less aggressive;
  • Amphetamines, which some have argued can be used to enhance motivation to take action;
  • Beta blockers are often prescribed to treat high blood pressure, but have also been found to decrease implicit racist responses;
  • Transcranial magnetic stimulation (TMS) is a type of neurostimulation that has been used to treat depression, but has also been reported as changing the way people respond to moral dilemmas;
  • Transcranial direct current stimulation (TDCS) is an experimental form of neurostimulation that has also been reported as making people more utilitarian; and
  • Deep brain stimulation is a neurosurgical intervention that some have hypothesized as having the potential to enhance motivation.

“What we found is that, yes, many of these techniques do have some effects,” Dubljevic says. “But these techniques are all blunt instruments, rather than finely tuned technologies that could be helpful. So, moral enhancement is really a bad idea.

“In short, moral enhancement is not feasible — and even if it were, history shows us that using science to in an attempt to manipulate morality is not wise,” Dubljevic says.

The researchers found different problems for each of the pharmaceutical approaches.

“Oxytocin does promote trust, but only in the in-group,” Dubljevic notes. “And it can decrease cooperation with out-group members of society, such as racial minorities, and selectively promote ethnocentrism, favoritism, and parochialism.”

The researchers also found that amphetamines boost motivation for all types of behavior, not just moral behavior. Moreover, there are significant risks of addiction associated with amphetamines. Beta blockers were found not only to decrease racism, but to blunt all emotional response which puts their usefulness into doubt. SSRIs reduce aggression, but have serious side-effects, including an increased risk of suicide.

In addition to physical side effects, the researchers also found a common problem with using either TMS or TCDS technologies.

“Even if we could find a way to make these technologies work consistently, there are significant questions about whether being more utilitarian in one’s decision-making actually makes one more moral,” Dubljevic says.

Lastly, the researchers found no evidence that deep brain stimulation had any effect whatsoever on moral behavior.

“Our goal here is to share a cautionary note with those who are discussing different techniques for moral enhancement,” Dubljevic says. “I am in favor of research that is done responsibly, but against dangerous social experiments.”

 

Potential risks of common MS treatment

In one of the most comprehensive studies to date, UBC researchers have identified potential adverse reactions of a commonly used multiple sclerosis drug.

The study aimed to identify potential adverse events related to beta-interferon treatment for relapsing-remitting multiple sclerosis by analyzing health records of over 2,000 British Columbians with multiple sclerosis between 1995 and 2008.

“Once a drug is released on the market, there are very few ways to systematically monitor adverse events,” said Helen Tremlett, senior author of the study and a professor in the department of medicine at the Djavad Mowafaghian Centre for Brain Health. “Clinical trials cannot identify all adverse effects of a drug treatment partly due to small sample sizes and relatively short follow-up periods.”

The study found an increased risk of events such as stroke, migraine and depression, as well as abnormalities in the blood with taking beta interferon for multiple sclerosis.

“Beta interferons are generally thought of as having a favourable safety profile, especially compared to the newer therapies for multiple sclerosis. And that is still the case; our study does not change that,” said Tremlett, Canada Research Chair in Neuroepidemiology. “However, very few studies had comprehensively and quantitatively assessed their safety in real world clinical practice. Our findings complement and extend on previous observations.”

The researchers found that there was a 1.8-fold increased risk of stroke, a 1.6-fold increased risk of migraine and a 1.3-fold increased risk of both depression and abnormalities in the blood. The researchers stress that patients and physicians should not change their treatment plans. The study is based on population-level data and the risk to individual patients will vary greatly depending on individual factors.

Tremlett hopes that their study will lead to further research to develop biomarkers to help identify patients who are at the greatest risk of having an adverse event.

“Further advances could enable personalized or precision medicine where patients who are at increased risk of having an adverse reaction can be identified. This could help guide discussions about individual treatment options and considerations,” she said.

