Posts Tagged ‘psychiatry’


Dr. Richard C. Friedman in an undated photo. “Straight people had the same personality issues, and they got away with murder,” his wife said, “but gay people were stigmatized, and he didn’t think that was right.” In an important book, he challenged the widely held Freudian notion that same-sex attraction was curable, finding it instead rooted in biology.

By Kim Severson

In the 1980s, when marriage and adopting children seemed impossible dreams for gay men, the psychoanalyst Richard C. Friedman became their champion.

His 1988 book, “Male Homosexuality: A Contemporary Psychoanalytic Perspective,” showed that sexual orientation was largely biological and presented a case that helped undermine the belief held by most Freudian analysts at the time that homosexuality was a pathology that could somehow be cured.

“I felt an ethical obligation to find the reasons for anti-homosexual prejudice,” he once told an interviewer. His wife, Susan Matorin, a clinical social worker at the Weill Medical College of Cornell, put it more plainly: “Straight people had the same personality issues, and they got away with murder, but gay people were stigmatized, and he didn’t think that was right.”

Dr. Friedman’s motivation wasn’t political. “He very much felt like you followed the science, and it didn’t matter what the political backdrop was,” his son, Jeremiah, a screenwriter in Los Angeles, said in a phone interview.

Although the American Psychiatric Association, the dominant mental health organization in the United States, changed its diagnostic manual in 1973 and stopped classifying homosexuality as an illness, psychoanalysts continued to describe homosexuality as a perversion, and many believed it could be cured.

Dr. Friedman, using studies of identical twins and theories of developmental psychology, made a scholarly rather than ideological case that biology rather than upbringing played a significant role in sexual orientation.

It was a direct challenge to popular Freudian theories and thrust him into the center of debates among the more established heavyweights of psychoanalysis. It led to a model in which analyst and patient simply assumed that homosexuality was intrinsic, said Jack Drescher, a professor of psychiatry at Columbia University who knew Dr. Friedman and would later offer his own critiques of Dr. Friedman’s theory as new approaches to working with gay and lesbian patients emerged.

“Given that he was a younger colleague, it was brave of him to take older experts on,” Professor Drescher said. But it was in keeping with who he was. “He had an edge and wasn’t afraid of anybody,” he said.

Dr. Friedman died on March 31 at his home in Manhattan. Though the specific cause was not clear, Ms. Matorin said, he had for years been grappling with a number of health problems, including cardiac and metabolic conditions. He was 79.

Richard C. Friedman was born on Jan. 20, 1941, in the Bronx, the oldest of three sons of William Friedman and Henrietta Fuerstein. His father was a food inspector for the city; his mother a teacher.

His parents instilled in their sons a deep love of learning — all three would go on to become doctors — and of music, insisting on violin and piano lessons. Dr. Friedman would help pay for medical school by playing the accordion at events, and he remained an excellent pianist.


Dr. Friedman’s 1988 book showed that sexual orientation was largely biological and presented a case that helped undermine the belief held by most Freudian analysts that homosexuality was a pathology that could be cured.

At the time, a child could still get beaten on the streets of the Bronx for being, like Richard, Jewish, and his family was deeply affected by genocide in Europe during World War II.

While he was at the Bronx High School of Science, he received a National Merit Scholarship and used it to attend Bard College in Annandale-on-Hudson, N.Y., graduating in 1961. Five years later he graduated from the University of Rochester School of Medicine and Dentistry and became a psychiatric resident at the New York State Psychiatric Institute and the Columbia Presbyterian Medical Center, both in Manhattan.

Although he was best known for his work on human sexuality, Dr. Friedman was equally proud of a study he did at the medical center that showed that medical interns performed poorly when they were sleep-deprived. The work helped change how medical schools trained up-and-coming doctors.

After enlisting in the United States Army Medical Corps, he became chief of inpatient psychiatry at William Beaumont Army Medical Center in El Paso, Texas, where he treated traumatized young men returning from the Vietnam War. It was there, his son said, that his suspicion of ingrained authority deepened.

Dr. Friedman would go on to become a clinical professor of psychiatry at Weill Cornell Medical College and a faculty member at Columbia University. He published more books and numerous articles on human sexuality, working with Dr. Jennifer Downey, a Manhattan psychiatrist and Columbia professor. He was also the longtime editor of the journal Psychodynamic Psychiatry.

