Tag: 8/11/22

Categories : Mental HealthTags : Leave a comment

Psilocybin Shows Promise in Treatment-resistant Depression

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Mushroom
Photo by Timothy Dykes on Unsplash

The largest and most rigorous clinical trial to date of psilocybin (a psychoactive ingredient in magic mushrooms), suggests the possibility that COMP360 psilocybin with psychological support could be a beneficial therapeutic strategy for people with treatment-resistant depression (TRD). The trial results were published in the New England Journal of Medicine.

Prompted by promising preliminary findings, this funded multi-centre, randomised, double-blind, phase 2b clinical trial was launched in 2018 to determine the safety and potential antidepressant effects of a single dose of COMP360 psilocybin (25mg or 10mg), compared to 1mg, with psychological support in people with TRD.

The trial, which included 233 people with TRD across 10 countries who received a single dose of 25mg COMP360 psilocybin experienced a highly statistically and clinically significant rapid reduction in symptoms of depression compared to 1mg at three weeks. This offers hope that COMP360 psilocybin with psychological support could be an effective antidepressant treatment paradigm for some people with TRD, if proven effective and safe in larger studies. COMPASS Pathways, the company that developed the psilocybin formulation., will be running a larger phase 3 programme of COMP360 psilocybin therapy in TRD, which is on schedule to begin in 2022.

KEY RESEARCH FINDINGS

  • 25mg COMP360 psilocybin with psychological support led to a statistically and clinically significantly reduction in symptoms of depression in people with TRD compared to 1mg at week 3.
  • 37% of people with TRD in the 25mg group met criteria for response at week 3 (≥ 50% decrease in depressive symptoms).
  • Approximately 30% of people with TRD in the 25mg group met criteria for remission at week 3 (29.1%).
  • 20% of people with TRD in the 25mg group met criteria for sustained response at week 12.
  • COMP360 psilocybin was generally well-tolerated.

Dr John R. Kelly, Psychiatrist and Clinical Senior Lecturer, Trinity College said: “This is the largest and most rigorous clinical trial of psilocybin to date. It shows a promising antidepressant signal for 25mg COMP360 psilocybin with psychological support and has paved the way for phase 3 clinical trials, which will determine whether it translates into a much-needed complementary treatment strategy in the psychiatry clinic.”

Source: Trinity College Dublin

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Better Outcomes with Bypass Surgery in Chronic Limb-threatening Ischaemia

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Performing open bypass surgery to restore circulation for people with a severe form of peripheral artery disease (PAD) resulted in better outcomes for specific patients compared to a less-invasive procedure, according to findings published in the New England Journal of Medicine.

PAD is a condition in which blood flow to one or both legs is reduced by a buildup of fatty plaque in the arteries. One in 10 of patients with this condition develop a severe form of PAD called chronic limb-threatening ischaemia (CLTI), a painful and debilitating condition that can lead to amputation if untreated. Up to about 22 million people worldwide have CLTI, which is also associated with an increased risk of heart attack, stroke, and death.

“Given the projected rise in the number of patients with chronic limb-threatening ischaemia, it is critically important that we understand the full impact of our interventions for this disease,” said Matthew Menard, MD, a study author and associate professor of surgery and co-director of the endovascular surgery program at Brigham and Women’s Hospital, Boston. “These findings help do that and also can assist clinicians and caregivers in providing the best possible care to patients.”

The Best Endovascular versus Best Surgical Therapy for Patients with CLTI (BEST-CLI) trial is a landmark study supported by the National Heart, Lung, and Blood Institute (NHLBI).

To compare effectiveness of two common treatments for CLTI, researchers enrolled 1830 adults who were planning to have revascularisation, a procedure used to restore blood flow in their blocked arteries, and who were eligible for both treatment strategies.

One treatment strategy was an open bypass surgery, in which blood is redirected around the blocked leg artery by using a segment of a healthy vein. The other strategy was an endovascular procedure, where a balloon is dilated and/or a stent is placed in the blocked segment of the artery to improve blood flow. To compare the surgical strategy to the less-invasive endovascular approach, researchers randomised participants into one of two parallel trials between 2014–2021.

