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Thursday, October 20, 2022

NIH now blocks access to important database if it thinks scientist’s research may enter 'forbidden' territory

 A policy of deliberate ignorance has corrupted top scientific institutions in the West. It’s been an open secret for years that prestigious journals will often reject submissions that offend prevailing political orthodoxies—especially if they involve controversial aspects of human biology and behavior—no matter how scientifically sound the work might be. The leading journal Nature Human Behaviour recently made this practice official in an editorial effectively announcing that it will not publish studies that show the wrong kind of differences between human groups.

American geneticists now face an even more drastic form of censorship: exclusion from access to the data necessary to conduct analyses, let alone publish results. Case in point: the National Institutes of Health now withholds access to an important database if it thinks a scientist’s research may wander into forbidden territory. The source at issue, the Database of Genotypes and Phenotypes (dbGaP), is an exceptional tool, combining genome scans of several million individuals with extensive data about health, education, occupation, and income. It is indispensable for research on how genes and environments combine to affect human traits. No other widely accessible American database comes close in terms of scientific utility.

My colleagues at other universities and I have run into problems involving applications to study the relationships among intelligence, education, and health outcomes. Sometimes, NIH denies access to some of the attributes that I have just mentioned, on the grounds that studying their genetic basis is “stigmatizing.” Sometimes, it demands updates about ongoing research, with the implied threat that it could withdraw usage if it doesn’t receive satisfactory answers. In some cases, NIH has retroactively withdrawn access for research it had previously approved.

Note that none of the studies I am referring to include inquiries into race or sex differences. Apparently, NIH is clamping down on a broad range of attempts to explore the relationship between genetics and intelligence.

What is NIH’s justification? Studies of intelligence do not pose any greater threat to the dignity of their participants than research based on non-genetic factors. With the customary safeguards in place, research activities such as genetically predicting an individual’s academic performance need be no more “stigmatizing” than predicting academic performance based on an individual’s family structure during childhood.

The cost of this censorship is profound. On a practical level, many of the original data-generating studies were set up with the explicit goal of understanding risk factors for various diseases. Since intelligence and education are also risk factors for many of these diseases, denying researchers usage of these data stymies progress on the problems the studies were funded to address. Scientific research should not have to justify itself on those grounds, anyway. Perhaps the most elemental principle of science is that the search for truth is worthwhile, regardless of its practical benefits.

NIH’s responsibility is to protect the safety and privacy of research participants, not to enforce a party line. Indeed, no apparent legal basis exists for these restrictions. NIH enforces hundreds of regulations, but you will search in vain for any grounds on which to ban “stigmatizing” research—whatever that even means.

The restrictions appear to be invented to impede research on certain topics that anonymous bureaucrats with ideological motivations have decided are out of bounds. It’s impossible to know whether senior NIH officials have instigated the restrictions or merely accepted them tacitly. Perhaps they are unaware of the problem; officials far down the bureaucratic ladder are responsible for approving specific applications.

NIH has historically enjoyed high levels of public confidence in its professionalism and integrity. That trust is now deteriorating. The decline began with evidence that its personnel may have been complicit in blocking investigations of the possibility that Covid-19 escaped from a Chinese laboratory. The restrictions on scholars’ access to the dbGaP don’t have nearly the same public visibility as the Covid story, but they strike equally at the heart of NIH’s integrity.

The federal government was under no obligation to assemble the magnificent database that is the dbGaP. Now that it has done so at taxpayer expense, however, it does have an obligation to provide access to that database evenhandedly—not to allow it for some and deny it to others, based on the content of their research.

Biden predicts Gisele Fetterman will be 'great, great lady in the Senate'

 President Biden predicted that Gisele Fetterman, wife of Pennsylvania Senate candidate John Fetterman, that she will be a "great lady in the senate."

Biden made the remark while visiting Pittsburgh, where he was acknowledging the renovation of a bridge that had made headlines after collapsing last year.

Biden thanked Fetterman, Pennsylvania's lieutenant governor, for attending the speech, saying that he would try to be brief for the sake of the lieutenant governor. During the brief acknowledgment, Biden made the comment that Fetterman's wife would do well in the Senate.

"John, thank you very much for running, I really do appreciate it," Biden said. "And Gisele, you're gonna be a great, great lady in the Senate."Biden's comment comes at an inopportune time as political rivals and media outlets continue to speculate about the Democratic candidate's health and capacity to hold public office after a stroke took him off the campaign trail in May.