“It is important for patients with multiple sclerosis to have ongoing review of the benefits and risks of therapy, and to identify supportive strategies, such as diet and exercise, that could optimize their brain health” said Dr. Anthony Traboulsee, co-author of the study, associate professor of neurology and director of the MS Clinic at UBC.

In addition to the negative effects, Tremlett and her colleagues identified a positive relationship. They found a reduced risk of bronchitis and upper respiratory infections with taking beta interferon for more than two years. These infections can be common and problematic in people with multiple sclerosis.

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Tai chi relieves insomnia in breast cancer survivors

If you’ve ever had insomnia, you know worrying about sleep makes it even harder to fall asleep. For the 30 percent of breast cancer survivors who have insomnia, sleepless nights can lead to depression, fatigue and a heightened risk of disease.

Now, new UCLA research shows that tai chi, a form of slow-moving meditation, is just as effective as cognitive behavioral therapy, which has been considered the “gold standard” treatment, with both showing enduring benefits over one year.

The results, published in the Journal of Clinical Oncology, show that tai chi promotes robust improvements in sleep health in breast cancer survivors with insomnia, with additional benefits of improving depressive symptoms and fatigue. Furthermore, both tai chi and cognitive behavioral therapy, which is a form of talk therapy, showed similar rates of clinically significant improvements in symptoms or remission of insomnia.

The American Academy of Sleep Medicine considers cognitive behavioral therapy the treatment of choice for insomnia. This approach involves identifying and changing negative thoughts and behaviors that are affecting the ability to fall asleep and stay asleep.

While cognitive behavioral therapy treats insomnia, it’s too expensive for some people and there is a shortage of trained professionals in the field, said Dr. Michael Irwin, the study’s lead author and a UCLA professor of psychiatry and director of the Cousins Center for Psychoneuroimmunology at the Semel Institute for Neuroscience and Human Behavior.

“Because of those limitations, we need community-based interventions like tai chi,” Irwin said. Free or low-cost tai chi classes are often offered at libraries, community centers or outdoors in parks. Do-it-yourselfers can find instructional videos on YouTube and smartphone apps.

In previous research, Irwin and colleagues found that tai chi, which relaxes the body and slows breathing, reduced inflammation in breast cancer survivors with the potential to lower risk for disease including cancer recurrence.

To test tai chi’s effect on insomnia, researchers recruited 90 breast cancer survivors, who had trouble sleeping three or more times per week and who also reported feeling depressed and fatigue during the daytime. The participants ranged in age from 42 to 83 and were randomly assigned to weekly cognitive behavioral therapy sessions or weekly tai chi instruction for three months. The tai chi group learned a Westernized form of the practice called tai chi chih.

The researchers evaluated the participants at intervals for the next 12 months to determine if they were having insomnia symptoms, as well as symptoms of fatigue and depression, and determined whether they showed improvement.

At 15 months, nearly half of the participants in both groups (46.7 percent in the tai chi group; 43.7 percent in the behavioral therapy group) continued to show robust, clinically significant improvement in their insomnia symptoms.

“Breast cancer survivors often don’t just come to physicians with insomnia. They have insomnia, fatigue and depression,” said Irwin, who is also a member of the UCLA Jonsson Comprehensive Cancer Center. “And this intervention, tai chi, impacted all those outcomes in a similar way, with benefits that were as robust as the gold standard treatment for insomnia.”

Many of the tai chi participants continued to practice on their own after the study concluded, reflecting the motivation he’s observed among breast cancer survivor, Irwin said. “They often are seeking health-promoting activities because they recognize that the mindfulness approach, or health-based lifestyle interventions, may actually protect them,” he said.

Effectiveness of yoga in treating major depression evaluated

When treating depression, the goal is to help individuals achieve full recovery and normal functioning. While traditional treatment such as medication or psychotherapy is effective for many patients, some may not fully recover even with these treatments. Researchers sought to determine if the addition of hatha yoga would improve treatment outcomes for these patients. They found that the benefits of yoga were less pronounced early in treatment, but may accumulate over time.