Intellectually restless, Dr. Friedman was a civic-minded student of history who was well-versed in Shakespeare, a devoted reader of biographies and a fan of opera, not to mention the New York Knicks.

He was also a methodical man with distinct tastes, his family said. He always carried a copy of the United States Constitution, and without fail he would slip on gaberdine pants, an oxford shirt, a tie and a blue blazer when he went to his office on Manhattan’s Upper West Side. Saturdays were more casual. He left off the tie.

In addition to his wife and son, he is survived by two daughters from a previous marriage, Heidi Friedman and Carla Greene; two brothers, Daniel and Joseph; and two grandchildren.

Although his critics found him to be unyielding in his views, coming off as if he thought he was the smartest person in the room (and often he was), he had a thriving private practice and devoted patients.

One was the author Andrew Solomon, whose book “The Noonday Demon: An Atlas of Depression” won the National Book Award for nonfiction in 2001. He was Dr. Friedman’s patient for 25 years. Without him, Mr. Solomon said, he might never have understood that as a gay man he could be married and have a family, or that he was capable of professional accomplishment.

“What was most striking was just his confidence and clarity,” Mr. Solomon said.


Jane Timmons-Mitchell, senior research associate at the Begun Center for Violence Prevention Research and Education at the university’s Jack, Joseph and Morton Mandel School of Applied Social Sciences


Screenshot of the virtual training taken by more than 33,000 middle-school educators across the nation.

Aside from car crashes, suicide is now the second-leading cause of death among young people in the United States, according to the Centers for Disease Control and Prevention. In Ohio alone, suicide is the leading cause of death for 10- to 14-year-olds, according to new data from the state’s health department.

Experts agree that among the most effective ways to prevent suicide among youth is getting adults to pay attention to the warning signs.

Toward that goal, new research from Case Western Reserve University examined the impact of virtual training on the mental-health and suicide-prevention skills of more than 33,000 mid­dle-school educators. The researchers found, overwhelmingly, that those who completed the training had “higher levels of preparedness” in identifying suicide warning signs than participants at the pre-test evaluation.

“Middle-school educators can play a big role in suicide prevention,” said Jane Timmons-Mitchell, a senior research associate at the Begun Center for Violence Prevention Research and Education at the university’s Jack, Joseph and Morton Mandel School of Applied Social Sciences. “These educators are the gatekeepers. It’s not just teachers—this is everyone in the educational system, from lunch ladies to bus drivers.”

The idea behind the research was to get more educators trained—and to bring more awareness to the importance of the training—in suicide prevention.

“Bus drivers, for example have a great baseline for what a student is usually like, and they’re on the frontlines and are able to watch out for behavior that’s out of the ordinary,” Timmons-Mitchell said.

The virtual training, Kognito At-Risk simulation, is essentially an online role-playing video game that replicates interactions with at-risk youth. The program also covers topics such as bullying, she said.

Timmons-Mitchell, lead evaluator on the research, said that of the 33,703 educators nationally who participated, more than 90% had never received any kind of mental-health training.

“The training by itself, while helpful, is just a part of the system,” she said. “The training helps teach them about the next steps, which includes getting the information to trained professionals such as guidance counselors.”

More than half the states nationally—and a few other countries—already require this type of training, Timmons-Mitchell said.

“There’s a consensus that more people than teachers need to be prepared,” she said. “This is a very straightforward concept. It’s commonly discussed in academia, but there is a real result here in the classrooms, lunchrooms and school buses around the country.”

The research was done with financial support from the Garrett Lee Smith Youth Suicide Prevention and Early Intervention grant program, administered by the U.S. Department of Health and Human Services.

Timmons-Mitchell was joined in the research by Glenn Albright, from Baruch College at City University of New York; Jeremiah McMillan, a doctoral candidate at the University of Georgia; Kristen Shockley, associate professor at the University of Georgia; and Seungjong Cho, a doctoral candidate at the Mandel School at Case Western Reserve.

For more information, contact Colin McEwen at colin.mcewen@case.edu.

Training middle-school educators to identify suicide warning signs


In a series of recently published studies using animals and people, Johns Hopkins Medicine researchers say they have further characterized a set of chemical imbalances in the brains of people with schizophrenia related to the chemical glutamate. And they figured out how to tweak the level using a compound derived from broccoli sprouts.

