Via coronavirus genome, tracing its origins, looking for dangerous mutations

As infectious disease specialists and epidemiologists race to contain the outbreak of the novel coronavirus centered on Wuhan, China, they’re getting backup that’s been possible only since the explosion in genetic technologies: a deep-dive into the DNA of the virus known as 2019-nCoV.
Analyses of the viral genome are already providing clues to the origins of the outbreak and even possible ways to treat the infection, a need that is becoming more urgent by the day: Early on Saturday in China, health officials reported 15 new fatalities in a single day, bringing the death toll to 41. There are now nearly 1,100 confirmed cases there.
Reading the DNA also allows researchers to monitor how 2019-nCoV is changing and provides a roadmap for developing a diagnostic test and a vaccine.

“The genetics can tell us the true timing of the first cases” and whether they occurred earlier than officials realized, said molecular biologist Kristian Andersen of Scripps Research, an expert on viral genomes. “It can also tell us how the outbreak started — from a single event of a virus jumping from an infected animal to a person or from a lot of animals being infected. And the genetics can tell us what’s sustaining the outbreak — new introductions from animals or human-to-human transmission.”
Scientists in China sequenced the virus’s genome and made it available on Jan. 10, just a month after the Dec. 8 report of the first case of pneumonia from an unknown virus in Wuhan. In contrast, after the SARS outbreak began in late 2002, it took scientists much longer to sequence that coronavirus. It peaked in February 2003 — and the complete genome of 29,727 nucleotides wasn’t sequenced until that April.

Since the sequencing of the first 2019-nCoV sample, from an early patient, scientists have completed nearly two dozen more, said Andrew Rambaut of the University of Edinburgh, an expert on viral evolution. That pace is “unprecedented and completely unbelievable,” said Andersen, who worked on sequencing the Ebola genome during the 2014 outbreak. “It’s just insane.”
The genome of the Wuhan virus is 29,903 bases long, one of many clues that have led scientists to believe it is very similar to SARS.
By comparing the two dozen genomes, scientists can address the “when did this start” question. The 24 available samples, including from Thailand and Shenzhen as well as Wuhan, show “very limited genetic variation,” Rambaut concluded on an online discussion forum where virologists have been sharing data and analyses. “This is indicative of a relatively recent common ancestor for all these viruses.”

Given what’s known about the pace at which viral genomes mutate, if nCoV had been circulating in humans since significantly before the first case was reported on Dec. 8, the 24 genomes would differ more. Applying ballpark rates of viral evolution, Rambaut estimates that the Adam (or Eve) virus from which all others are descended first appeared no earlier than Oct. 30, 2019, and no later than Nov. 29.
The progenitor virus itself was almost certainly one that circulates harmlessly in bats (as SARS does) but has an “intermediate reservoir” in one or more animals that come into contact with people, Andersen said. Presumably, that reservoir is one of the species of animals at the Wuhan market thought to be ground zero for the outbreak. The ancestor of 2019-nCoV existed in that species for some unknown time, never infecting people, until by chance a single virus acquired a mutation that made it capable of jumping into and infecting humans.
The genome sequences suggest that was a one-time-only jump. “The genomes [from the 24 samples] are very uniform,” Andersen said. “If there had been multiple introductions,” including from many different animals, “there would be more genomic diversity. This was a single introduction.”
That means that what’s sustaining the spread is human-to-human transmission (suggesting that closing Wuhan’s animal market is very much an after-the-horse-has-fled-the-barn reaction).