The first trial, defined as cohort 1, included 1434 adults who were judged to be the best candidates for the bypass surgery because they had an adequate amount of an optimal vein (the single-segment great saphenous vein) preferred for the procedure. Participants were then randomly assigned to have either a surgical bypass or endovascular procedure. Researchers followed the trial participants for up to seven years.

The second trial, defined as cohort 2, included 396 adults who were not the best candidates for the open bypass because they did not have an adequate amount of the preferred saphenous vein. They were randomised to have either an endovascular procedure or a bypass that used alternate graft material instead of the saphenous vein. Participants were followed-up for up to three years.

At the end of the trial, the researchers found that participants in cohort 1 who received the bypass were 32% less likely to have major medical events related to CLTI than those who had an endovascular procedure. This result was driven by a 65% reduction in major repeat surgeries or procedures to retain blood flow in the lower leg and a 27% reduction in major amputations. No differences were found in death rates between the participants who received the bypass surgery and those who received an endovascular procedure.

Adults in cohort 2 – those who did not have the optimal vein for the bypass – had no major differences in outcomes based on having had an open bypass or an endovascular procedure.

“Our findings support complementary roles for these two treatment strategies and emphasise the need for preprocedural planning to assess patients and inform what treatment is selected,” said co-principal investigator Alik Farber, MD, at Boston Medical Center.

Common symptoms of CLTI include leg and foot pain, foot infections, and open sores on the leg and foot that don’t fully heal. Without having a procedure to redirect or open blocked blood flow to the lower body, about 4 in 10 adults with CLTI have a lower leg or foot amputation.

BEST-CLI is the largest CLTI clinical trial to date and builds on prior research that aims to answer questions about the risks and benefits of revascularisation strategies for CLTI.

Source: NIH/National Heart, Lung and Blood Institute

Categories : Gastrointestinal Obstetrics & GynaecologyTags : Leave a comment

Even in Remission, IBD is a Risk Factor for Preterm Birth

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Inflammatory bowel disease is a risk factor for giving birth preterm even when in apparent disease remission, according to a study published in the journal eClinicalMedicine. If corroborated, the results may eventually affect recommendations for women with ulcerative colitis wishing to conceive.

Inflammatory bowel disease (IBD) is chronic inflammatory disease with a prevalence of approximately 0.5%. IBD, which includes ulcerative colitis and Crohn’s disease, and – unlike irritable bowel syndrome (IBS) – causes visible damage to the mucosa lining the intestines. IBD is characteristic for its recurrent tendency for symptoms to relapse, followed by periods of remission.

Onset of IBD commonly occurs at age 15–30, so questions about its impact on pregnancy and the foetus are common. IBD has previously been linked to negative birth outcomes, such as preterm birth (< 37 weeks of pregnancy), mainly in women showing signs of active disease.

Also, women without obvious IBD activity often have microscopic inflammation in the intestinal mucosa. Until now, however, it has been unknown whether even microscopic inflammation may be associated with risks in pregnancy.

Higher risk of preterm birth

The present study, shows that microscopic inflammation in IBD, especially ulcerative colitis, is linked to an elevated risk of giving birth prematurely.

Among babies born to women with microscopic inflammation due to IBD, 9.6% were preterm, while 6.5% of children were born preterm to women without microscopic inflammation of IBD. This corresponds to a relative risk increase of 46 percent. Microscopic inflammation was not clearly associated with other adverse pregnancy outcomes, such as growth restriction.

The results are based on register data on women in Sweden, diagnosed with IBD in 1990–2016, in whom information was available on the microscopic appearance of the intestine shortly before pregnancy. The study included 1223 children of women with microscopic IBD inflammation of the intestine and 630 children of women with IBD but with microscopically healed intestinal mucosa.

Through register linkages, data were also retrieved from several national health registers, such as the Swedish Medical Birth Register and the Swedish Quality Register for Inflammatory Bowel Desiease (SWIBREG).