In a series of recently published studies using animals and people, Johns Hopkins Medicine researchers say they have further characterized a set of chemical imbalances in the brains of people with schizophrenia related to the chemical glutamate. And they figured out how to tweak the level using a compound derived from broccoli sprouts.

They say the results advance the hope that supplementing with broccoli sprout extract, which contains high levels of the chemical sulforaphane, may someday provide a way to lower the doses of traditional antipsychotic medicines needed to manage schizophrenia symptoms, thus reducing unwanted side effects of the medicines.

“It’s possible that future studies could show sulforaphane to be a safe supplement to give people at risk of developing schizophrenia as a way to prevent, delay or blunt the onset of symptoms,” adds Akira Sawa, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Schizophrenia Center.

Schizophrenia is marked by hallucinations, delusions and disordered thinking, feeling, behavior, perception and speaking. Drugs used to treat schizophrenia don’t work completely for everyone, and they can cause a variety of undesirable side effects, including metabolic problems increasing cardiovascular risk, involuntary movements, restlessness, stiffness and “the shakes.”

In a study described in the Jan. 9 edition of the journal JAMA Psychiatry, the researchers looked for differences in brain metabolism between people with schizophrenia and healthy controls. They recruited 81 people from the Johns Hopkins Schizophrenia Center within 24 months of their first psychosis episode, which can be a characteristic symptom of schizophrenia, as well as 91 healthy controls from the community. The participants were an average of 22 years old, and 58% were men.

The researchers used a powerful magnet to measure and compare five regions in the brain between the people with and without psychosis. A computer analysis of 7-Tesla magnetic resonance spectroscopy (MRS) data identified individual chemical metabolites and their quantities.

The researchers found on average 4% significantly lower levels of the brain chemical glutamate in the anterior cingulate cortex region of the brain in people with psychosis compared to healthy people.

Glutamate is known for its role in sending messages between brain cells, and has been linked to depression and schizophrenia, so these findings added to evidence that glutamate levels have a role in schizophrenia.

Additionally, the researchers found a significant reduction of 3% of the chemical glutathione in the brain’s anterior cingulate cortex and 8% in the thalamus. Glutathione is made of three smaller molecules, and one of them is glutamate.

Next, the researchers asked how glutamate might be managed in the brain and whether that management is faulty in disease. They first looked at how it’s stored. Because glutamate is a building block of glutathione, the researchers wondered if the brain might use glutathione as a way to store extra glutamate. And if so, the researchers questioned if they could use known drugs to shift this balance to either release glutamate from storage when there isn’t enough, or send it into storage if there is too much.

In another study, described in the Feb. 12 issue of the journal PNAS, the team used the drug L-Buthionine sulfoximine in rat brain cells to block an enzyme that turns glutamate into glutathione, allowing it to be used up. The researchers found that theses nerves were more excited and fired faster, which means they were sending more messages to other brain cells. The researchers say shifting the balance this way is akin to shifting the brain cells to a pattern similar to one found in the brains of people with schizophrenia. Next, the researchers wanted to see if they could do the opposite and shift the balance to get more glutamate stored in the form of glutathione. They used the chemical sulforaphane found in broccoli sprouts, which is known to turn on a gene that makes more of the enzyme that sticks glutamate with another molecule to make glutathione. When they treated rat brain cells with glutathione, it slowed the speed at which the nerve cells fired, meaning they were sending fewer messages. The researchers say this pushed the brain cells to behave less like the pattern found in brains with schizophrenia.

“We are thinking of glutathione as glutamate stored in a gas tank,” says Thomas Sedlak, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences. “If you have a bigger gas tank, you have more leeway on how far you can drive, but as soon as you take the gas out of the tank it’s burned up quickly. We can think of those with schizophrenia as having a smaller gas tank.”

Because sulforaphane changed the glutamate imbalance in the rat brains and affected how messages were transmitted between the rat brain cells, the researchers wanted to test whether sulforaphane could change glutathione levels in healthy people’s brains and see if this could eventually be a strategy for people with mental disorders. For their study, published in April 2018 in Molecular Neuropsychiatry, the researchers recruited nine healthy volunteers (four women, five men) to take two capsules with 100 micromoles daily of sulforaphane in the form of broccoli sprout extract for seven days.

The volunteers reported that a few of them were gassy and some had stomach upset when eating the capsules on an empty stomach, but overall the sulforaphane was relatively well tolerated.

