Breakthrough in Making Much Less Addictive Opioids

Important research this is, for it shows that the powerful pain relief opioids provide doesn’t have to be such a dangerous double-edged sword.

In the US, more than one-third of the population experiences some form of acute or chronic pain; in older adults this number rises to 40 percent.

The most common condition linked to chronic pain is chronic depression, which is a major cause of suicide.

To relieve severe pain, people go to their physician for powerful prescription painkillers, opioid drugs such as morphine, oxycodone and hydrocodone.

Almost all the currently marketed opioid drugs exert their analgesic effects through a protein called the “mu opioid receptor” (MOR).

MORs are embedded in the surface membrane of brain cells, or neurons, and block pain signals when activated by a drug.

However, many of the current opioids stimulate portions of the brain that lead to additional sensations of “rewarding” pleasure, or disrupt certain physiological activities. The former may lead to addiction, or the latter, death.

Which part of the brain is activated plays a vital role in controlling pain. For example, MORs are also present in the brain stem, a region that controls breathing.

Activating these mu receptors not only dulls pain but also slows breathing. Large doses stop breathing, causing death.

Activating MORs in other parts of the brain, including the ventral tegmental area and the nucleus accumbens, block pain and trigger pleasure or reward, which makes them addictive. But so far there is no efficient way to turn these receptors “on” and “off” in specific areas.

But there is another approach because not all opioids are created equal. Some, such as morphine, bind to the receptor and activate two signaling pathways: one mediating pain cessation and the other producing side effects like respiratory depression.

Other drugs favor one pathway more than the other, like only blocking pain – this is the one we want.

“Biased opioids” to kill pain

But MOR isn’t the only opioid receptor. There are two other closely related proteins called kappa and delta, or KOR and DOR respectively, that also alter pain perception but in slightly different ways.

Yet, currently there are only a few opioid medications that target KOR, and none that target DOR. One reason is that the function of these receptors in the brain neurons remains unclear.

Recently KOR has been getting attention as extensive studies from different academic labs show that it blocks pain without triggering euphoria, which means it isn’t addictive.

Another benefit is that it doesn’t slow respiration, which means that it isn’t lethal. But although it isn’t as dangerous as MOR, activating KOR does promote dysphoria, or unease, and sleepiness.

This work suggests it is possible to design a drug that only targets the pain pathway, without side effects. These kind of drugs are called “biased” opioids.

[…]

The exciting news is that researchers in the Roth lab have discovered several promising compounds based on the KOR structure that selectively binds and activates KOR, without cavorting with the more than 330 other related protein receptors.

Now our challenge is to transform these molecules into safer drugs.

Research: Depressive Episodes Can Damage Memory

The extent of the damage depends on the severity and length of the depressive episodes. This new research gives a concrete example of why it is important to improve mental health outcomes — it turns out that depression can have directly negative effects on the brain, and there are plenty of implications for human society based on that.

During a depressive episode the ability of the brain to form new brain cells is reduced. Scientists of the Ruhr-Universität Bochum examined how this affects the memory with a computational model. It was previously known that people in an acute depressive episode were less likely to remember current events. The computational model however suggests that older memories were affected as well. How long the memory deficits reach back depends on how long the depressive episode lasts. The team around the computational neuroscientist Prof Dr Sen Cheng published their findings in the journal PLOS ONE on 7th June 2018.

Computational model simulates a depressive brain

In major depressive disorder patients may suffer from such severe cognitive impairments that, in some cases, are called pseudodementia. Unlike in the classic form of dementia, in pseudodementia memory recovers when the depressive episode ends. To understand this process, the scientists from Bochum developed a computational model that captures the characteristic features of the brain of a patient with depressions. They tested the ability of the model to store and recall new memories.

As is the case in patients, the simulation alternated between depressive episodes and episodes without any symptoms. During a depressive episode, the brain forms fewer new neurons in the model.

Whereas in previous models, memories were represented as static patterns of neural activity, the model developed by Sen Cheng and his colleagues views memories as a sequence of neural activity patterns. “This allows us not only to store events in memory but also their temporal order,” says Sen Cheng.