Rolling Stone reporter Kara Voght tweeted and deleted a post calling Gisele Fetterman the "de facto candidate" for her husband's U.S. Senate campaign.

Voght’s updated tweet changed the description of Mrs. Fetterman from "de facto candidate" to "key surrogate for her husband" in his campaign, seemingly to downplay the impression that John Fetterman is incapable of leading the campaign.

Gisele Fetterman ripped NBC journalist Dasha Burns for claiming he had a "difficult" time with small talk prior to their interview, suggesting she should face "consequences."

Gisele Fetterman claimed that Burns’ statements were a "disservice" to her husband, to the disabled community and to Americans in general.

Burns received a torrent of criticism from liberal media figures after noting that Fetterman had a "difficult time" engaging her and her team in small talk prior to the interview. She added that Fetterman was fine once they got to the discussion, which was aided by closed-captioned questions for the candidate.

Republican Dr. Mehmet Oz is trailing Fetterman 48% to 46%, which is within the margin of error of 4.4 percentage points, in an AARP poll of likely voters released this week.

After Biden ended his speech, he seemed to momentarily lose track of where he should leave the stage, before exiting and greeting those in attendance.

https://www.foxnews.com/politics/biden-predicts-gisele-fetterman-will-be-great-great-lady-senate

As Covid Hit, Washington Officials Traded Stocks With Exquisite Timing

 Federal officials working on the government response to Covid-19 made well-timed financial trades when the pandemic began—both as the markets plunged and as they rallied—a Wall Street Journal investigation found.

In January 2020, the U.S. public was largely unaware of the threat posed by the virus spreading in China, but health officials were on high alert and girding for a crisis.

A deputy to top health official Anthony Fauci reported 10 sales of mutual funds and stocks totaling between $157,000 and $480,000 that month. Collectively, officials at another health agency, Health and Human Services, reported 60% more sales of stocks and funds in January than the average over the previous 12 months, driven by a handful of particularly active traders.

By March, agencies across the government were working on wide-reaching measures to prop the economy and markets. Then-Transportation Secretary Elaine Chao purchased more than $600,000 in two stock funds while her agency was involved in the pandemic response and her husband, Republican Sen. Mitch McConnell, was leading negotiations over a giant, market-boosting stimulus bill.

And as the government was devising a loan package aimed specifically at helping companies including Boeing Co. and General Electric Co., a Treasury Department official involved in administering the aid acquired shares of both companies.

Federal officials owned millions of dollars of stock in industries most affected by the pandemic and the government’s response. About 240 officials at health agencies and at the Pentagon, a key player in the vaccine rollout, reported owning a total of between $9 million and $28 million in stocks of drug, manufacturing and biotechnology companies that won federal contracts related to Covid-19 in 2020 and 2021, the Journal’s analysis found.

Nearly 400 officials across 50 agencies reported owning stocks in airline, resort, hotel, restaurant and cruise companies in early 2020, the review found.

By March, every major agency was drawn into the pandemic response. That month was the most active for trading by officials across the federal government, including at HHS, in the Journal’s analysis of financial disclosure forms for about 12,000 officials spanning 2016 to 2021. Federal officials reported more than 11,600 trades that month, 44% more than in any other month in the analysis.

The health agencies didn’t respond to requests for comment. A Pentagon spokeswoman said most defense personnel don’t work on matters affecting large defense contractors or affecting the finances of private companies, and said the department is “committed to preventing conflicts of interest.”

Senior federal officials are required to disclose their financial assets and transactions and those of their spouses and dependent children in annual reports.

Federal employees are barred from working on matters in which they have a significant financial stake, from trading on nonpublic information learned on the job and from taking any official action that creates an appearance of a conflict of interest.

Agency ethics officials rarely have a complete picture of what employees are working on or privy to, especially during a fast-moving, governmentwide mobilization in response to a national emergency.

Most agencies’ ethics rules focus on what kinds of stocks officials can trade, not when they can trade. And there are no restrictions on federal officials’ investing in diversified mutual funds, which were more volatile than usual early in the pandemic. Ethics officials certified that the employees identified by the Journal were in compliance with these rules.

Three days into January 2020, top U.S. health officials were alerted to an unexplained virus sickening people in China.

By late January, Centers for Disease Control and Prevention leaders were rushing to develop accurate tests, National Institutes of Health officials were taking the first steps toward developing a vaccine, and the Food and Drug Administration was racing to facilitate prevention and treatment options for the novel coronavirus.