The researchers used MRS again to monitor three brain regions for glutathione levels in the healthy volunteers before and after taking sulforaphane. They found that after seven days, there was about a 30% increase in average glutathione levels in the subjects’ brains. For example, in the hippocampus, glutathione levels rose an average of 0.27 millimolar from a baseline of 1.1 millimolar after seven days of taking sulforaphane.

The scientists say further research is needed to learn whether sulforaphane can safely reduce symptoms of psychosis or hallucinations in people with schizophrenia. They would need to determine an optimal dose and see how long people must take it to observe an effect. The researchers caution that their studies don’t justify or demonstrate the value of using commercially available sulforaphane supplements to treat or prevent schizophrenia, and patients should consult their physicians before trying any kind of over-the-counter supplement. Versions of sulforaphane supplementsare sold in health food stores and at vitamin counters, and aren’t regulated by the U.S. Food and Drug Administration.

“For people predisposed to heart disease, we know that changes in diet and exercise can help stave off the disease, but there isn’t anything like that for severe mental disorders yet,” says Sedlak. “We are hoping that we will one day make some mental illness preventable to a certain extent.”

Sulforaphane is found in a variety of cruciferous vegetables, and was first identified as a “chemoprotective” substance decades ago by Paul Talalay and Jed Fahey at Johns Hopkins.

According to the World Health Organization, schizophrenia affects about 21 million people worldwide.

https://www.eurekalert.org/pub_releases/2019-05/jhm-bsc050619.php


A growing body of research suggests psychedelic mushrooms may have therapeutic benefits for certain conditions. Now a movement seeks to decriminalize them.

Douglas rattles around a collection of glass jars in the storage closet of his Denver apartment. They’re filled with sterilized rye grains, covered in a soft white fungus — a mushroom spawn. Soon, he’ll transplant it in large plastic bins filled with nutrients such as dried manure and coconut fiber.

Over the course of two weeks, a crop of mushrooms that naturally contain psilocybin, a psychoactive ingredient, will sprout. The species he grows include psilocybe cubensis.

“I mean, it’s a relatively quiet thing to do. There’s just lots of waiting,” says Douglas, which is his middle name. He didn’t want to be identified because this is an illegal grow-and-sell operation; psychedelic mushrooms were federally banned in 1970, along with several other hallucinogens.

“Mushrooms are really easygoing, especially psilocybin,” he says. “They kind of just grow themselves.”

Denver is at the forefront of a national movement that seeks to access these mushrooms, largely for medicinal use. On Tuesday, voters are weighing in on a ballot measure to decriminalize them. And while that may sound ambitious, a campaign in Oregon is gathering signatures for a ballot measure in the 2020 election and seeks to legalize mushrooms with a medical prescription for use in approved clinics.

In Iowa, Republican lawmaker Jeff Shipley recently proposed two bills: one removing psilocybin from the state’s list of controlled substances, and the other legalizing it for medical use. And last year, a campaign in California did not get enough signatures to qualify for the ballot. The group that led the campaign hopes to try again in 2020, according to their Facebook page.

For Douglas, it’s a sign that change is on the horizon, one that could have implications for his business, which he says he runs for the supplemental income, but also because he believes mushrooms are beneficial.

“Cultivating psilocybin and offering medicine to people to change their lives, that will be my mission, or my way of serving others,” he says.

With his DIY setup of glass jars, large plastic bins and a pressure cooker for sterilization, Douglas can produce up to $1,000 of mushrooms a month. He learned how to do this thanks to Internet videos. He purchased his first mushroom spores online and received them in the mail; companies legally are allowed to sell spores since they don’t contain psilocybin.

If the Denver ballot measure passes, adults 21 and older who are caught with psilocybin mushrooms, or even growing them for personal use, would become the “lowest law enforcement priority” for local police. Plus, the city and county of Denver would be barred from spending any money to prosecute psilocybin cases.

The notion that state laws around mushrooms could be loosened up, much like they have been for cannabis, is not without controversy. Matthew Johnson, who has spent the past 15 years researching psychedelics at Johns Hopkins University in Baltimore, says decriminalization of illegal drugs is generally a good thing, but he wouldn’t support policy that encourages people to use psilocybin without professional supervision.

“(This therapy) needs to be done by appropriately trained and credentialed medical and psychological professionals,” he says.