The research, entitled “Adjunctive yoga v. health education for persistent major depression: a randomized controlled trial,” has been published in Psychological Medicine. The research was led by Lisa Uebelacker, PhD, a research psychologist in the Psychosocial Research Department at Butler Hospital, a Care New England hospital, and an associate professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University. The team also included Gary Epstein-Lubow, MD; Ana M. Abrantes, PhD; Audrey Tyrka, MD, PhD; Brandon A. Gaudiano, PhD; and Ivan W. Miller III, PhD, of Butler Hospital and the Warren Alpert Medical School; Geoffrey Tremont, PhD and Tanya Tran of Rhode Island Hospital and the Warren Alpert Medical School; Tom Gillette of Eyes of the World Yoga; and David Strong of the University of California, San Diego.

“The purpose of this study was to examine whether hatha yoga is effective for treating depression when used in addition to antidepressant medication,” explained Dr. Uebelacker. “We did not see statistically significant differences between hatha yoga and a control group (health education) at 10 weeks, however, when we examined outcomes over a period of time including the three and six months after yoga classes ended, we found yoga was superior to health education in alleviating depression symptoms.”

According to Dr. Uebelacker, this is the largest study of yoga for depression to date. The team enrolled individuals with current or recent major depression who were receiving antidepressant medication and continued to have clinically significant depression symptoms. Participants were randomized into two groups — those who participated in a hatha yoga class and a control group who took part in a health education class. The intervention phase lasted 10 weeks and participants were followed for six months afterward.

“We hypothesized that yoga participants would show lower depression severity over time as assessed by the Quick Inventory of Depression Symptomatology (QIDS), as well as better social and role functioning, better general health perceptions and physical functioning, and less physical pain relative to the control group,” said Dr. Uebelacker. “We found that yoga did indeed have an impact on depression symptoms.”

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Ordinary sounding expressions of teen angst may signal early depression

While it’s estimated at least one in 10 teens in the U.S. suffer from depression at some point, few will use the word “depressed” to describe negative emotions hanging over them. Instead, new research at the 2017 Pediatric Academic Societies Meeting in San Francisco suggests, they’re likely to use terms such as “stressed,” or “down,” and other words that may sound like ordinary teen angst but could be a signal of more serious, pre-depressive symptoms.

Researchers will present the abstract, “Understanding teen expression of sadness in primary care: A qualitative exploration” on Sunday, May 7, at the Moscone West Convention Center. For the study, they analyzed a sample of screening interviews with 369 teens ages 13 and 18 at risk for depression who participated in the Promoting Adolescent Health Study (PATH), a large, randomized control trial funded by the National Institutes of Mental Health.

“Much of what a teen is feeling and experiencing is easy to attribute to the ups and downs of teen angst,” said abstract co-author Daniela DeFrino, PhD, RN, an assistant professor of research in the University of Illinois at Chicago College of Medicine and College of Nursing. “But, sometimes, there is so much more under the surface that can lead to depression,” she said.

For the PATH study, adolescents who reported feeling down irritable or hopeless during the past two weeks in private, written responses to two brief screening questions received a call from the study team. During the call, researchers used validated measures to screen for those at risk for depression.

“Teens rarely stated they were depressed, but described bursts of feeling stressed and sad that often came and went,” DeFrino said. For example, a teen might say, “I always find somehow to go back to stressful mode,” DeFrino said, or, “I get really mad at people very easily. They don’t understand why I’m upset. Sometimes I don’t either.”

Other common symptoms the teens in the study reported:

  • Increased anger and irritability toward others.
  • Loss of interest in activities they previously enjoyed.
  • Marked difficulty falling and staying asleep, as well as sleeping too much.

Recruited from the Chicago and Boston areas, PATH study participants were 68 percent female, 21 percent Hispanic, 26 percent African-American and 43 percent white. More than half of the teens’ mothers and fathers (60 percent and 54 percent, respectively) were college graduates.