On Jan. 24, four days after the CDC publicly reported the first confirmed U.S. Covid-19 infection, Hugh Auchincloss, principal deputy director at the NIH’s National Institute of Allergy and Infectious Diseases, summed up the state of his agency in an email: “New coronavirus all the time.”

That same day, while the stock market remained lofty, Dr. Auchincloss reported selling $15,001 to $50,000 of a stock mutual fund. Days later he sold two more mutual funds and a stock, Chevron Corp., according to his financial disclosures, which give wide dollar ranges. That was just the beginning.

Dr. Auchincloss was invited to a Jan. 29 meeting of an NIH working group called the International Clinical Research Subcommittee. The top agenda item was “Wuhan coronavirus—plans for a response,” according to emails released in response to public-records requests.

On the last day of January, an email sent to Dr. Auchincloss and his boss, Dr. Fauci, signaled the severity of the threat. Public Health Service officers had been told they could be deployed, a health official wrote, and could assist with “quarantine efforts.”

Dr. Auchincloss disclosed six sales of mutual funds that day, totaling between $111,006 and $315,000 in value.

His January sales amounted to the largest number of transactions he had reported for a single month since 2018, according to his financial disclosures.

Each holding he sold fell sharply in the market downturn that soon followed, as the public and investors started paying attention to the threat posed by Covid-19.

Dr. Auchincloss, who retained some other holdings, didn’t respond to requests for comment. The National Institute of Allergy and Infectious Diseases declined to make him available for an interview.

The agency said that financial disclosure reports are routinely reviewed by NIH ethics officials to ensure compliance with reporting requirements and resolve potential conflicts of interest. It declined to say whether Dr. Auchincloss made the trades himself or had a managed account.

“As a matter of employee privacy, we will not disclose the additional information requested because it is beyond the public financial disclosure reporting requirements,” the agency said.

Among officials involved in the CDC’s early pandemic response was Stephen Redd, a veteran epidemiologist serving as deputy director for Public Health Service and Implementation Science at the agency. His role involved collecting information about the state of the virus and the federal response in order to brief lawmakers.

The CDC had a clear view of the virus’s threat by the end of January, Dr. Redd later told a student interviewer in Atlanta. “It was easy to see it was going to be a really big problem,” he said.

Dr. Redd disclosed sales of between $95,004 and $250,000 in stocks and bonds in January. He reported the sale in February of $100,001 to $250,000 of bonds, along with purchases of between $2,002 and $30,000 of short-term bond funds, a low-risk investment.

Dr. Redd said he had no advance knowledge of these trades, which he said were in his wife’s retirement account and made by a financial adviser. He said he didn’t learn of them until that summer, although he was required by law to report any trades made in his or his wife’s accounts within 30 days.

He acknowledged that federal officials are “responsible for knowing” about their financial transactions. He said neither he nor his wife knew why the adviser made the trades.

Dr. Redd said that ethics officials later told him he hadn’t reported the trades in the required 30-day period, but that the officials didn’t raise any questions about the trades’ timing. Dr. Redd, who retired in the fall of 2020, said he wasn’t aware of any guidance about trading during the early months of the pandemic.

“I don’t know that there’s anything that said, ‘If you think that something bad is going to happen, you shouldn’t trade,’” he said. “It’s mostly about disclosure.”

The CDC didn’t respond to multiple requests for comment.

In late February 2020, as awareness of the viral threat grew, officials in the Trump administration faced a different problem: turbulent financial markets. Treasury and Federal Reserve officials began to coordinate on measures to stabilize them.

U.S. stocks sank on Feb. 20, and over the next week, equity markets worldwide recorded their largest single-week declines since the 2008 global financial crisis. Yields on 10-year and 30-year U.S. Treasury securities fell to record lows, as investors fled to these relatively safer assets.

On Feb. 28, Fed Chairman Jerome Powell signaled in a written statement that the central bank was prepared to cut interest rates, a stimulatory move aimed at quelling the economic disruption.

In the seven days preceding that statement, officials at the Treasury and Fed reported more than twice as many trades as they made during the same seven days of 2019.

They reported more than three stock or fund purchases for every sale from Feb. 21 to Feb. 27, 2020, according to the Journal analysis of financial disclosures.

Treasury Department officials as a group reported about 30% more stock and fund purchases in February than the average over the previous 12 months.

Two Fed bank presidents resigned last year after they disclosed a series of investments during Fed market interventions in response to Covid-19. The central bank in February 2022 prohibited its top officials from buying individual stocks and sector funds and barred trading during periods of “heightened financial market stress.”