Research suggests that psilocybin is not addictive, causes few ER visits compared to other illegal drugs and could be used to treat a number of ailments. Johnson believes the most promising research is on treating anxiety and depression in cancer patients. In a study he conducted with other researchers at Johns Hopkins, he says they found even a single dose can positively affect an individual for several months.

“It’s really unprecedented in medical history to see effects for depression that are caused by a single medication,” he says.

Preliminary research has been conducted for other potential uses, including curbing nicotine addiction and for treatment-resistant depression. And while Johnson believes psilocybin could one day become a groundbreaking treatment, he’s emphatic about the potential risks involved.

“The most common side effect is the so-called ‘bad trip,’ ” he says. “(It) can be well-managed in a medical research setting, but that sometimes leads to dangerous behavior when out in the wild.”

Under the influence of psilocybin, people can panic and put themselves in unsafe situations; there have been fatalities, he says.

Johnson says he thinks that, in as little as five years, research on psilocybin will lead to the first medication approved by the Federal Drug Administration. Once that happens, he thinks the government will have to remove it as a Schedule 1 drug — a substance like heroin that the DEA considers to have “no accepted medical use and a high potential for abuse.”

Until then, Deanne Reuter, the assistant special agent in charge at the DEA’s Denver office, says the agency will continue prosecuting cases of psilocybin possession and trafficking.

“Any controlled substance is a concern,” she says. “It’s obviously on a Schedule 1 for a reason.”

Reuter admits they don’t see many cases of psilocybin trafficking. Typically, they’ll bust a drug dealer carrying several types of narcotics, including mushrooms.

“The trafficking of psilocybin seems to be like a small, niche kind of community,” she says.

Douglas would agree. He has little competition and knows most of the people he sells his product to. Still, he knows the work he does it risky.

“With decriminalization and stuff I can operate a little bit more freely, have to worry less,” he says.

If the Denver ballot measure passes, it wouldn’t protect someone like him, who’s selling mushrooms for profit. Still, he says it’d be a step closer to a future where he can freely provide people with something he believes in.

https://www.npr.org/sections/health-shots/2019/05/07/720828367/a-growing-push-to-loosen-laws-around-psilocybin-treat-mushrooms-as-medicine

The Food and Drug Administration (FDA) approved Friday the first medical device to treat childhood attention deficit hyperactivity disorder, or ADHD.

The device, approved for children ages 7 to 12 who do not currently take ADHD medicine, delivers a low-level electrical pulse to a patch placed on the forehead that interacts with the parts of the brain responsible for ADHD symptoms.

“This new device offers a safe, non-drug option for treatment of ADHD in pediatric patients through the use of mild nerve stimulation, a first of its kind,” Carlos Peña, director of the Division of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health, said in a statement.

“Today’s action reflects our deep commitment to working with device manufacturers to advance the development of pediatric medical devices so that children have access to innovative, safe and effective medical devices that meet their unique needs.”

The device, called the Monarch external Trigeminal Nerve Stimulation System (eTNS), is marketed by NeuroSigma and is only available by prescription and must be monitored by a caregiver.

eTNS, which is designed to fit inside one’s pocket, is connected by wire to a patch that is placed on the forehead while sleeping and delivers a “tingling” electrical impulse to branches of the trigeminal nerve.

“While the exact mechanism of eTNS is not yet known, neuroimaging studies have shown that eTNS increases activity in the brain regions that are known to be important in regulating attention, emotion and behavior,” the FDA said.

The FDA also conducted a trial with 62 children with ADHD in which a group that used eTNS had “significant improvement” in their symptoms as opposed to another group that used a placebo.

Side effects of the treatment include drowsiness, an increase in appetite, trouble sleeping, teeth clenching, headache and fatigue. The device should not be placed near a phone or used by children on an insulin pump, pacemaker or implanted neurostimulator, the FDA said.

The FDA found no serious adverse events associated with eTNS.

The device is not currently covered by insurance and has a price tag of just over $1,000 for a starter kit, according to the NeuroSigma website.

https://thehill.com/policy/healthcare/439836-fda-gives-green-light-to-first-medical-device-to-treat-adhd-in-children

By Simon Makin

The Food and Drug Administration’s approval last month of a depression treatment based on ketamine generated headlines, in part, because the drug represents a completely new approach for dealing with a condition the World Health Organisation has labelled the leading cause of disability worldwide. The FDA’s approval marks the first genuinely new type of psychiatric drug—for any condition—to be brought to market in more than 30 years.