Prospect of new treatment targets

“Our results suggest that IBD treatment aimed at not merely alleviate symptoms of IBD, but also microscopically heal the intestine, can reduce the risk of giving birth preterm,” sayd first author and corresponding author is Karl Mårild, associate professor of paediatrics at Sahlgrenska Academy, University of Gothenburg. “If our results hold up in future studies, they may therefore be the basis for recommendations to confirm microscopic healing before pregnancy, to reduce such risks.”

“Even a modestly increased relative risk of preterm birth is important, given that preterm birth can greatly affect the child’s health in both the short and the long term. Preterm birth is still one of the most common causes of death for children under the age of five in Sweden,” Karl Mårild concludes.

Source: University of Gothenburg

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New Monoclonal Antibody Prevents Malaria Infection in African Adults

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Mosquito, a malaria parasite vector
Photo by Егор Камелев on Unsplash

One dose of a new monoclonal antibody safely protected healthy, non-pregnant adults from malaria infection during the malaria season in Mali. The antibody was up to 88.2% effective at preventing infection over a 24-week period, demonstrating for the first time that a monoclonal antibody can prevent malaria infection in an endemic region. These findings were published in The New England Journal of Medicine.

The only WHO-recommended vaccine against vaccine, RTS,S (Mosquirix), provides partial protection against clinical malaria during the early years of life when given to children aged 5 to 17 months in four doses over a 20-month period. Other drugs consisting of small chemical compounds that effectively prevent malaria infection are also available for infants and young children as well as travellers. The requirement for frequent dosing of these drugs can limit adherence, however, and the emergence of drug resistance may also limit their usefulness. Thus, there is an urgent need for new, fast-acting, infrequently dosed interventions that safely provide strong protection against malaria infection.

Malaria is caused by Plasmodium parasites, which mosquitos inject into into the skin and bloodstream in a form called sporozoites. These travel to the liver, where they mature and multiply before spreading throughout the body via the bloodstream to cause illness. P. falciparum is the Plasmodium species most likely to result in severe malaria infections, which, if not promptly treated, may lead to death.

The Phase 2 NIAID-USTTB trial evaluated the safety and efficacy of a one-time, intravenous infusion of a monoclonal antibody called CIS43LS. This antibody was previously shown to neutralise the sporozoites of P. falciparum in the skin and blood before they could infect liver cells. Researchers led by Robert A. Seder, MD, isolated a naturally occurring form of this antibody from the blood of a volunteer who had received an investigational malaria vaccine, and then modified the antibody to extend the length of time it would remain in the bloodstream.

The study team for the Phase 2 trial enrolled 369 healthy, non-pregnant adults aged 18 to 55 years in the rural communities of Kalifabougou and Torodo in Mali, where intense P. falciparum transmission typically occurs from July through December each year.

The first part of the trial assessed the safety of three different intravenous doses of CIS43LS – 5mg/kg of body weight, 10 mg/kg and 40 mg/kg – in 18 study participants, with six participants per dose level. The study team followed these participants for 24 weeks and found the antibody infusions were safe and well-tolerated.

The second part of the trial assessed the efficacy of two different doses of CIS43LS compared to a placebo. Three hundred and thirty participants were assigned at random to receive either 10mg/kg of the antibody, 40mg/kg, or a placebo by intravenous infusion. No one knew who was assigned to which group until the end of the trial. The study team followed these individuals for 24 weeks, testing their blood for P. falciparum weekly for the first 28 days and every two weeks thereafter. Any participant who developed symptomatic malaria during the trial received standard treatment from the study team.

The investigators analysed the efficacy of CIS43LS two ways. Based on the time to first P. falciparum infection over the 24-week study period, the high dose (40 mg/kg) of CIS43LS was 88.2% effective at preventing infection and the lower dose (10 mg/kg) was 75% effective. An analysis of the proportion of participants infected with P. falciparum at any time over the 24-week study period found the high dose was 76.7% at preventing infection and the lower dose was 54.2% effective.