At emergency meetings on March 3 and March 15, 2020, the Fed slashed short-term rates to near zero and imposed other market-supporting measures.

On March 13, then-President Donald Trump announced a federal partnership with the private sector to increase the nation’s testing capability for Covid, inviting top executives at 10 companies, including Target Corp., Walmart Inc., CVS Pharmacy Inc. and Walgreens Boots Alliance Inc., to the White House for the announcement.

Roughly 300 federal officials reported owning stock in at least one of the 10 companies at the time, their financial disclosures show.

As the pandemic’s toll mounted, Congress in mid-March was negotiating with the administration over a package providing funds for individuals and companies hit by the fallout.

The rate cuts hadn’t immediately calmed investors. Stock trading was halted for 15 minutes on the morning of March 16 when the S&P 500 fell 7%, triggering a so-called circuit breaker. The index staggered to the closing bell, down 12%.

That same day, Ms. Chao, the transportation secretary, made three purchases in stock funds that track the S&P 500 and the U.S. stock market broadly, totaling between $600,003 and $1.2 million, according to her financial disclosures.

After Republican frustration with a previous piece of relief legislation, Ms. Chao’s husband, then-Senate Majority Leader McConnell, had taken the reins in Congress on a much larger bill. He released his first draft on March 19.

Ms. Chao was also working on the pandemic response. Her agency—part of the White House Coronavirus Task Force—was helping repatriate Americans abroad, conducting screenings at airports, establishing health protocols for airlines and cruise ships and coordinating with international counterparts, she told a House committee.

The S&P 500 hit bottom on March 23. From its high on Feb. 19, it had dropped nearly 34%.

The next day, the administration and Congress neared a deal on the stimulus bill. The stock market soared on the news—and with it Ms. Chao’s mutual fund investment from eight days earlier.

Mr. Trump signed the Coronavirus Aid, Relief, and Economic Security Act, or Cares Act, on March 27, handing out pens to guests, including Ms. Chao and Mr. McConnell. Ms. Chao released a statement praising the administration’s pandemic response, saying the bill “ensures that critical federal resources will soon reach where they are needed.”

By the end of the month, her investment in the S&P fund had gained 8%. By the end of the year, it was up 57%, according to its net asset value.

Ms. Chao’s total disclosed purchases in March 2020 were between $669,009 and $1.5 million, her second-highest monthly total in the Journal’s review of her four years as transportation secretary.

A spokesman for Ms. Chao said she periodically adjusts her investments in mutual funds based on the advice of financial professionals. “These funds are held separately from her husband and managed without his consultation,” the spokesman said.

A spokesman for Mr. McConnell referred the Journal to the statement by Ms. Chao’s representative.

At around the same time, a Treasury official later involved in administering the stimulus package made a series of well-timed trades.

Early on, the Trump administration made it clear it wouldn’t leave Boeing or the rest of the aviation and airline sector hanging, as the travel industry was thrown into turmoil. “We have to protect Boeing,” Mr. Trump said March 17. “We’ll be helping Boeing.”

The Treasury Department publicly detailed what it wanted to see in the stimulus legislation on March 18, including $50 billion in loans for airlines and $450 billion for “severely distressed sectors” and small businesses.

Two days later, Treasury domestic finance counselor Jeff Goettman reported purchases of 15 stocks, including Boeing and General Electric, totaling between $29,015 and $260,000, according to his financial disclosure.

Boeing was in close contact with Treasury officials as it lobbied the administration and Congress for federal aid.

Days after Mr. Goettman’s stock purchases, lawmakers inserted a $17 billion provision for companies deemed essential to national security, which congressional officials said at the time was partly designed to help Boeing.

The provision stayed in the final legislation, authorizing the Treasury to administer the loan fund. Then-Secretary Steven Mnuchin later said the fund had been created with companies including Boeing and GE in mind.

Mr. Goettman convened the group that administered the legislation’s $80 billion for airlines—which included the national-security loan fund—according to his bio on the website of Virginia Gov. Glenn Youngkin, for whom he now serves as chief of staff. Boeing didn’t ultimately apply because it objected to the condition that the U.S. take an equity stake or warrants for shares in loan recipients, its chief executive said at the time.

A week after Mr. Goettman’s March 20 stock purchases, Boeing’s shares were up 70%, and GE’s were up 17%.

Mr. Goettman declined to comment.