Although better known as a party drug, the anesthetic ketamine has spurred excitement in psychiatry for almost 20 years, since researchers first showed that it alleviated depression in a matter of hours. The rapid reversal of symptoms contrasted sharply with the existing set of antidepressants, which take weeks to begin working. Subsequent studies have shown ketamine works for patients who have failed to respond to multiple other treatments, and so are deemed “treatment-resistant.”

Despite this excitement, researchers still don’t know exactly how ketamine exerts its effects. A leading theory proposes that it stimulates regrowth of synapses (connections between neurons), effectively rewiring the brain. Researchers have seen these effects in animals’ brains, but the exact details and timing are elusive.

A new study, from a team led by neuroscientist and psychiatrist Conor Liston at Weill Cornell Medicine, has confirmed that synapse growth is involved, but not in the way many researchers were expecting. Using cutting-edge technology to visualize and manipulate the brains of stressed mice, the study reveals how ketamine first induces changes in brain circuit function, improving “depressed” mice’s behavior within three hours, and only later stimulating regrowth of synapses.

As well as shedding new light on the biology underlying depression, the work suggests new avenues for exploring how to sustain antidepressant effects over the long term. “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine,” says Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health, who was not involved in the study. “This work will likely set a path for what treatments should be doing before we move them into the clinic.”

Another reason ketamine has researchers excited is that it works differently than existing antidepressants. Rather than affecting one of the “monoamine” neurotransmitters (serotonin, norepinephrine, and dopamine), as standard antidepressants do, it acts on glutamate, the most common chemical messenger in the brain. Glutamate plays an important role in the changes synapses undergo in response to experiences that underlie learning and memory. That is why researchers suspected such “neuroplasticity” would lie at the heart of ketamine’s antidepressant effects.

Ketamine’s main drawback is its side effects, which include out-of-body experiences, addiction and bladder problems. It is also not a “cure.” The majority of recipients who have severe, difficult-to-treat depression will ultimately relapse. A course of multiple doses typically wears off within a few weeks to months. Little is known about the biology underlying depressive states, remission and relapse. “A big question in the field concerns the mechanisms that mediate transitions between depression states over time,” Liston says. “We were trying to get a better handle on that in the hopes we might be able to figure out better ways of preventing depression and sustaining recovery.”

Chronic stress depletes synapses in certain brain regions, notably the medial prefrontal cortex (mPFC), an area implicated in multiple aspects of depression. Mice subjected to stress display depressionlike behaviors, and with antidepressant treatment, they often improve. In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

For the experiment, some mice became stressed when repeatedly restrained, others became so after they were administered the stress hormone corticosterone. “That’s a strength of this study,” says neuroscientist Anna Beyeler, of the University of Bordeaux, France, who was not involved in the work, but wrote an accompanying commentary article in Science. “If you’re able to observe the same effects in two different models, this really strengthens the findings.” The team first observed the effects of subjecting mice to stress for 21 days, confirming that this resulted in lost spines. The losses were not random, but clustered on certain dendrite branches, suggesting the damage targets specific brain circuits.

The researchers then looked a day after administering ketamine and found that the number of spines increased. Just over half appeared in the same location as spines that were previously lost, suggesting a partial reversal of stress-induced damage. Depressionlike behaviors caused by the stress also improved. The team measured brain circuit function in the mPFC, also impaired by stress, by calculating the degree to which activity in cells was coordinated, a measure researchers term “functional connectivity.” This too improved with ketamine.

When the team looked closely at the timing of all this, they found that improvements in behavior and circuit function both occurred within three hours, but new spines were not seen until 12 to 24 hours after treatment. This suggests that the formation of new synapses is a consequence, rather than cause, of improved circuit function. Yet they also saw that mice who regrew more spines after treatment performed better two to seven days later. “These findings suggest that increased ensemble activity contributes to the rapid effects of ketamine, while increased spine formation contributes to the sustained antidepressant actions of ketamine,” says neuroscientist Ronald Duman, of the Yale School of Medicine, who was not involved in the study. Although the molecular details of what happens in the first hours are not yet fully understood, it seems a restoration of coordinated circuit activity occurs first; this is then entrenched by neuroplasticity effects in synapses, which then maintain behavioral benefits over time.