DeFrino said the teens often noted school pressure related to homework and expectations to succeed as sources of stress and difficulty. Arguments with parents, verbal and emotional abuse, divorce, separation, neglect, sexual abuse and home relocation were among major reasons cited for worsening mood. Teens also often attributed new feelings of sadness to deaths from illness and suicides of family members or friends.

The researchers also noted that, unrelated to expressed feelings of depression, two-thirds of the teens had visited their primary healthcare providers for physical illnesses such as ulcers, migraines, stomach pains and fatigue. These visits could offer an opportunity for a health care provider to identify feelings and check in with mental health concerns as well, DeFrino said.

“Teens may be experiencing a lot of internal turmoil and difficult life stresses that we can easily overlook if we don’t probe with sensitive questioning and understanding,” DeFrino said. “Reframing these feelings as outward symptoms of pre-depression by the primary care provider would allow for connection to and discussion about the importance of mental health with the teen and parent.”

Dr. DeFrino will present the abstract, “Understanding teen expression of sadness in primary care: A qualitative exploration,” at the Mental Health/Substance Use poster session from 4:15 p.m. to 7:30 p.m.

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Neurons faulty wiring leads to serotonin imbalance, depression-like behavior in mice

Columbia scientists have identified a gene that allows neurons that release serotonin — a neurotransmitter that regulates mood and emotions — to evenly spread their branches throughout the brain. Without this gene, these neuronal branches become entangled, leading to haphazard distribution of serotonin, and signs of depression in mice. These observations shed light on how precise neuronal wiring is critical to overall brain health, while also revealing a promising new area of focus for studying psychiatric disorders associated with serotonin imbalance — such as depression, bipolar disorder, schizophrenia and autism.

The findings were published in Science.

“By pinpointing the genes that guide the organization of neurons, we can draw a line between changes to those genes, and the cellular, circuitry and behavioral deficiencies that can occur as a result,” said Tom Maniatis, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, the Isidore S. Edelman Professor and Chair of department of Biochemistry & Molecular Biophysics at Columbia University Medical Center and the studys’ senior author.

Today’s research is the result of parallel efforts by Dr. Maniatis, his lab and collaborators across Columbia to understand how individual neurons in the brain ‘see’ each other — and how each of their hundreds, or even thousands, of branches wind through the brain without getting tangled up along the way.

To investigate this problem, Dr. Maniatis and his team focused on a group of genes called clustered protocadherins, or Pcdhs. More than a decade ago, Dr. Maniatis’ lab discovered the human Pcdh gene cluster, and later studies by Maniatis and others revealed that these genes encode a cell surface “barcode” by which individual neurons can distinguish themselves from other neurons.

Subsequently, collaborative studies with fellow Zuckerman Institute structural biologists Barry Honig, PhD, and Larry Shapiro, PhD, revealed the precise mechanism by which the Pcdh code is assembled at the cell surface, and how this code is “read” when neurons come in contact with each other. This allows neurons to prevent entanglements by recognizing — and steering clear of — their own branches, a process known as self-avoidance.

In the two papers published in Science, Dr. Maniatis and his team examined the function of Pcdhs in the wiring of olfactory sensory neurons (which impart a sense of smell), and serotonergic neurons (which produce and release serotonin). The olfactory sensory neuron (OSN) study revealed that the diversity of Pcdhs, working together, produced the necessary combinations of cell-coating molecules to provide each neuron its unique identity. In the absence of diversity, OSNs fail to wire properly in the brain, and the mice fail to distinguish between different odors.

The serotonergic neuron study revealed another important function of Pcdhs.

“The main job of these neurons is to distribute serotonin uniformly throughout the brain, which is responsible for maintaining mood balance,” said Dr. Maniatis, who is also director of Columbia’s Precision Medicine Initiative. “To do this, the neurons lay their branches out in a precise, evenly-spaced pattern — a process called axonal tiling. However, the exact mechanism that allows them to do this remained elusive.”