The Treasury declined to comment on his trading. A spokesman said: “The Treasury Department follows regulations issued by the Office of Government Ethics and we expect all employees to follow them. These regulations include the disclosure of stock purchases, recusals to avoid conflicts of interest and a prohibition against using nonpublic information to inform financial activities.”

Mr. Goettman disclosed more GE stock purchases on March 27 and April 1, totaling between $2,002 and $30,000.

On April 2, Mr. Trump, using authority granted in a Korean War-era law, ordered the federal government to help six medical-device manufacturers, including GE, secure supplies they needed to make ventilators for hospitalized Covid patients.

Mr. Goettman reported additional GE share purchases that day, bringing his GE investment to the range of $3,003 to $45,000.

Two weeks later, HHS disclosed a $336 million government contract with GE to produce 50,000 ventilators. The stock rose more than 5% on the news.

https://www.msn.com/en-us/money/markets/as-covid-hit-washington-officials-traded-stocks-with-exquisite-timing/ar-AA139maA

Does Spinal Cord Stimulation Improve Diabetic Neuropathy?

 Good afternoon. I'm going to talk to you about the SENZA-PDN trial. This is a randomized controlled trial conducted in patients with peripheral diabetic neuropathy. It's a really important indication because these people suffer from large losses in their quality of life. Although we can treat these patients' pain with analgesics, often these therapies aren't effective.

In this trial, we took 216 patients in the United States across 18 centers who had their peripheral diabetic neuropathy for at least a year in spite of taking usual-care medication. They also had to have a pain VAS > 5 on a scale where 0 represents no pain and 10 max pain.

We randomized them to continue with their usual medical management, which in this case was analgesic treatment, or to usual care plus a new technology that I'm very excited to talk to you about today, which is called spinal cord stimulation.

The patients we recruited who received the spinal cord stimulator demonstrated much improved levels of pain and quality of life compared with the usual-care group, who virtually did not change their level of pain or their quality of life compared with their baseline assessment.

I'm going to focus on what happened after that 6-month period. One of the things we did in the trial design was to allow patients to cross over if they failed to get therapeutic benefit from the therapy they were receiving. Given that, we observed that 90% of patients elected to cross over from their usual care to receiving a spinal cord stimulator.

We followed up with everybody for an additional 18 months. We looked at their data out to 24 months and what we found was very interesting. Essentially, the improvements that we saw at 6 months were continued to 24 months in both the group that received spinal cord stimulation at the outset and in those who crossed over and received a spinal cord stimulator at 6 months.

Of course, the importance of that observation is that these benefits aren't just short term but indeed are sustained over a 2-year period in those who received a stimulator from the outset. That's important because when you do these trials, one of the things that can happen when you're measuring patient-reported outcomes is a placebo effect.

Are these improvements in the stimulator arm purely due to people knowing they're getting something additional to their care? Usually placebo effects tend to dissipate in the longer term. The fact that we now have these longer-term data, I think you would agree, provides further support that this intervention with spinal cord stimulation may be an effective one for this population of people with painful diabetic neuropathy.

What are the implications of these findings? First, we need to recognize that spinal cord stimulation is not a routine therapy currently available for people with painful diabetic neuropathy. Indeed, if you look across the globe, whether you're in the United States, Europe, or wherever, clinical guidelines do not currently recommend spinal cord stimulation. Of course, with this evidence, we anticipate clinical guidelines being updated in the future to reflect this.

Working on the basis, then, that we do have a therapy for patients, how might we make this available? What would be involved? First, spinal cord stimulation is a technology we've had available for the better part of three decades, and we've traditionally used it in the treatment of people with chronic low back pain. We know what this therapy is and we know how to do it.

What does it involve? It involves bringing the patient into the hospital after an initial period of assessment. They will go into the OR — the technology is very similar to a cardiac pacemaker — and it is implanted into their lower back. Under the skin is a battery attached to two leads, and those leads are then effectively implanted under local anesthetic into the intrathecal space of the spinal cord.

The clinician will then test with the patient on the slab to check that they've got the sweet spot where, if they activate the stimulator, the patient perceives an improvement in their pain. Once that's done, we close up the wound, and the patient is allowed to go out, be fully ambulant, and effectively undertake what we call a trial period, which can be up to maybe a month, where they wear the device. We will give them a diary, ask them to record their pain scores, and then bring them back.

If that all goes well, we'll then perform what we call a permanent implant. We will finalize the implementation of the implant and then the patient can go out from the clinic and wear the device during their normal activity.