Unfortunately, genetic analysis can’t identify what animal species the coronavirus jumped from into humans. But an analysis by a team from the Wuhan Institute of Virology, posted to the preprint server bioRxiv, determined that the genome of this coronavirus (the seventh known to infect humans) is 96% identical to that of a bat coronavirus, suggesting that species is the original source. (Writing in the New England Journal of Medicine on Friday, another team of scientists in China reported that the new coronavirus is 86.9% identical to the bat SARS-like coronavirus.)
Virologists differ on whether it’s possible to read out viral properties from just the genome sequence, such as whether the microbe is spread by coughing, sneezing, touching, or merely breathing. But the analysis by the Wuhan Institute team found that it enters human cells using the same doorway that SARS did. Called angiotensin converting enzyme 2 (ACE2), the door is a receptor to which a “spike protein” on the virus’s surface first attaches and then enables the virus to fuse with the host cell.
If ACE2 is “druggable,” blocking it could conceivably treat 2019-nCoV. “It should be expected and worth to test if ACE2 targeting … drugs can be used for nCoV-2019 patients,” the scientists wrote.
The genome sequences have more to give. They “will be crucially important for development of diagnostics [and] vaccines,” said biologist Richard Ebright of Rutgers University.
For instance, the genome-editing technology CRISPR is the basis for Cambridge, Mass.-based startup Sherlock Biosciences’ diagnostics, which promise to slash how long it takes to make a definitive identification. In the U.S, that’s now done only by sending samples to the Centers for Disease Control and Prevention, which uses a technology invented in the 1980s, polymerase chain reaction or PCR, to identify the presence of coronavirus.
“Our vision is that our [CRISPR-based] SHERLOCK and INSPECTR platforms are tailor-made for outbreaks like coronavirus,” said Sherlock CEO Rahul Dhanda, who declined to discuss “specific plans related to coronavirus.”
And as scientists keep adding 2019-nCoV genome sequences to their collection, they could get an early glimpse of whether the virus is mutating in a way that could make it more dangerous or more transmissible. “You need continuous sequencing,” Andersen said.

DNA sleuths read the coronavirus genome, tracing its origins and looking for dangerous mutations

New virus can infect with no symptoms, sicken otherwise healthy people

Two papers published Friday in the journal the Lancet offer some of the first rigorous analyses of patients who contracted a novel coronavirus that has broken out in China and spread to other countries. Among their discoveries: The virus does not only affect people with other, underlying health conditions, and people who are not showing symptoms can still be carrying the virus.
In one study, researchers analyzed data from the first 41 patients who were admitted to hospitals with confirmed cases of the infection in the central Chinese city of Wuhan, where the outbreak is believed to have originated last month. Two-thirds had been to a large seafood market that also sold wild animals for meat and is thought to be where the virus jumped from an animal source to people. The median age of the patients was 49.
The patients displayed a wide range of symptoms, many of which were similar to those caused by SARS, another coronavirus, which caused a global outbreak in 2002-2003 that started in China. All of them had pneumonia, and most had fever and cough. Some people had fatigue; rarer symptoms included headache and diarrhea. The researchers noted that patients with SARS more frequently had runny noses, sore throats, and diarrhea than those with the novel coronavirus, which is provisionally being called 2019-nCoV.

One key finding: It’s not only people with other health conditions that are getting sick, the researchers reported. Some of the fatal cases caused by the virus have been among people with underlying diseases like diabetes, liver disease, and hypertension, but the majority of the first 41 patients infected with the disease in Wuhan were healthy. The researchers noted that SARS infections similarly did not only affect people with other conditions.

About a third of the 41 patients needed intensive care, and six of them died. Some of the patients with more serious illnesses suffered from a dangerous immune system overreaction called a cytokine storm, but the researchers said they still did not have a good understanding of how the virus affects the immune system.
As of Friday, there were more than 830 cases of the coronavirus infection in China, with 25 deaths, and a handful of cases in places — including Thailand, Japan, South Korea, and the United States — that were in people who traveled to those countries from China.
The second paper focused on one family who came down with pneumonia in Shenzhen. Five family members had recently traveled to Wuhan and had the virus, as did one relative who had not traveled to Wuhan.
So far, authorities have only confirmed human-to-human transmission of the virus among families and in health care clinics — settings where people are likely to be in close contact with each other, according to the World Health Organization. This appears to be the case with the family that was studied. Still, health officials do not know exactly how efficiently the virus can pass among people.
One child with the virus did not show any symptoms. Health authorities have said that people with the virus have shown a range of symptoms, from very mild to very severe. But an asymptomatic infection raises the question of whether people have to be showing signs of the disease to pass it to people, a question that experts are rushing to answer.
“Because asymptomatic infection appears possible, controlling the epidemic will also rely on isolating patients, tracing and quarantining contacts as early as possible, educating the public on both food and personal hygiene, and ensuring health care workers comply with infection control,” Dr. Kwok-Yung Yuen from the University of Hong Kong-Shenzhen Hospital, who led the research, said in a statement.

