Liam Davenport

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

Comprehensive evaluation, multidisciplinary care, individualized treatment, and ongoing follow-up are all key to the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC), according to the first European guidelines for this rare disease.

The guidelines were recently published in the European Thyroid Journal.

Lead author Chantal A. Lebbink told this news organization one of the key takeaways for clinicians is that management of pediatric thyroid nodules and DTC is «challenging and cannot be captured in a one-size-fits-all model.”

She also underlined the need for a “multidisciplinary approach in pediatric thyroid cancer expertise centers.”

Above all, Ms. Lebbink, who is a PhD student in the department of pediatric endocrinology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands, said that pediatric DTC “is not adult DTC in a small person; it has different genetics and a different clinical behavior.”

The authors noted that DTC may be a rare disease, but its worldwide incidence is rising. It has several histologic subtypes, although the “vast majority” of cases are papillary thyroid carcinoma.

Crucially, there are “important differences” between adult and pediatric DTC in terms of their clinical, molecular, and pathologic characteristics, with pediatric patients commonly presenting with more advanced disease with greater lymph node involvement, distant metastases, and multifocal disease.

“However, despite the aggressive presentation, the overall survival rates are excellent,” Ms. Lebbink said.

There are also differences in genetic alterations between adult and pediatric patients. RET-PTC and NTRK fusions are more common in pediatric patients, while mutations in BRAF V600E and RAS point mutations are less frequent.
 

First European guidelines on thyroid cancer, thyroid nodules in children

Despite these differences, and the existence of U.S. guidelines, until now there have been no European recommendations on the management of pediatric thyroid nodules and DTC.

The European Thyroid Association therefore convened a panel of experts in pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology, and tasked them with looking at diagnostics and staging, treatment, and follow-up.

The 2015 American Thyroid Association pediatric guideline was used as framework for the European guideline, with the expert panel identifying areas of discordance and outstanding clinical questions (Thyroid. 2015 Jul;25[7]:716-59).

To answer these questions, they searched PubMed and identified 3,251 studies, of which 45 studies met the inclusion criteria. From this they developed a comprehensive set of recommendations. These include that a child with suspected or proven cancer be referred to an experienced multidisciplinary team and their likely benefit from higher- versus lower-intensity treatment be established.

In addition, children should undergo a preoperative evaluation, with neck palpation, comprehensive neck ultrasonography, and laboratory work-up as a minimum, with further testing suggested in case of a family history or extensive disease.

Total thyroidectomy is the recommended treatment, although the authors call for further studies to assess the impact of limited surgery, and they suggest that prophylactic central lymph node dissection be reserved for advanced cases.

Crucially, all children “should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC,” they wrote.
 

RAI therapy recommended for all children, in contrast to ATA guidelines

Radioactive iodine (I-131) therapy is recommended for all children following total thyroidectomy, with treatment following an individual patient-based approach.

This differs slightly from the ATA guidelines, which recommend against radioactive iodine (RAI) therapy for children with low-risk differentiated thyroid cancer that is mostly confined to the thyroid (N0 or minimal N1a disease). A study presented at the recent 2022 annual meeting of the ATA found that such children who were spared RAI showed no increases in risk of remission compared with those who did receive it.

The ETA guidelines then go on to recommend that children should be followed up with thyroid-stimulating hormone monitoring and suppression to low-normal levels, as well as serum thyroglobulin measurement and neck ultrasound, although other imaging modalities are not recommended.

In children with persistent or recurrent cervical disease, “surgery or I-131 therapy are indicated depending on the size, tumor load, and degree of progression,” and the authors said that cases of radioactive refractory disease should be “thoroughly investigated.”

Patients should also be counseled on the risk of the late effects of treatment for DTC and undergo monitoring, with follow-up continued for at least 10 years. Any subsequent follow-up should be “the result of shared decision-making between the physician and the patient.”
 

Evidence for molecular testing is scarce

Ms. Lebbink said that developing the guidelines nevertheless revealed a series of gaps in current knowledge, notably that the evidence for molecular testing “and the clinical implications in the preoperative stage are scarce.”

Specifically, the “positive and negative predictive value of molecular testing in fine needle biopsy specimen for the presence of DTC in a thyroid nodule must be further investigated.»

She also said that there has been a shift towards less aggressive treatment, due to a reluctance to performed prophylactic central neck dissection, and to offer I-131 therapy after surgery.

“However, before less aggressive treatment could be recommended,” Ms. Lebbink said, “it first must be investigated if there are differences in outcomes,” such as recurrence rates, disease-free survival rates, and survival rates between patients who do and do not receive the treatments.

No funding was declared. One author has reported relationships with Sanofi, AstraZeneca, Bayer, and GE. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

A version of this article first appeared on Medscape.com.

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

A version of this article first appeared on Medscape.com.

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

A version of this article first appeared on Medscape.com.

VIENNA – 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 this news organization 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.”

Dr. 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 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.

A 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.

Dr. 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, Dr. 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, Dr. 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 (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .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 (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .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 noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. 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 coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair 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,” Dr. Weiser added.

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

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

Dr. Brannan 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 cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (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.”

Dr. 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 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. Dr. 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.

A version of this article first appeared on Medscape.com.

VIENNA – 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 this news organization 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.”

Dr. 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 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.

A 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.

Dr. 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, Dr. 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, Dr. 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 (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .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 (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .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 noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. 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 coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair 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,” Dr. Weiser added.

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

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

Dr. Brannan 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 cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (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.”

Dr. 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 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. Dr. 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.

A version of this article first appeared on Medscape.com.

VIENNA – 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 this news organization 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.”

Dr. 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 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.

A 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.

Dr. 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, Dr. 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, Dr. 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 (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .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 (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .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 noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. 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 coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair 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,” Dr. Weiser added.

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

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

Dr. Brannan 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 cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (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.”

Dr. 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 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. Dr. 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.

A version of this article first appeared on Medscape.com.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.

Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.

AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.

Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.

To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.

The update was published online in Clinical Gastroenterology and Hepatology.
 

Some key takeaways

Among its 14 best practice statements, it describes three situations indicative of AKI:

• A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
• A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
• Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.

The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.

Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.

Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.

She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.

In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
 

‘Timely’ update

Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”

This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.

Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.

He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.

Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.

Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.

“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.

“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”

Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

This article was updated 12/12/2022.

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

A version of this article first appeared on Medscape.com.

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

A version of this article first appeared on Medscape.com.

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

A version of this article first appeared on Medscape.com.

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.