What we've found in the chronic low back pain areas is that these people can get benefit from these devices over the longer term. I've talked about 24 months. Typically, the battery life of these devices now is as long as 8 or 9 years. We will certainly have to bring the patient back on an annual basis to assess them. At some point, we may also need to change their battery. That's a very simple procedure to do under local anesthetic.

We've heard the evidence. How do I go about accessing this technology? It's important to say that the regulators, both in the United States (the FDA) and in Europe, have approved this technology as clinically efficacious and safe. However, in Europe and in the United States, this technology has not routinely been recognized by insurance or for availability within the UK National Health Service.

For that to happen, both insurers and bodies, such as the National Institute for Health and Care Excellence in the UK, need to take the advice I've talked to you about today, examine the robustness, look at issues such as cost-effectiveness, and then make a final decision on whether this technology would represent good value for money for populations, be that based in North America, Europe, or elsewhere in the globe.

The technology is not available to the patient just yet, but we hope that that decision-making will follow in the coming months or a couple of years.

Rod S. Taylor, MSc, PhD, is  Professor, Department of Public Health, University of Glasgow, Glasgow, Scotland, United Kingdom


Karuna:' Amazing' Phase 3 Results for Novel Schizophrenia Combo Drug

 The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics) achieves significant and clinically meaningful improvements in schizophrenia symptom scores without causing problematic adverse effects, new research suggests.

Results from the phase 3 EMERGENT-2 trial, which included more than 250 patients with schizophrenia, showed that those who received xanomeline-trospium for 5 weeks achieved a significant reduction in Positive and Negative Syndrome Scale (PANSS) total scores of more than nine points compared with their peers who received placebo. In addition, the improvements started at week 2.

Alongside significant reductions in both positive and negative symptoms, the results suggest the agent was well tolerated, with treatment-emergent adverse events (TEAEs) largely mild to moderate and transient in nature.

Lead investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York, told Medscape Medical News that the upcoming EMERGENT-3 study will have a "European component" and that the "readout is expected most likely in the first quarter of next year."

Correll suggested that if leads to "two positive studies and reasonable safety," the novel agent may become part of the "next generation of antipsychotics that are not related to postsynaptic dopamine blockade."

The findings for EMERGENT-2, presented here at the 35th European College of Neuropsychopharmacology (ECNP) Congress as a poster and as an oral presentation, were an update of topline results released earlier this year.

Novel Compound

Xanomeline-trospium is a novel compound that combines the dual M1/M4-preferring muscarinic receptor agonist effect of xanomeline with the peripherally restricted muscarinic receptor antagonist effect of trospium.

previous phase 2 trial that compared the drug with placebo in almost 200 patients suggested it significantly reduced psychosis symptoms, leading to the current phase 3 trial.

Correll noted that xanomeline-trospium reduces psychosis via a "bottom up and top down approach."

He said that on one hand, M4 agonism decreases acetylcholine in the ventral tegmental area and the associated stratum, "which then decreases dopamine levels from the bottom up," while the M1 agonism stimulates GABA and decreases dopamine from the "top down."

M1 agonism, however, also stimulates the cholinergic system peripherally, "which can give you nausea, vomiting, and also some blood pressure and pulse" problems, Correll said.

That was the limitation when this approach was studied by Lilly as a treatment for patients with Alzheimer's disease, but the addition of trospium means "you're buffering somewhat the cholinergic peripheral effects," he said.

While that can conversely lead to dyspepsia, dry mouth, and constipation, Correll noted that the adverse effects of the novel agent are "mitigated by titration," with patients taking up to 8 days to reach the full dose.

The result is that the drug was "overall tolerated, and the effect sizes were quite astounding," he reported.

Intermittent, Time Limited TEAEs

The current trial included 252 patients aged 18–65 years (mean age, 45 years) who were confirmed to have schizophrenia and who had recently experienced a worsening of psychotic symptoms that warranted hospitalization. Three quarters of the participants were men, and a similar proportion were Black. Approximately one quarter were White.

All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo; scores fell by 21.2 points with the active treatment, vs 11.6 points with placebo (< .0001).

The significant improvement in PANSS total score began at week 2 (< .05) and continued to accrue over the course of the study.

Xanomeline-trospium was also associated with significant reductions in PANSS positive subscale scores in comparison with placebo (< .0001), as well as with reductions in PANSS negative subscale scores (< .01) and PANSS Marder negative subscale scores (< .01).