In a series of experiments in mice, Dr. Maniatis’ team pinpointed a single gene within the Pcdh cluster, called Pcdh-alpha-c2, that was responsible for the ability of serotonergic neurons to assemble into a tiled pattern throughout the brain, and thus evenly distribute serotonin.

“We were surprised to find that, unlike other neurons that displays distinct barcodes of diverse Pcdhs, all serotonergic neurons display a single functional recognition protein,” said Dr. Maniatis. “Thus, serotonergic axonal branches can recognize and repel one another, leading to their even spacing.”

“We found that deleting the Pcdh-alpha-c2 caused serotonergic neuron branches to become tangled and clumped together,” Dr. Maniatis continued. “Serotonin was released, but it wasn’t distributed evenly throughout the brain.”

Silencing Pcdh-alpha-c2 also resulted in striking behavioral changes. Compared to normal, healthy mice, Pcdh-alpha-c2-deficient mice showed behavioral despair (reduced desire to escape) and enhanced fear memory (increased freezing when frightened) — both classic signs indicative of depression.

“Serotonin imbalance has long been linked to a variety of psychiatric disorders, including depression, bipolar disorder and schizophrenia, but most studies focus on problems with the production or uptake of serotonin, not on problems with the brain’s wiring itself,” said Dr. Maniatis. “Wiring anomalies are clearly a new place to look.”

Today’s results may also inform studies of autism. After an exhaustive genetic analysis of autistic individuals and their families by an international consortium of investigators, several hundred genes have been identified that are associated with the disorder, as documented by the Simons Foundation Autism Research Initiative (SFARI) human gene module. Among these genes is the Pcdh gene cluster — including Pcdh-alpha-c2.

“For this pair of studies published today, we focused on two types of neurons that are well understood and have been deeply explored, but this is only the starting point,” said Dr. Maniatis. “If we are to truly understand how the brain is wired both in health and in disease, then the rest of the brain is where we have to go next.”

Gender differences in depression appear at age 12

An analysis just published online has broken new ground by finding gender differences in both symptoms and diagnoses of depression appearing at age 12.

The analysis, based on existing studies that looked at more than 3.5 million people in more than 90 countries, confirmed that depression affects far more females than males.

The study, published by the journal Psychological Bulletin, should convince doubters that depression largely, but not entirely, affects females, says co-author Janet Hyde, a professor of psychology and gender and women’s studies at the University of Wisconsin-Madison.

“We found that twice as many women as men were affected. Although this has been known for a couple of decades, it was based on evidence far less compelling than what we used in this meta-analysis. We want to stress that although twice as many women are affected, we don’t want to stereotype this as a women’s disorder. One-third of those affected are men.”

The gender gap was evident in the earliest data studied by co-authors Hyde; Rachel Salk, now a postdoctoral fellow in psychiatry at the University of Pittsburgh School of Medicine; and Lyn Abramson, a professor of psychology at UW-Madison. “The gap was already present at age 12, which is earlier than previous studies have found,” says Hyde. We used to think that the gender difference emerged at 13 to 15 years but the better data we examined has pushed that down to age 12.”

The gender difference tapers off somewhat after adolescence, “which has never been identified, but the depression rate is still close to twice as high for women,” Hyde says.

Puberty, which occurs around age 12 in girls, could explain the onset, Hyde says. “Hormonal changes may have something to do with it, but it’s also true that the social environment changes for girls at that age. As they develop in puberty, they face more sexual harassment, but we can’t tell which of these might be responsible.”

Although the data did not cover people younger than 12, “there are processes going on at 11 or 12 that are worth thinking about, and that matters in terms of intervening,” Hyde says. “We need to start before age 12 if we want to prevent girls from sliding into depression. Depression is often quite treatable. People don’t have to suffer and face increased risk for the many related health problems.”