In a commentary piece also published Friday by the Lancet, Dr. David Heymann, an infectious disease epidemiologist at the London School of Hygiene and Tropical Medicine, wrote that “the picture these two manuscripts paint is of a disease with a 3-6 day incubation period and insidious onset.”
The researchers who wrote the two papers and other experts cautioned that these were small studies with limited numbers of patients in a rapidly evolving outbreak. But they noted that sharing information like this as quickly and rigorously as possible can help shape the response.
“The information in these articles are pieces of the jigsaw puzzle that are being fit together by WHO as it continues to collect official reports and informal information from its virtual groups of national clinicians, epidemiologists, and virologists working at outbreak sites and brought together from around the world,” Heymann wrote. “When pieced together, these emerging data will permit regular refinement of the risk assessment, and real-time guidance to countries for patient management and outbreak control, including the best case definition for use in surveillance around outbreak sites and elsewhere.”

New coronavirus can cause infections with no symptoms and sicken otherwise healthy people, studies show

First clinical studies find Wuhan virus closely resembles SARS

The new coronavirus rapidly spreading in China and nearby countries seems to trigger symptoms similar to those seen in the severe acute respiratory distress syndrome (SARS) coronavirus outbreak in 2003, two new studies show.

Published Jan. 24 in The Lancet journal, these are the first clinical studies conducted on patients struck by the new coronavirus, dubbed 2019-nCoV. As of Friday morning, there were 830 confirmed cases and 26 deaths in China tied to the coronavirus, which originated in the central Chinese city of Wuhan.
Officials at the U.S. Centers for Disease Control and Prevention on Friday also announced a second U.S. case of the virus, in a person in Illinois. The first case occurred in a man in Washington state. Both patients had returned from travel in China, the CDC said, and are being monitored.
The two new studies examine the course of infection in some of the first cases of the Wuhan virus.
In one study, researchers looked at clinical records, laboratory results, imaging findings and epidemiological data on the first 41 infected people admitted to the hospital in Wuhan between Dec. 16, 2019 and Jan. 2, 2020.
Patients were typically middle-aged (average age 49), three-quarters were men, and two-thirds had visited a local seafood market thought to be where the virus originated.
Similar to the 2003 SARS outbreak in China, most patients who came down with the Wuhan coronavirus were healthy, without any chronic underlying health issues. And symptoms also resembled those of SARS, said Chinese researchers led by Bin Cao, from the China-Japan Friendship Hospital and Capital Medical University, both in Beijing.
All of the hospitalized patients had developed pneumonia, nearly all (98%) had a fever, three-quarters developed a cough, 44% felt fatigued, and 55% had some shortness of breath. Symptoms such as headache or diarrhea were rare, however.
On the other hand, “despite sharing some similar symptoms to SARS [such as fever, dry cough, shortness of breath], there are some important differences,” Cao said in a Lancet news release.
For example, people with the new virus typically didn’t have runny noses or other symptoms involving the upper respiratory tract, he said. And very few had intestinal symptoms such as diarrhea, which occurred in about a quarter of SARS patients.
Severe illness—enough to require admittance to the ICU—occurred in about a third of the hospitalized patients, Cao’s team said, and six patients died.
A condition involving immune system dysfunction known as a “cytokine storm” occurred in some of these very ill patients, but it’s not yet clear how the new virus affects the immune system, the researchers said.
As of Jan. 22, a majority of patients in the study (68%) have recovered enough to be discharged from the hospital, the report noted.
In the second study, the first to involve gene analysis, researchers tracked the course of 2019-nCoV in a family of seven people. Five family members had recently traveled to Wuhan and were found to carry 2019-nCoV, and one family member who had not traveled with them also was found to be infected with the virus.
None of the infected family members had visited food markets or animals while in Wuhan, suggesting that person-to-person transmission was at play.
The seventh family member—a child whose mother said had worn a surgical mask during their stay in Wuhan—was not infected with the virus.
As well, a second child was infected but showed no clinical symptoms of the illness, according to researchers led by Dr. Kwok-Yung Yuen, from the University of Hong Kong-Shenzhen Hospital. That suggests that 2019-nCoV could be spread person-to-person by people who don’t even realize they are infected, the researchers said.
“Our findings are consistent with person-to person transmission of this new coronavirus in hospital and family settings, and the reports of infected travelers in other countries,” Yuen said in the release. “Because asymptomatic infection appears possible, controlling the epidemic will also rely on isolating patients, tracing and quarantining contacts as early as possible, educating the public on both food and personal hygiene, and ensuring health care workers comply with infection control.”
Examining the course of illness among the various family members, symptoms appeared to develop within a few days of contact with sick individuals.
Gene tests revealed that five of the family members carried a form of 2019-nCoV that had a type of protein allowing it to enter healthy cells. Yuen’s team was also able to use samples from two patients to map the full genome of 2019-nCoV.
“With the improved surveillance network and laboratory capability developed following the SARS pandemic, China has now been able to recognize this new outbreak within a few weeks and has made the virus genome publicly available to help control its spread,” said study co-author Dr. Rosana Wing-Shan Poon, from the University of Hong Kong.
“Learning the lessons from SARS, which started as animal-to-human transmission, all game meat trading should be better regulated to terminate this potential transmission route,” Poon said. “Further investigations are needed to clarify the potential threat posed by this emerging virus and asymptomatic cases.”