Although 75.4% of patients who received xanomeline-trospium experienced a TEAE, in comparison with 58.4% of the placebo group, very few experienced a serious TEAE (just 1.6% in both groups).

TEAEs leading to discontinuation occurred in 7.1% of the active-treatment group, vs 5.6% of the placebo group. The overall discontinuation rates from the trial were 25% and 21%, respectively.

The most common TEAEs with xanomeline-trospium were constipation (21.4%), dyspepsia (19.0%), nausea (19.0%), vomiting (14.3%), and headache (13.5%).

The results showed that cholinergic TEAEs typically began within the first 2 weeks of treatment and were "intermittent and time limited in nature," the investigators note. Moreover, average blood pressure levels were "similar" between the xanomeline-trospium and placebo groups "at each time point throughout the trial," they add.

Correll reported that whereas the EMERGENT studies are testing xanomeline-trospium as a monotherapy, the ARISE program will be examining it as an "augmentation" treatment. "And that's relevant because, let's face it, patients do not switch" treatments, he said.

He suggested that if xanomeline-trospium is able to have a synergistic effect with other drugs, "we might be able to treat people who are currently not benefiting enough from postsynaptic dopamine blockade to maybe get a little bit closer" to the benefits seen with clozapine, which "also has problematic side effects."

"Really Revolutionary"

Following the oral presentation of the study by co-author Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, Massachusetts, the results were warmly received.

Session co-chair Mark Weiser, MD, chairman at the Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, said the agent is "really revolutionary in the field.

"It's a non-dopamine compound which helps for schizophrenia, so we're all very optimistic about it," Weiser added.

Nevertheless, he asked Brannan whether the occurrence of gastrointestinal adverse effects with xanomeline-trospium led to "functional unblinding of the study."

Bannan answered that the investigators were "really worried about this prior to EMERGENT-1" but that formal testing suggested it was not a problem.

Bannan said that although this has not yet been formally tested for the current trial, he believes that it is "highly unlikely" that functional unblinding occurred, inasmuch as the "percentages are about in the same range as we saw in EMERGENT-1."

Speaking to ECNP Congress Daily in a conference roundup video, session co-chair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt, Frankfurt am Main, Germany, also highlighted the study.

He said that along with a study of dexmedetomidine sublingual film for agitation associated with schizophrenia or bipolar disorder that was also presented in the session, the current trial is "pivotal."

Reif noted that the effect size shown with xanomeline-trospium was "really amazing."

"We are in a really exciting time in treating mental disorders," he said. "Industry is finally investing again, and really has new compounds that will make it to the market."

Karuna plans to submit a new drug application with the US Food and Drug Administration for KarXT in mid-2023. The drug is also in development for the treatment of psychiatric and neurologic conditions other than schizophrenia, including Alzheimer's disease.

The study was funded by Karuna Therapeutics. Correll has reported relationships with Karuna, as well as AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Viatris, Otsuka, and UpToDate. Brannan is an employee of Karuna Therapeutics.

35th European College of Neuropsychopharmacology (ECNP) Congress: Abstracts P.0193 and S07.05. Presented October 16, 2022.

https://www.medscape.com/viewarticle/982783

Similar Quality of Life Reported by Teens With Diagnosed, Undiagnosed ADHD

 Teens diagnosed with attention-deficit/hyperactivity disorder in childhood reported similar overall quality of life compared with teens with ADHD behaviors but no childhood diagnosis, a new study finds.

The results align with findings from other studies suggesting lower quality of life (QOL) in teens with ADHD, but the current study is the first known to focus on the association between ADHD diagnosis itself vs. ADHD symptoms, and QOL, the researchers wrote. The findings show that at least some of the reduced QOL is associated with the diagnosis itself, they explained.

The researchers directly compared 393 teens with a childhood ADHD diagnosis to 393 matched teens with no ADHD diagnosis but who had hyperactive/inattentive behaviors.

The researchers reviewed self-reports from individuals who were enrolled in a population-based prospective study in Australia. The primary outcome was quality of life at age 14-15, which was measured with Child Health Utility 9D (CHU9D), a validated quality of life measure.

Study Results

Overall, teens with and without an ADHD diagnosis reported similar levels of overall quality of life; the mean difference in the primary outcome CHU9D score was –0.03 (P = .10). Teens with and without an ADHD diagnosis also showed similar scores on measures of general health, happiness, and peer trust, the researchers noted.