The results described averages across the nations covered in the study, Hyde says, but similar results emerged from the studies focusing on the United States.

The UW-Madison researchers looked at both diagnoses of major depression, and at symptom measure of depression, Hyde says. “Symptoms are based on self-reported measures — for example, ‘I feel blue most of the time’ — that do not necessarily meet the standard for a diagnosis of major depression. To meet the criteria for major depression, the condition must be evaluated much more rigorously.”

The researchers looked at the relationship between depression and gender equity in income. Surprisingly, nations with greater gender equity had larger gender differences — meaning women were disproportionately diagnosed with major depression. “This was something of the opposite of what was expected,” says Hyde. “It may occur because, in more gender-equitable nations, women have more contact with men, and therefore compare themselves to men, who don’t express feelings of depression because it doesn’t fit with the masculine role.”

Curiously, no relationship in either direction appeared for depression symptoms.

Despite the prevalence of and growing concern about depression, “this was the first meta-analysis on gender differences in depression,” Hyde says. “For a long while, I wondered why nobody had done this, but once I got into it, I realized it’s because there is too much data, and nobody had the courage to plow through it all. We did, and it took two years.”

 

Antidepressant may enhance drug delivery to the brain

NIH rat study suggests amitriptyline temporarily inhibits the blood-brain barrier, allowing drugs to enter the brain.

New research from the National Institutes of Health found that pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, enhances drug delivery to the brain by inhibiting the blood-brain barrier in rats. The blood-brain barrier serves as a natural, protective boundary, preventing most drugs from entering the brain. The research, performed in rats, appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.

Although researchers caution that more studies are needed to determine whether people will benefit from the discovery, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others. The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.

According to Ronald Cannon, Ph.D., staff scientist at NIH’s National Institute of Environmental Health Sciences (NIEHS), the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body’s circulation before they pass into the brain.

To get an idea of how P-glycoprotein works, Cannon said to think of the protein as a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would get turned away, being ushered back around the revolving door and out into the street.

“For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain,” Cannon said. “They don’t get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics.”

Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein’s pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS. In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.

NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline’s action on P-glycoprotein as rapid and reversible. It’s these advantages that make the therapy so appealing.

“Most inventions developed at the bench don’t make it to the clinic, but I’m hopeful that our findings will translate into better treatment options for doctors and their patients,” Banks said.

Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.

“As our nation faces increases in Alzheimer’s disease, autism, and opioid abuse, we’re hopeful that this discovery will help address these serious health challenges,” said NIEHS Director Linda Birnbaum, Ph.D.

 

Chemotherapy drug may increase vulnerability to depression

A chemotherapy drug used to treat brain cancer may increase vulnerability to depression by stopping new brain cells from growing, according to a new King’s College London study out today in Translational Psychiatry.

Depression is thought to be the least recognised symptom in people with cancer. It has previously been difficult to determine if some people with cancer develop depression as a result of chemotherapy or the stress of having cancer itself.

Although an early animal study, these findings are the first to suggest that chemotherapy causes behavioural and biological brain changes related to depression that are separate from the psychological distress resulting from a cancer diagnosis.

Recent research has shown that depression is most common in cancer patients who have brain cancer. Studies show that around 30 per cent of patients with brain cancer experience depression and the disorder is thought to be highly under-diagnosed. For example, one recent study pointed out that 90 per cent of patients self-reported symptoms of depression, whereas only 20 per cent were classified as having clinical depression.

Most cancer patients are treated with chemotherapy as a lifesaving intervention that stops all cells in the body from dividing. The primary outcome of this treatment is to kill rapidly dividing cancer cells, but disrupting this process can have potential side effects related to cell division, such as hair loss. Researchers now know from animal studies that chemotherapy may similarly stop the growth of new brain cells (neurogenesis).

In their new study, scientists from King’s College London set out to examine whether the effects of chemotherapy on neurogenesis could alter biological brain mechanisms which increase vulnerability for depression.