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More information: The U.S. Centers for Disease Control and Prevention has more about coronaviruses.

https://medicalxpress.com/news/2020-01-clinical-wuhan-virus-resembles-sars.html

Can lithium halt progression of Alzheimer’s disease?

There remains a controversy in scientific circles today regarding the value of lithium therapy in treating Alzheimer’s disease. Much of this stems from the fact that because the information gathered to date has been obtained using a multitude of differential approaches, conditions, formulations, timing and dosages of treatment, results are difficult to compare. In addition, continued treatments with high dosage of lithium render a number of serious adverse effects making this approach impracticable for long term treatments especially in the elderly.

In a new study, however, a team of researchers at McGill University led by Dr. Claudio Cuello of the Department of Pharmacology and Therapeutics, has shown that, when given in a formulation that facilitates passage to the brain, lithium in doses up to 400 times lower than what is currently being prescribed for mood disorders is capable of both halting signs of advanced Alzheimer’s pathology such as amyloid plaques and of recovering lost cognitive abilities. The findings are published in the most recent edition of the Journal of Alzheimer’s Disease.
Building on their previous work
“The recruitment of Edward Wilson, a graduate student with a solid background in psychology, made all the difference,” explains Dr. Cuello, the study’s senior author, reflecting on the origins of this work. With Wilson, they first investigated the conventional lithium formulation and applied it initially in rats at a dosage similar to that used in clinical practice for mood disorders. The results of the initial tentative studies with conventional lithium formulations and dosage were disappointing however, as the rats rapidly displayed a number of adverse effects. The research avenue was interrupted but renewed when an encapsulated lithium formulation was identified that was reported to have some beneficial effects in a Huntington disease mouse model.
The new lithium formulation was then applied to a rat transgenic model expressing human mutated proteins causative of Alzheimer’s, an animal model they had created and characterized. This rat develops features of the human Alzheimer’s disease, including a progressive accumulation of amyloid plaques in the brain and concurrent cognitive deficits.
“Microdoses of lithium at concentrations hundreds of times lower than applied in the clinic for mood disorders were administered at early amyloid pathology stages in the Alzheimer’s-like transgenic rat. These results were remarkably positive and were published in 2017 in Translational Psychiatry and they stimulated us to continue working with this approach on a more advanced pathology,” notes Dr. Cuello.
Encouraged by these earlier results, the researchers set out to apply the same lithium formulation at later stages of the disease to their transgenic rat modelling neuropathological aspects of Alzheimer’s disease. This study found that beneficial outcomes in diminishing pathology and improving cognition can also be achieved at more advanced stages, akin to late preclinical stages of the disease, when amyloid plaques are already present in the brain and when cognition starts to decline.
“From a practical point of view our findings show that microdoses of lithium in formulations such as the one we used, which facilitates passage to the brain through the brain-blood barrier while minimizing levels of lithium in the blood, sparing individuals from adverse effects, should find immediate therapeutic applications,” says Dr. Cuello. “While it is unlikely that any medication will revert the irreversible brain damage at the clinical stages of Alzheimer’s it is very likely that a treatment with microdoses of encapsulated lithium should have tangible beneficial effects at early, preclinical stages of the disease.”
Moving forward
Dr. Cuello sees two avenues to build further on these most recent findings. The first involves investigating combination therapies using this lithium formulation in concert with other interesting drug candidates. To that end he is pursuing opportunities working with Dr. Sonia Do Carmo, the Charles E. Frosst-Merck Research Associate in his lab.
He also believes that there is an excellent opportunity to launch initial clinical trials of this formulation with populations with detectable preclinical Alzheimer’s pathology or with populations genetically predisposed to Alzheimer’s, such as adult individuals with Down Syndrome. While many pharmaceutical companies have moved away from these types of trials, Dr. Cuello is hopeful of finding industrial or financial partners to make this happen, and, ultimately, provide a glimmer of hope for an effective treatment for those suffering from Alzheimer’s disease.
“NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats,” by Wilson, Do Carmo, Cuello, et al. was published online on December 16, 2019 in the Journal of Alzheimer’s Disease.