“These first field results demonstrating that a monoclonal antibody safely provides high-level protection against intense malaria transmission in healthy adults pave the way for further studies to determine if such an intervention can prevent malaria infection in infants, children, and pregnant women,” Dr Seder said. “We hope monoclonal antibodies will transform malaria prevention in endemic regions.”

Dr Seder and colleagues have developed a second antimalarial monoclonal antibody, L9LS, that is much more potent than CIS43LS and therefore can be administered in a smaller dose as a more convenient subcutaneous injection. An early-phase NIAID trial of L9LS in the United States found that the antibody was safe and prevented malaria infection for 21 days in 15 out of 17 healthy adults exposed to P. falciparum in a carefully controlled setting. Two larger, NIAID-sponsored Phase 2 trials assessing the safety and efficacy of L9LS in infants, children and adults are underway in Mali and Kenya.

Source: NIH/National Institute of Allergy and Infectious Diseases

Categories : COVID NeurologyTags : Leave a comment

Delayed COVID Recovery could be a Protective Mechanism against Hypoxia

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COVID patients placed on ventilators can take a long time to regain consciousness. New research published the Proceedings of the National Academy of Sciences now shows that these delays may serve a purpose: protecting the brain from oxygen deprivation.

The existence of such a brain-preserving state could explain why some patients wake up days or even weeks after they stop receiving ventilation, and it suggests that physicians should take these lengthy recovery times into account when determining a patient’s prognosis.

In their study, investigators connect the pattern seen among those who have survived severe COVID with similar delays known to occur in a small fraction of cardiac arrest patients.

“The delayed recoveries in COVID patients are very much like the rare cases we’ve documented in previous research. In this new paper, we describe a mechanism to explain what we’re seeing in both types of patients,” said study co-senior author Dr Nicholas D. Schiff, a neurology professor at Weill Cornell Medicine.

He suggests that this mechanism is the brain protecting itself, pointing to animals, most notably painted turtles, that can tolerate extended periods without oxygen.

More than a decade ago, Dr Schiff and his colleagues first observed these delays among comatose cardiac arrest patients who received cooling therapy to reduce brain damage caused by a loss of blood flow. In one such case, a 71-year-old patient took 37 days to awaken, before ultimately making a near-complete recovery.

During the pandemic, Dr Schiff performed neurology consultations for COVID patients, and he soon began seeing similar, delayed awakenings occurring when patients were taken off ventilators and stopped receiving movement-limiting sedatives.

In a separate analysis of a large cohort of COVID patients from Weill Cornell Medicine and two other major U.S. medical centres, Dr Schiff and his colleagues, including co-author of the current paper, Dr Emery N. Brown, professor of anaesthesia at Harvard Medical School, found that a quarter of patients who survived ventilation took 10 days or longer to recover consciousness. The more oxygen deprivation they suffered while on the ventilator, the longer that delay.

In the prior study of cardiac patients, the researchers recorded a distinctive pattern in brain activity, one also seen in patients under deep anaesthesia. (Recordings from COVID patients are extremely limited.) Dr Schiff read that a similar pattern had been seen in the brains of painted turtles, which can withstand up to five months without oxygen under ice in the winter. To do so, they activate the same inhibitory system within the brain targeted by anaesthetics given to human cardiac and COVID patients but in novel ways developed by evolutionary specialisations.

Drs Schiff and Brown propose that, by chance, the same protective response emerges in the patients.

“It is our theory that oxygen deprivation as well as practices in the ICU, including commonly used anaesthetics, expose elements of strategies that animals use to survive in extreme conditions,” Dr Schiff said.

“These observations may offer new insights into the mechanisms of how certain anaesthetics produce unconsciousness and new approaches for ICU sedation and for fostering recovery from disorders of consciousness,” Dr Brown added.

When patients fail to regain consciousness for an extended time, physicians may recommend withdrawing life-supporting care. This threshold is typically set at 14 days or less for cardiac patients, while no such guidelines exist for COVID.

In light of this new research, however, so long as they lack brain injuries, physicians should avoid making negative projections about these patients’ potential to recover, note the researchers.

Source: Weill Cornell Medicine