They administered a chemotherapy drug to mice called Temozolomide (TMZ), using the same procedure that human patients would experience in a clinic. Mice receiving the chemotherapy drug showed a significant reduction in growth of new brain cells in the hippocampus — a region associated with emotion and memory. Results from the study show that the more the drug decreased neurogenesis, the greater the increase in stress hormones when exposed to stress.

When researchers looked at the mice’s behaviour following treatment, they observed several changes related to depression, including robust deficits in novelty processing and a decrease in preference for a rewarding sugar solution. A lack of pleasure seeking, as observed in mice that received the chemotherapy drug, is a core diagnostic symptom of depression.

Dr Martin Egeland, first author of the study, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘Although these preliminary findings are based on mice, our results suggest that chemotherapy may stunt the growth of new brain cells, which has biological and behavioural consequences that may leave people less able to cope with the stress of having cancer.

‘Despite the potential side effects, chemotherapy is essential for increasing survival rates in cancer patients. However, understanding the specific effects of chemotherapy on mood could lead to improved treatments and increase quality of life for those affected by cancer.’

Dr Sandrine Thuret, senior author of the study also from the IoPPN at King’s College London, said: ‘Our study highlights the importance of protecting brain stem cells or building up a reserve of cells before cancer treatment. This could help to preserve the mood and cognitive functions these cells are known to regulate, and could also improve quality of life for people with cancer.

‘We now need to explore whether neurogenesis enhancing interventions or drugs, such as antidepressants, can alleviate this deficit in new brain cells after chemotherapy takes place.’

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Materials provided by King’s College London. Note: Content may be edited for style and length.

Novel mode of antidepressant action may help patients unresponsive to SSRIs

Antidepressants treat symptoms of depression by increasing levels of brain signaling molecules (neurotransmitters) such as serotonin, as with the most widely used type of antidepressant, selective serotonin reuptake inhibitors (SSRIs). However, many of the 350 million people worldwide thought to be affected with depression do not respond to SSRI treatment.

Now, researchers in the Department of Neuroscience and Cell Biology at Osaka University have found that an activator of the serotonin type 3 receptor (5HT3R) produces antidepressant effects in mice and increases nerve cell growth in the part of the brain responsible for memory and spatial navigation (the hippocampus). They also showed that it functions using a different mechanism than the commonly used SSRI fluoxetine, and therefore may be suitable for patients with depression who do not respond favorably to current medication.

The team of researchers used mice lacking part of 5HT3R to explore the function of the 5HT3R activator. The activator had antidepressant effects and initiated nerve cell growth in the hippocampus in control mice but not in those lacking part of the receptor.

In contrast, fluoxetine showed similar antidepressant actions and nerve cell growth in both control and knockout mice because it requires the type 1A rather than 5HT3R for its actions.

To explore the 5HT3R activator mode of action, hippocampal nerve cells expressing the receptor were chemically stained to investigate protein expression. The same cells were shown to express both the receptor and the growth factor IGF1.

“Treatment of control mice with the receptor activator led to increases in IGF1 secretion,” study coauthor Shoichi Shimada says. “However, the activator had no effect in mice lacking part of the receptor.” In addition, protein signaling involving IGF1 in the hippocampus was found to be necessary for nerve cell growth that was dependent on 5HT3R.

Fluoxetine must be given to patients for long periods to have any antidepressant effect, but just 3 days of 5HT3R activator treatment produced notable responses in mice.

“IGF1 combined with the activator produced characteristic changes in nerve cell growth that were not seen following fluoxetine administration,” corresponding author Makoto Kondo says. “This may explain why the response times are so different.”

Another difference is that the type 1A and 5HT3R are expressed in different cell types of the hippocampus which adds support to their use of distinct mechanisms of antidepressant action.

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Materials provided by Osaka University. Note: Content may be edited for style and length.

Expressing gratitude makes us healthier: Who wouldn’t be grateful for that?