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More information: Edward N. Wilson et al, NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats, Journal of Alzheimer’s Disease (2019). DOI: 10.3233/JAD-190862

https://medicalxpress.com/news/2020-01-lithium-halt-alzheimer-disease.html

Novartis, GBT sickle cell drugs too expensive, draft U.S. report says

Sickle cell disease drugs made by Novartis and Global Blood Therapeutics (GBT) may not be cost effective at current prices, a draft report published on Friday suggested, widening the debate over U.S. healthcare affordability.

Novartis and GBT disputed the preliminary conclusions by the Boston-based Institute for Clinical and Economic Review (ICER). The institute scrutinised Novartis’s Adakveo and GBT’s Oxbryta, both approved last year, and Emmaus Medical’s Endari, to treat the inherited disease that disproportionately affects African Americans.
The finding that the costs of all three medicines would likely have to be slashed to achieve acceptable cost-effectiveness thresholds comes as Congress and U.S. President Donald Trump weigh action over high healthcare costs.
Insurers and governments use privately funded ICER’s conclusions to help set reimbursement rates.
ICER said it concluded that Adakveo’s annual cost should be $25,410, down from an estimated $88,000 bill, and that Oxbryta must be trimmed to $9,218 from about $84,000, to meet cost-effectiveness thresholds. Endari must be cut to $3,859 from $24,000 to be cost-effective, the group added.
“Treatment costs were the main driver of the cost-effectiveness results,” said ICER, which is taking public comment until Feb. 20 before final publication this year.
Shares in GBT fell more than 5.5% on Friday, while Novartis shares closed 0.3% lower.
ICER seeks to measure how many years of good health – a quality-adjusted life year, or QALY – may be gained with a new treatment, and the incremental cost for that health gain.
At the current estimated costs for Adakveo, Oxbryta and Endari, all the QALYs exceeded $1 million, ICER said, well above the $150,000 the group ordinarily considers an appropriate cost-effectiveness threshold.
Novartis countered that ICER had not appropriately weighed Adakveo’s benefits, including reducing pain crises suffered by sickle cell disease (SCD) patients or potentially helping cut hospital stays.
“We look forward to gaining a better understanding of the approach ICER used to make its assessment and to helping them better understand the value of Adakveo,” Novartis said.