Impact on brain stronger than thought

The computational model was able to recall memories more accurately, if the responsible brain region was able to form many new neurons, just like the scientists expected. However, if the brain region formed fewer new brain cells, it was harder to distinguish similar memories and to recall them separately.

The computational model not only showed deficits in recalling current events, it also struggled with memories that were collected before the depressive episode. The longer the depressive episode lasted the further the memory problems reached back.

“So far it was assumed that memory deficits only occur during a depressive episode,” says Sen Cheng. “If our model is right, major depressive disorder could have consequences that are more far reaching. Once remote memories have been damaged, they do not recover, even after the depression has subsided.”

Article Examining Depression

The article mentions standards such as medication and counseling, but perhaps the best way to reduce high depressive rates in the population is to restructure society to make it much better for most people than it is currently.

Clinical depression has surged to epidemic proportions in recent decades, from little-mentioned misery at the margins of society to a phenomenon that is rarely far from the news. It is widespread in classrooms and boardrooms, refugee camps and inner cities, farms and suburbs.

At any one time it is estimated that more than 300 million people have depression – about 4% of the world’s population when the figures were published by the World Health Organization (WHO) in 2015. Women are more likely to be depressed than men.

Depression is the leading global disability, and unipolar (as opposed to bipolar) depression is the 10th leading cause of early death, it calculates. The link between suicide, the second leading cause of death for young people aged 15-29, and depression is clear, and around the world two people kill themselves every minute.

While rates for depression and other common mental health conditions vary considerably, the US is the “most depressed” country in the world, followed closely by Colombia, Ukraine, the Netherlands and France. At the other end of the scale are Japan, Nigeria and China.

[…]

Things have improved since people with mental illness were believed to be possessed by the devil and cast out of their communities, or hanged as witches. But there remains a widespread misunderstanding of the illness, particularly the persistent trope that people with depression should just “buck up”, or “get out more”.

[…]

The WHO estimates that fewer than half of people with depression are receiving treatment. Many more will be getting inadequate help, often focused on medication, with too little investment in talking therapies, which are regarded as a crucial ally.

[…]

There have been positive experiments with both ketamine and psilocybin, the active ingredient in magic mushrooms. Further hopes for a new generation of treatments have been raised by recent discoveries of 44 gene variants that scientists believe raise the risk of depression. Another controversial area of research is treatment for low immunity and mooted links between depression and inflammation.

Countries are increasingly recognising the need to train more psychologists to replace or complement drug treatments.

And perhaps most importantly, there is a cultural movement to make it easier for people to ask for help and speak out about their illness.

Link Between Depression and Increased Brain Aging in Older Adults Found

The new research shows another reason to take mental health problems seriously. Suboptimal cognitive function in older adults both decreases general welfare and leads to worse outcomes via less informed decisions in political democracy.

Psychologists at the University of Sussex have found a link between depression and an acceleration of the rate at which the brain ages. Although scientists have previously reported that people with depression or anxiety have an increased risk of dementia in later life, this is the first study that provides comprehensive evidence for the effect of depression on decline in overall cognitive function (also referred to as cognitive state), in a general population.

For the study, published today, Thursday 24 May 2018, in the journal Psychological Medicine, researchers conducted a robust systematic review of 34 longitudinal studies, with the focus on the link between depression or anxiety and decline in cognitive function over time. Evidence from more than 71,000 participants was combined and reviewed. Including people who presented with symptoms of depression as well as those that were diagnosed as clinically depressed, the study looked at the rate of decline of overall cognitive state — encompassing memory loss, executive function (such as decision making) and information processing speed — in older adults.

Importantly, any studies of participants who were diagnosed with dementia at the start of study were excluded from the analysis. This was done in order to assess more broadly the impact of depression on cognitive ageing in the general population. The study found that people with depression experienced a greater decline in cognitive state in older adulthood than those without depression. As there is a long pre-clinical period of several decades before dementia may be diagnosed, the findings are important for early interventions as currently there is no cure for the disease.