Expressing gratitude has become trendy; these days, you can easily find a stock of gratitude journals and notebooks at your local stationery store or bookseller, or search for tips on how to express gratitude in your life.

As it turns out, all this expression of gratitude is a good thing for our minds and bodies. In a new article in the National Communication Association’s Review of Communication, authors Stephen M. Yoshimura and Kassandra Berzins explore the connection between gratitude expression and psychological and physical well-being. As one might expect, positivity begets positive results for our well-being.

What the authors write may seem obvious: “Gratitude consistently associates with many positive social, psychological, and health states, such as an increased likelihood of helping others, optimism, exercise, and reduced reports of physical symptoms.” However, the authors argue that not enough research has been done on the communication of gratitude and its effect on well-being, and they propose further avenues for analysis of gratitude messages and their impact.

Expressions of gratitude are often a response to others’ acts of generosity — if you receive a gift from someone, or an act of kindness, you reciprocate by showing gratitude, sometimes publicly, to highlight the giver’s altruistic act. Gratitude is a different emotion from happiness because it so often stems from the actions of another individual. “To experience it, one must receive a message, and interpret the message,” the authors write.

Numerous studies show that expressing and experiencing gratitude increases life satisfaction, vitality, hope, and optimism. Moreover, it contributes to decreased levels of depression, anxiety, envy, and job-related stress and burnout. Perhaps most intriguing is that people who experience and express gratitude have reported fewer symptoms of physical illness, more exercise, and better quality of sleep. Who wouldn’t be grateful for that?

While the immediate effects of gratitude expression are clear, the authors argue that it also contributes to long-term success in relationships and personal well-being — “up to six months after a deliberate expression to one’s relationship’s partner.” Just as we periodically boost our immune systems through vaccines, we can boost our relationships and mental state by expressing gratitude to our partners on a regular basis. The authors leave us with a general health practice: Why not regularly communicate gratitude to enhance our social connectedness?

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Materials provided by National Communication Association. Note: Content may be edited for style and length.

Using Instagram can increase adolescents’ closeness to friends

Your food, your vacation, your carefully curated life — all posted for your friends in a filtered image. Some may scoff at adolescents’ use of social media networks as they pine for likes. Is this just frivolous behavior? Or are they really just solidifying their social connections to friends? A recent study by a researcher at the University of Leuven found that adolescents’ use of Instagram actually strengthened the closeness of their friendships.

Eline Frison (University of Leuven) will present her findings at the 67th Annual Conference of the International Communication Association in San Diego, CA. From 2013-2014, Frison set up a large-scale longitudinal panel study to investigate the relationships between Flemish adolescents’ social networking site use and their well-being. Students filled out paper-and-pencil surveys between 6 month periods. The surveys asked students about their use of social networking sites like Facebook, Snapchat, and Instagram, and their well-being (depressive symptoms, life satisfaction, loneliness).

The data analyzed revealed that frequent use of Instagram at one point was related to greater depression six months later. However, using Instagram at one point was also related to increased closeness to friends (perception that they are appreciated and loved by their friends) six months later, which in turn was related to lower levels of depression.

Various researchers have investigated the impact of using Facebook on young people’s well-being, and some have examined the impact of Instagram on individuals’ mental health. This study is the first to investigate the longitudinal relationship between Instagram use and well-being in an adolescent sample, and the first to examine the role of adolescents’ closeness to friends in this relationship.

“This age group may be particularly at risk for the impact of Instagram, given the increasing popularity of Instagram in adolescence and given the increase of depressive symptoms during this stage of life,” said Frison. “This study offers practitioners greater insight into the outcomes of adolescents’ Instagram use. More specifically, using Instagram can be both beneficial and harmful for adolescents’ well-being. If using Instagram stimulates adolescents’ closeness to friends, it is beneficial in the long run, but if Instagram is not capable of that stimulation, it is harmful in the long run.”

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Materials provided by International Communication Association. Note: Content may be edited for style and length.