‘FLAWED, PREMATURE’

San Francisco-based GBT contended that ICER’s review conflicts with the U.S. Food and Drug Administration’s goal of speeding medicines to patients.
“ICER’s review is flawed, premature and risks adversely impacting access to new, potentially transformative therapies,” GBT said.
U.S.-based Emmaus could not immediately be reached for comment.

ICER said its draft report may change based on public comments, including from drugmakers. It also acknowledged setting a drug’s price may go beyond traditional measures of clinical effectiveness and cost-effectiveness, to include other, non-financial considerations.
Recent advances in treating long-neglected sickle cell disease include the three medicines reviewed by ICER and an experimental gene therapy from Bluebird Bio Inc..
Still, costs are of particular interest. More than half of the roughly 100,000 U.S. sickle cell disease patients are covered by government health insurance.
https://www.reuters.com/article/us-health-cost-effectiveness/novartis-gbt-sickle-cell-drugs-too-expensive-draft-u-s-report-says-idUSKBN1ZN224

With Wuhan virus genetic code in hand, scientists begin work on a vaccine

When a newly organized vaccine research group at the U.S. National Institutes of Health (NIH) met for the first time this week, its members had expected to be able to ease into their work. But their mandate is to conduct human trials for emerging health threats – and their first assignment came at shocking speed.
In just three months time, they likely will be testing the first of a number of potential experimental vaccines against the new SARS-like coronavirus that is spreading in China and beyond.
“I told them, ‘you are going to have your baptism of fire, folks’,” Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases within NIH, said of his inaugural address to the group this week.
Three months from gene sequence to initial human testing would be the fastest the agency has ever gotten such a vaccine off the ground, Fauci said.
The outbreak, which began in the central Chinese city of Wuhan in December, as of Friday had infected more than 800 people in China and killed 26. Cases have also been confirmed in Thailand, Vietnam, Singapore, Japan, South Korea, Taiwan, Nepal and the United States.
Chinese scientists were able to quickly identify the genetic sequence of the new coronavirus and officials posted it publicly within a few days, allowing scientific research teams to get to work right away.

With the genetic code in hand, scientists can start vaccine development work without needing a sample of the virus.
During the deadly 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, it took U.S. scientists 20 months to go from genetic sequence to the first phase of human trials. By that time, the outbreak was under control.
This time, research groups worldwide are already executing plans to test vaccines, treatments and other countermeasures to stop the newly identified virus from spreading globally.
MULTI-PRONGED APPROACH
They are attacking from several angles, with global health and epidemic response agencies hoping at least one treatment will be in human trials within a few months.
Fauci’s agency is partnering with U.S. biotech Moderna Inc, which specializes in vaccines based on ribonucleic acid (RNA) – a chemical messenger that contains instructions for making proteins.
That team hopes to make an RNA vaccine based on one of the crown-like spikes on the surface of the coronavirus that gives the family of viruses their name, an approach that, unlike many vaccines, would not expose people to the virus.
At the University of Queensland in Australia, scientists backed by the global health emergency group the Coalition for Epidemic Preparedness Innovations (CEPI) said they are working on what they describe as a “molecular clamp” vaccine approach.
The technology adds a gene to viral proteins to stabilize them and trick the body into thinking it is seeing a live virus and create antibodies against it.
Keith Chappell, an expert in the University’s school of chemistry and molecular biosciences, said the technology is designed as “a platform approach to generate vaccines against a range of human and animal viruses.”
It has already shown promising results in lab tests on other dangerous viruses such as Ebola and the coronavirus that causes Middle East Respiratory Syndrome (MERS)- a cousin of SARS and the Wuhan virus.
Novavax, which already has a vaccine in development against MERS, says it is now working on one for the Wuhan coronavirus.
Scientists also are turning to infection-fighting proteins known as monoclonal antibodies, or mAbs, that were developed against the SARS and MERS coronaviruses.