Lead authors of the paper, Dr Darya Gaysina and Amber John from the EDGE (Environment, Development, Genetics and Epigenetics in Psychology and Psychiatry) Lab at the University of Sussex, are calling for greater awareness of the importance of supporting mental health to protect brain health in later life.

Dr Gaysina, a Lecturer in Psychology and EDGE Lab Lead, comments: “This study is of great importance — our populations are ageing at a rapid rate and the number of people living with decreasing cognitive abilities and dementia is expected to grow substantially over the next thirty years.

“Our findings should give the government even more reason to take mental health issues seriously and to ensure that health provisions are properly resourced. We need to protect the mental wellbeing of our older adults and to provide robust support services to those experiencing depression and anxiety in order to safeguard brain function in later life.”

44 Genomic Variations Linked to Major Depression in New Research

Genetic variations (variants) are the roughly 0.5% share of DNA that makes individuals unique, as about 99% of human DNA is shared across humans. The word genome represents the entire set of genetic material someone’s made of. With that being said, this research is important because major depressive disorder can be a really crippling affliction, and the more that’s known about it, the more effectively it can be treated or prevented.

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A new meta-analysis of more than 135,000 people with major depression and more than 344,000 controls has identified 44 genomic variants, or loci, that have a statistically significant association with depression.

Of these 44 loci, 30 are newly discovered while 14 had been identified in previous studies. In addition, the study identified 153 significant genes, and found that major depression shared six loci that are also associated with schizophrenia.

Results from the multinational, genome-wide association study were published April 26 in Nature Genetics.

The study was an unprecedented global effort by over 200 scientists who work with the Psychiatric Genomics Consortium. Co-leaders of the study are Patrick F. Sullivan, MD, FRANZCP, Yeargen Distinguished Professor of Psychiatry and Genetics and Director of the Center for Psychiatric Genomics at the University of North Carolina School of Medicine; and Naomi Wray, PhD, Professorial Research Fellow at the University of Queensland in Australia.

“This study is a game-changer,” Sullivan said. “Figuring out the genetic basis of major depression has been really hard. A huge number of researchers across the world collaborated to make this paper, and we now have a deeper look than ever before into the basis of this awful and impairing human malady. With more work, we should be able to develop tools important for treatment and even prevention of major depression.”

“We show that we all carry genetic variants for depression, but those with a higher burden are more susceptible,” Wray said. “We know that many life experiences also contribute to risk of depression, but identifying the genetic factors opens new doors for research into the biological drivers.”

“This pioneering study is incredibly important, for two reasons,” said Josh Gordon, MD, PHD, Director of the U.S. National Institute of Mental Health. Dr. Gordon was not an author on this paper.

“First, it reaffirms the value of large-scale collaborations, particularly in identifying the complex genetics underlying psychiatric illness. Second, it confirms the genetic roots for depression, offering important biological clues that we hope will lead to new and better treatments.”

“Major depression represents one of the world’s most serious public health problems,” said Steven E. Hyman, MD, former director of the U.S. National Institute of Mental Health who is now Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Dr. Hyman was not an author on this paper. “Despite decades of effort there have been, until now, only scant insights into its biological mechanisms. This unfortunate state of affairs has severely impeded treatment development, leaving the many people who suffer from depression with limited options. This landmark study represents a major step toward elucidating the biological underpinnings of depression,” Hyman said.

Other findings of the study include:

  • The results can be used for improved therapies — targets of known antidepressant medications were enriched in the genetic findings
  • The genetic basis of depression overlaps importantly with other psychiatric disorders like bipolar disorder and schizophrenia
  • Intriguingly, the genetic basis of depressive disorder also overlaps with that for obesity and multiple measures of sleep quality, including daytime sleepiness, insomnia and tiredness

Ketamine Nasal Spray Shows Effectiveness at Treating Major Depression and Suicidal Thoughts

There’s definitely something to be said about ketamine’s apparent effectiveness at immediately making many suicidal people no longer want to end their lives. The importance of caution in using it should be noted though.