To prove that new synapses were a cause of antidepressant effects, rather than just coinciding with the improved behaviors, the team used a newly developed optogenetic technique, which allowed them to eliminate newly formed spines using light. Optogenetics works by introducing viruses that genetically target cells, causing them to produce light-sensitive proteins. In this case, the protein is expressed in newly formed synapses, and exposure to blue light causes the synapse to collapse. The researchers found that eliminating newly formed synapses in ketamine-treated mice abolished some of the drug’s positive effects, two days after treatment, confirming that new synapses are needed to maintain benefits. “Many mechanisms are surely involved in determining why some people relapse and some don’t,” Liston says, ” but we think our work shows that one of those involves the durability of these new synapses that form.”

And Liston adds: “Our findings open up new avenues for research, suggesting that interventions aimed at enhancing the survival of these new synapses might be useful for extending ketamine’s antidepressant effects.” The implication is that targeting newly formed spines might be useful for maintaining remission after ketamine treatment. “This is a great question and one the field has been considering,” Duman says. “This could include other drugs that target stabilization of spines, or behavioral therapies designed to engage the new synapses and circuits, thereby strengthening them.”

The study used three behavioral tests: one involving exploration, a second a struggle to escape, and a third an assessment of how keen the mice are on a sugar solution. This last test is designed to measure anhedonia—a symptom of depression in which the ability to experience pleasure is lost. This test was unaffected by deleting newly formed spines, suggesting that the formation of new synapses in the mPFC is important for some symptoms, such as apathy, but not others (anhedonia)—and that different aspects of depression involve a variety of brain circuits.

These results could relate to a study published last year that found activity in another brain region, the lateral habenula, is crucially involved in anhedonia, and injecting ketamine directly into this region improves anhedonia-related behavior in mice. “We’re slowly identifying specific regions associated with specific behaviors,” Beyeler says. “The factors leading to depression might be different depending on the individual, so these different models might provide information regarding the causes of depression.”

One caveat is that the study looked at only a single dose, rather than the multiple doses involved in a course of human treatment, Zarate says. After weeks of repeated treatments, might the spines remain, despite a relapse, or might they dwindle, despite the mice still doing well? “Ongoing effects with repeated administration, we don’t know,” Zarate says. “Some of that work will start taking off now, and we’ll learn a lot more.” Of course, the main caution is that stressed mice are quite far from humans with depression. “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans,” Beyeler says.

https://www.scientificamerican.com/article/behind-the-buzz-how-ketamine-changes-the-depressed-patients-brain/

By Elizabeth Chuck and Lauren Dunn

The intrusive thoughts started weeks after Stephanie Hathaway gave birth: an overwhelming feeling that her daughter deserved a better mother; that her husband deserved a better wife; that her future was hopeless.

“They just played on repeat in my head,” Hathaway, 33, of South Glastonbury, Connecticut, said. “I was holding my baby one night, and my husband was at a meeting, and I just thought, ‘Oh, my goodness. If I put the baby down, I might hurt myself.’”

Hathaway was diagnosed with postpartum depression — the intense sadness, anxiety or despair that occurs within the first year after giving birth, according to the Centers for Disease Control and Prevention. It affects about one in nine women, although the rate may be as high as one in every five women, the CDC finds.

Hathaway’s doctor put her on antidepressants, which helped some, but it took two weeks for the medication to kick in, and even longer until her doctor found the appropriate dosage for her. As she waited for relief, Hathaway found herself struggling to bond with her newborn, Hadley, who is now 4.

“It’s heartbreaking,” Hathaway, who had never suffered from depression before and is now a mother to two girls, said. “That’s not what I expected to feel.”

Up until this point, new mothers experiencing postpartum depression have been prescribed the same antidepressants used for treating depression in the general population, such as selective serotonin reuptake inhibitors. The drugs can take weeks to take effect, and do not address the hormonal changes that women go through during and after pregnancy.

But on Tuesday, the Food and Drug Administration approved the first drug specifically developed for postpartum depression, called brexanolone, or Zulresso.

Brexanolone is novel because it has a synthetic form of the hormone allopregnanolone, a progesterone derivative, in it. The hormone increases throughout a woman’s pregnancy and then plummets after she gives birth, a possible contributor to postpartum depression.

“This can potentially transform women’s lives and that of their families,” said Dr. Steve Kanes, chief medical officer of Sage Therapeutics, the Cambridge, Mass., biopharmaceutical company that developed brexanolone. “It’s not just the mother who suffers when there’s postpartum depression. It’s the newborn. It’s the other people in their family.”