The hope is that similarities with the Wuhan virus will offer enough overlap in the antibodies to help people infected in the China outbreak.
Vir Biotechnology Chief Scientific Officer Herbert Virgin said his company has a library of monoclonal antibodies that have shown some success against SARS and MERS in lab tests.
Some of these antibodies have been shown to neutralize coronaviruses, Virgin said, and “may have the potential to treat and prevent (the) Wuhan coronavirus.”
https://www.reuters.com/article/us-china-health-vaccines/with-wuhan-virus-genetic-code-in-hand-scientists-begin-work-on-a-vaccine-idUSKBN1ZN2J8

‘Single Biggest Contributor’ to Medical and Mental Illness

Stephen M. Strakowski, MD: Hello. I’m Dr Stephen M. Strakowski, acting senior associate dean for research at the Dell Medical School at the University of Texas at Austin. I’m speaking today with two of my expert colleagues here. Dr Elizabeth Lippard is an assistant professor in our department and has been here the longest of anybody else other than me. Dr Charles Nemeroff joined us about a year ago and is now acting as chair in the department of psychiatry, in addition to creating and directing the Institute for Early Life Adversity Research.
We’re speaking with Drs Lippard and Nemeroff about a seminal paper they just published in the American Journal of Psychiatry, reviewing the impact of early life adversity on people, their lives, their medical history, and potentially what goes on in the brain. I want to talk with them today about how all of us who practice mental health care might apply their important work.
To begin, can you tell us about the field of early life adversity and how common such experiences are in patients?
Charles B. Nemeroff, MD, PhD: The entire field was really launched by the phenomenal Adverse Childhood Experiences (ACE) Study, which was funded by the Centers for Disease Control and Prevention (CDC). Investigators went to Kaiser Permanente in San Diego and sampled 17,000-plus individuals.
The results were just astounding. In this nonclinical general population, the rates of child abuse in the form of physical abuse, sexual abuse, emotional abuse, and neglect were remarkably high, ranging—depending on the category—from about 8% to 25%. These results have since been confirmed in several subsequent studies from the CDC and others. This is really a public health tragedy.
Strakowski: It sounds like an epidemic. If we imagined a new virus suddenly affecting 1 in 4 kids, I assume that people would be quite upset and doing something about it.
Nemeroff: This is the single biggest contributor to the risk for psychiatric and medical disorders, more than any single gene or factor. It increases the risk for heart disease, stroke, depression, drug abuse, suicide. It’s awful.

Strakowski: How should people be thinking about the potential impact of these risks?
Elizabeth Lippard, PhD: Piggybacking on what Charlie was saying, if you look at the prevalence of childhood maltreatment, early life stress, and mood disorders, you see rates as high as 50%-60%. If you look at individuals with mood disorders and comorbid addiction, rates are even higher.
We consistently see across studies that it’s associated not only with increased risk for onset, but also increased risk for disease recurrence. In terms of mood disorders, this means more mood symptoms occurring over time with greater severity. You also see a relationship in terms of more complicated clinical cases: more comorbidities, with addiction and medical morbidities as well.

Considering the clinical impact that it’s having on disease outcomes, and how prevalent child maltreatment is, this is a large percentage of disease burden that can be directly contributed to early life stress. It points to a very powerful target that we need to be thinking about when treating disease.
Strakowski: I think when a lot of us consider these kinds of abusive histories, we tend to then jump to post-traumatic stress disorder (PTSD) as the only consequence that we need to contemplate. But you’re saying that it’s much broader than that.
Lippard: Yes, definitely. Whenever you think about childhood maltreatment, it really crosses diagnostic boundaries. It increases the risk for mood disorders, addiction, PTSD, schizophrenia, etc., and you see it across the board.

The Physical Tolls of Early Trauma

Nemeroff: If you look at victims of child abuse and neglect when they are adults with psychiatric disorders, they are much more treatment resistant than patients with comparable disease severity without this history. We believe that the reason for that is that early life trauma results in brain and body changes that persist for the lifetime of the individual. These folks have a different biology, a different brain, and their treatment response for bipolar disorder, for depression, for PTSD is just terribly worse than it is for people without this history.