A nasal spray formulation of ketamine shows promise in the rapid treatment of symptoms of major depression and suicidal thoughts, according to a new study published online today in The American Journal of Psychiatry (AJP).

The double-blind study compared the standard treatment plus an intranasal formulation of esketamine, part of the ketamine molecule, to standard treatment plus a placebo for rapid treatment of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. The study involved 68 participants randomly assigned to one of two groups — either receiving esketamine or placebo twice a week for four weeks. All participants continued to receive treatment with antidepressants throughout. The researchers looked at effects at four hours after first treatment, at 24 hours and at 25 days.

[…]

The results of the study support nasal spray esketamine as a possible effective rapid treatment for depressive symptoms in patients assessed to be at imminent risk for suicide, according to the authors. Esketamine could be an important treatment to bridge the gap that exists because of the delayed effect of most common antidepressants. Most antidepressants take four to six weeks to become fully effective.

This study was a proof-of-concept, phase 2, study for esketamine; it must still go through a phase 3 study before possible FDA approval. It was funded by Janssen Research and Development, LLC.

The authors caution that more research is needed on the potential for abuse of ketamine. That caution is also the focus of an accompanying AJP editorial also published online today. In the editorial, AJP Editor Robert Freedman, M.D., along with members of the AJP Editorial Board, note the known potential for abuse and existing reports of abuse of prescribed ketamine. They discuss the need for additional research relating to the abuse potential of ketamine during phase 3 trials, such as monitoring of patients’ craving and potential ketamine use from other sources.

While it is the responsibility of physicians to provide a suicidal patient with the fullest range of effective interventions, the AJP Editor’s note, “protection of the public’s health is part of our responsibility as well, and as physicians, we are responsible for preventing new drug epidemics.” The Editors suggest the need for broad input in the development of effective controls on the distribution and use of ketamine.

Raw Fruits and Vegetables May Provide Better Mental Health Outcomes

Mental health problems are a really significant undercurrent issue in countries across the world today, and so even more minor studies like this can be helpful at addressing them.

Seeking the feel good factor? Go natural.

That is the simple message from University of Otago researchers who have discovered raw fruit and vegetables may be better for your mental health than cooked, canned and processed fruit and vegetables.

Dr Tamlin Conner, Psychology Senior Lecturer and lead author, says public health campaigns have historically focused on aspects of quantity for the consumption of fruit and vegetables (such as 5+ a day).

However, the study, just published in Frontiers in Psychology, found that for mental health in particular, it may also be important to consider the way in which produce was prepared and consumed.

“Our research has highlighted that the consumption of fruit and vegetables in their ‘unmodified’ state is more strongly associated with better mental health compared to cooked/canned/processed fruit and vegetables,” she says.

Dr Conner believes this could be because the cooking and processing of fruit and vegetables has the potential to diminish nutrient levels.

“This likely limits the delivery of nutrients that are essential for optimal emotional functioning.”

For the study, more than 400 young adults from New Zealand and the United States aged 18 to 25 were surveyed. This age group was chosen as young adults typically have the lowest fruit and vegetable consumption of all age groups and are at high risk for mental health disorders.

The group’s typical consumption of raw versus cooked and processed fruits and vegetables were assessed, alongside their negative and positive mental health, and lifestyle and demographic variables that could affect the association between fruit and vegetable intake and mental health (such as exercise, sleep, unhealthy diet, chronic health conditions, socioeconomic status, ethnicity, and gender).

“Controlling for the covariates, raw fruit and vegetable consumption predicted lower levels of mental illness symptomology, such as depression, and improved levels of psychological wellbeing including positive mood, life satisfaction and flourishing. These mental health benefits were significantly reduced for cooked, canned, and processed fruits and vegetables.

“This research is increasingly vital as lifestyle approaches such as dietary change may provide an accessible, safe, and adjuvant approach to improving mental health,” Dr Conner says.

* The top 10 raw foods related to better mental health were: carrots, bananas, apples, dark leafy greens such as spinach, grapefruit, lettuce, citrus fruits, fresh berries, cucumber, and kiwifruit.