Brexanolone is not a pill. The drug is delivered intravenously over the course of a 60-hour infusion, meaning it must be administered in a medically supervised setting, such as a skilled facility or a hospital, rather than at patients’ homes.

IMPROVEMENT IN JUST 24 HOURS

Clinical trials for the drug were promising — not just in the number of women it helped, but in the near-instantaneous relief that is provided.

In double-blind, placebo-controlled trials, many women with moderate to severe postpartum depression saw a marked improvement of their symptoms within just 24 hours of receiving the drug. That improvement was still present 30 days after the infusion, the length of the trial.

“This is for postpartum depression, but it is a step in understanding how we treat depression more broadly,” said Dr. Samantha Meltzer-Brody, director of the perinatal psychiatry program at the University of North Carolina at Chapel Hill and the academic principal investigator in the brexanolone trials. “We have had the same treatments for depression for 30 years. There’s an enormous need for new, novel ways to treat depression, and to treat it quickly.”

The drug’s approval comes just weeks after the FDA signed off on esketamine, a fast-acting nasal spray that uses the active ingredients in the club drug ketamine, as a treatment for severe depression.

For patients who are depressed, rapid relief is a priority. Hathaway, the Connecticut mother, was again diagnosed with postpartum depression after she gave birth to her second, a girl named Brenley who is now 2. This time, the antidepressants did not help at all, and Hathaway felt herself slipping deeper and deeper into a state of hopelessness.

She participated in a brexanolone trial, and her response was striking. Between hours 12 and 18 of the 60-hour infusion, she noticed her despair had waned.

“I woke up from a nap, and the thoughts were gone. And they never came back,” Hathaway said. “And then hour after hour, I got my energy back. I got my appetite back. I was eating because I was actually hungry, not because people were making me eat.”

A COMMON CONDITION

Postpartum depression afflicts as many as 400,000 women in the United States each year. It can include disturbances in sleep or eating patterns in addition to feelings of sadness or apathy. Affected women are often confused and guilt-ridden about why they are feeling down during what is supposed to be a happy time, said Dr. Christine C. Greves, an obstetrician-gynecologist at Orlando Health Winnie Palmer Hospital for Women and Babies.

“As women, we feel like we were born to have a child, and there’s a white picket fence, and life will be great,” said Greves, who does not have ties to Sage Therapeutics. “Then regular life comes into play. You have a child and then you top that with extensive fatigue, hormones, expectations that just can’t be met. It’s all fantasy until we actually have the baby. And then you do feel guilty, because we all want to be Super Mom.”

In the past decade, experts say, there has been more awareness about postpartum depression and more efforts among obstetricians and pediatricians to screen mothers for it.

But having a drug specifically aimed at treating postpartum depression will be one of the most significant steps toward removing any stigma still associated with the condition, said Dr. Kimberly Yonkers, professor of psychiatry, epidemiology and obstetrics, gynecology and reproductive sciences at the Yale School of Medicine.

“It does women a service because it really brings attention to a major medical problem and provides legitimacy, and hopefully will encourage people, whether they use this medication or not, to seek and obtain treatment,” said Yonkers, who does not have ties to the drug company. “We’re all thrilled about that.”

SOME SIDE EFFECTS, AND A HEFTY PRICE TAG

The most common side effects during the brexanolone trial were drowsiness and dizziness. The drug is not believed to have any long-term safety concerns. Kanes, Sage Therapeutics’ chief medical officer, said he expects it will be deemed safe for all mothers, including breastfeeding mothers, but the company is waiting for an FDA ruling on breastfeeding.

The drug comes with a hefty price tag: Sage says it is expected to cost somewhere between $20,000 to $35,000 for the infusion. That does not include the price of a stay in whatever facility it is administered in. It is not clear yet how much insurance would cover.

Kanes pointed out that while high, the cost is a one-time price.

“That’s such an important piece as to why this is so novel. We’re talking about a single treatment that has durable effects,” he said. “This really is a one-time intervention that gets people on their way. It’s transformative.”

For Hathaway, the brexanolone infusion enabled her to return home and be the mother to her daughters that she had wanted to be before postpartum depression took over.

“It’s given them their mom back,” she said. “This is what it was supposed to be like.”

https://www.nbcnews.com/health/womens-health/fda-approves-first-drug-postpartum-depression-n984521