Strakowski: You perfectly anticipated my next question. Do we have some idea of what early life trauma is doing to the person’s brain or body that is setting them up for these consequences?
Lippard: We do. There’s a wealth of research out there pointing toward long-lasting neurobiological and immune mechanisms, as well as the hypothalamic pituitary adrenal stress response system, and changes within these systems that may be contributing to these outcomes.
In terms of the brain, we see long-lasting changes in structure and function within systems that regulate stress response and emotional, higher-order cognitive processes. It really is giving us an insight into the brain systems that may be so critical for developing psychopathology over time following childhood maltreatment.

One of the things that’s really striking to me when you look at the literature is the more recent emergence of longitudinal studies, which suggest that changes in the brain really can predict future mood symptoms, recurrence, and severity. Traditionally, we started with a wealth of cross-sectional studies in this area, but now these longitudinal studies coming out have given us a lot of power to hone in on certain systems of the brain that can hopefully be targeted for intervention.

Ask Patients About Their Childhoods, Regardless of Your Specialty

Strakowski: Clinicians and providers across many different specialties will be watching this. This applies to patients with psychiatric conditions but, as you implied, medical conditions as well. How do you recommend they ask their patients about this?
Nemeroff: First, for the clinicians out there, it’s extremely important that you get this information from the patient. You need to know it.
There are several screening tools available to help you obtain this information. There’s the ACE questionnaire, although I’m not particularly fond of it. I think the Childhood Trauma Questionnaire is somewhat better. There are others as well. These are self-rating scales, so they won’t take any of your time. We have every patient fill out the scales, which gives you a good indication of their history, as patients will often put things down on paper that they don’t want to tell you.
Second, it often takes several visits with a patient before they’re comfortable enough to talk about their trauma. I’ve seen many patients with treatment-resistant depression who finally revealed to me that they had suffered a childhood rape or some other awful experience. If you’re seeing a treatment-resistant patient, you should be thinking about child abuse and neglect.
Strakowski: In anticipating my talk with you both today, I gave some thought to my own clinical practice. On a given day in my clinic, I bet 80% of the young people I treat have these histories. It’s hard to overexaggerate the risk.

An Epidemic Without a Solution

Strakowski: From a treatment perspective, do you consider maybe doing something differently if you are aware that a patient has this history?
Nemeroff: We know that in every study that we looked at, when you parse out the patients with early life trauma and compare them to those who don’t have that history, they have a poorer outcome. But part of the problem is that there are no treatment trials that have specifically asked this question. In terms of designing a treatment, my gut feeling, which is not science, is that they would do better with a combination of pharmacotherapy and psychotherapy.

One of my concerns is that, as pharmaceutical companies come to realize that these patients actually have poor treatment outcomes, they’re starting to eliminate them from clinical trials.
Strakowski: Which is the exact opposite of what we wish would happen.
Nemeroff: It’s sort of like what’s happened with pregnancy; we don’t know how to treat pregnant women because they’re never allowed in trials.

Strakowski: To me, it sounds like we have an epidemic for which we’re not aggressively trying to find a solution. Does it feel like the psychiatric or psychological professional associations and organizations are making this issue sufficiently visible to engender some response?
Nemeroff: I think that a number of the organizations you’re referring to have done their best, but it’s not enough. First, from a medical education point of view, there is very little training about child abuse and neglect in the curriculum.
Strakowski: I probably received none, roughly 200 years ago when I was in training, and I’m guessing the same is true for you.

Nemeroff: Absolutely. There’s very little attention paid to this. Of all of the physicians, I think pediatricians have been the most sensitive to this. But as Beth alluded to, this a population with an increased risk for diabetes, certain forms of cancer, heart disease, and stroke, and specialists in those areas don’t ask about child abuse and neglect.
Strakowski: There’s a lot more detail to this very important topic in the paper, authored by Drs Lippard and Nemeroff, which is titled “The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease Vulnerability and Poor Treatment Response in Mood Disorders.” I hope you all will take a look at that, and I hope you found our conversation interesting. Thank you all for listening today.
Stephen Strakowski, MD, is the founding chair and professor of psychiatry at Dell Medical School, University of Texas. His research focuses on the brain changes that occur at the onset of bipolar disorder.
https://www.medscape.com/viewarticle/923389#vp_1