The researchers also reviewed eight other prespecified, self-reported measures: academic self-concept, global health, negative social behaviors, overall happiness, peer trust, psychological sense of school membership, self-efficacy, and self-harm.

Teens diagnosed with ADHD in childhood were more than twice as likely to report self-harm (odds ratio 2.53, P less than .001) and displayed significantly more negative social behaviors (mean difference 1.56, P = .002), compared with teens without an ADHD diagnosis.

Teens diagnosed with ADHD in childhood also scored significantly worse on measures of sense of school membership (mean difference −2.58, P less than .001), academic self-concept (mean difference, −0.14; P = .02), and self-efficacy (mean difference −0.20; P = .007), compared to teens without an ADHD diagnosis.

The average age at ADHD diagnosis was 10 years, and 72% of the ADHD-diagnosed group were boys. No significant differences were noted for levels of hyperactive/inattentive behaviors and between girls and boys, but girls overall and children with the highest levels of hyperactive and inattentive behaviors reported generally worse outcomes, regardless of ADHD diagnosis, the researchers noted.

Don't Rush to Diagnosis

Although rates of ADHD diagnosis in children continue to rise, the prevalence of hyperactivity and inattentive behaviors appears stable, which suggests a problem with diagnosis, senior author Alexandra Barratt, MBBS, MPH, PhD, professor of public health at the University of Sydney, Australia, said in an interview.

"Our hypothesis was that children who had been diagnosed, and we assume treated for, ADHD would have better outcomes, compared to children matched for hyperactivity/inattention behaviors who were left undiagnosed and untreated, but we were surprised to find that, at best, outcomes were unchanged, and for some outcomes, worse," Barratt said.

"Our study provides evidence that diagnosing ADHD may lead, inadvertently, to long-term harms, particularly for children with mild or borderline hyperactivity and inattention behaviors," she emphasized.

"We can't say from this study what to do instead, but previously one of our team has looked at stepped diagnosis as an alternative option for children with mild or borderline hyperactivity and inattention behaviors," she said.

The stepped diagnosis includes such actions as gathering behavior data from multiple sources, and conducting a period of watchful waiting without presumption of a diagnosis or active treatment.

Given the findings of the new study, "I would ask that health professionals considering a child who may have ADHD be aware that there is an evidence gap around the long-term impact of an ADHD diagnosis on children, and to proceed cautiously," Barratt said. As for additional research, independent, high-quality, randomized controlled trials of ADHD diagnosis in children with mild or borderline hyperactivity/inattention behaviors are urgently needed, with long-term, patient-centered outcomes including quality of life she noted.

ADHD Screening Needs Improvement

The incidence and prevalence of ADHD is on the rise, but much of the perceived increase in ADHD may be due to overdiagnosis, "and a lack of robust thorough psychological testing as standard of care for diagnosis," Peter Loper, MD, a pediatrician and psychiatrist at the University of South Carolina, Columbia, said in an interview.

The current study "reinforces the necessity of consistent screening for comorbid mental health problems, and specifically for thoughts of self-harm, in those children who are diagnosed with ADHD," he said.

Expressing his lack of astonishment about the study findings, Loper said: "Previous data indicates that while following initial diagnosis of a medical or mental health problem, patients may experience a sense of relief; however, this is followed shortly thereafter by feelings of insufficiency or anxiety related to their specific diagnosis."

"As it stands now, ADHD is often diagnosed in children and adolescents using basic screening questionnaires," said Loper. "The findings of this study may bolster calls for more robust and thorough psychological testing for supporting the diagnosis of ADHD," he said.

Individuals diagnosed with ADHD can sometimes have difficulty with social skills and relating to others, said Loper. "They may be more prone to internalize their poor school performance as due to being 'stupid' or 'dumb,' " he said. Children and teens with ADHD should, whenever possible, be involved in extracurricular activities that support the development of social skills, he said. Parents' praise of the process/effort, rather than focusing only on outcomes such as grades, is very important for the esteem of children and teens with ADHD, he added.

The study limitations included the use of observational data vs. data from randomized trials, and the potential for confounding factors in propensity scoring, the researchers wrote. Additional limitations include the size of the sample, which may have been too small to detect additional differences between diagnosed teens and matched controls, they noted.

"As the study authors appropriately cite, a large, randomized trial would be very helpful in supporting additional understanding of this issue," Loper added.

The study was supported by the National Health and Medical Research Council The researchers and Loper had no financial conflicts to disclose.

https://www.medscape.com/viewarticle/982793