Esketamine: a New Approach for Patients with Treatment-Resistant Depression

Hopkins THE NEWSLETTER OF THE JOHNS HOPKINS DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES FALL 2019

Esketamine: A New Approach for Patients with Treatment-Resistant Depression

ne thing almost all psychiatrists can The reason esketamine is so effective, explains multiple sclerosis agree on,” says psychiatry researcher Kaplin, is that it’s delivered not only through a and transverse OAdam Kaplin, “is this: We need antide- different receptor, but via an ion channel — a myelitis centers pressants that work more quickly and for more much faster route to deliver a signal down the of excellence. people.” neuron highway of the brain. “It targets dozens “That’s good Indeed, the serotonin selective reuptake of brain connections at once, not just one, and news for my inhibitors (SSRIs) that aim to strengthen the manipulates the neurotransmitter glutamate, patients with brain’s circuits and neurotransmitters normally which many neurons in the brain use to MS and other take seven to 14 days to begin to reduce communicate with each other.” autoimmune diseases,” symptoms. That delay poses an increased risk Ketamine is not without controversy. Classified he says, pointing out that of suicide for people with treatment-resistant as a schedule III controlled substance, it’s an 50% of patients with MS Illustration of a depression, says Kaplin. analog of phencyclidine (PCP) and became a suffer from depression. ketamine molecule. Now, after three years of studying how the drug popular party/club drug, nicknamed “Special K.” Suicide from depression is the esketamine — a more potent form of ketamine — But Kaplin is quick to defend its reputation. third leading cause of death in patients with MS might relieve symptoms in these patients, Kaplin He notes that in 1970, the FDA approved across their lifespan. and his colleagues are hopeful. “What’s really ketamine for use as an anesthetic in pediatric and So far, Kaplin says, electroconvulsive therapy important about this drug,” he says, “is that it’s adult surgeries because of its high level of safety has offered the best approach for treatment- the first to work for treatment-resistant depression and immediate response. Used in the recent rescue resistant psychotic depression. But it’s not without with immediate effect. It also appears to reduce of 12 young boys and their soccer coach from a side effects. These include confusion, memory loss, suicidal ideation.” flooded cave in Thailand, the drug is listed on nausea and headaches. Ketamine, too, has possible Kaplin’s research, part of a multisite, the World Health Organization’s list of essential side effects, including mild nausea, dizziness and international trial, investigated the biological medicines. confusion, but patients are closely observed for basis of depression and usefulness of intranasal “Ketamine has a vital role in surgery,” says at least two hours after treatment to ensure their esketamine to treat it. Johns Hopkins will soon Kaplin, “and the findings in our trials in patients safety, after which the side effects are gone. begin offering the FDA-approved intranasal with treatment-resistant depression have been Seeing the positive effect of esketamine on treatment to patients with intractable depression encouraging.” In these studies, he notes, the patients, says Kaplin, “has been like watching the in a supervised clinic setting (see sidebar). dose is significantly lower than club use or as an World Cup. It’s kind of an end goal for us: It’s Collectively, across all sites participating in anesthetic. not perfect, but for patients who don’t respond the trial, the response rate was between 53% and The esketamine trials also suggest an anti- to other treatments, esketamine can provide 69% during the first month of inflammatory effect, notes Kaplin, who serves immediate relief from despair.” n treatment. as psychiatric consultant for the Johns Hopkins

“Unlike other antidepressants, esketamine targets dozens of brain connections at once.” — ADAM KAPLIN Nearly 25 million adults have been taking antidepressants for at least two years — a 60% Johns Hopkins Esketamine Clinic Among First increase since 2010. in the U.S. Soon patients with treatment-resistant depression may be eligible to receive 15 million Approximately esketamine nasal spray treatments. adults 15.5 million adults • The treatment is for patients • Each patient is informed about have been taking with at least two failed serious adverse outcomes and antidepressants for antidepressant regimens. need for monitoring. at least five years — • Each nasal spray container • Patients are enrolled 7.2 million doubling the rate since provides exactly two doses. in a registry to further adults 2010. • Administration is medically characterize risks and supervised. support. Source: Centers for Disease Control and • Patients are monitored by a • Esketamine is used alongside an Prevention health care provider for at antidepressant. least two hours. 2010 2019

To learn more: 410-502-0622 U.S. ADULTS TAKING ANTIDEPRESSANTS

HOPKINS BRAIN WISE • FALL 2019 • 1 FROM THE DIRECTOR SCHIZOPHRENIA RESEARCH

Lab Studies Dive Headfirst into Pathways Touched by Schizophrenia

series of complementary studies that Johns Hopkins psychiatrist Thomas Sedlak and colleagues completed on animals and people A sheds light on a potentially novel approach for schizophrenia treatment targeting metabolic pathways in the brain. The studies further charac- terized the chemical imbalances in the brains of people with schizophrenia Jimmy Potash, M.D., M.P.H. relating to the antioxidant glutathione, and they showed that using sulforaphane — a natural compound derived from broccoli sprouts — can tweak Of Grants, Innovation glutathione levels. A January 2019 study in JAMA Psychiatry demonstrated that people with and Clinical Support psychosis averaged 4% less of the neurotransmitter glutamate (a building block of glutathione) and 3% less glutathione in the brain, compared with healthy As the leaves turn toward brilliant col- controls. A February 2019 study in the Proceedings of the National Academy of ors, I thought I’d let you know about some things that are turning out well in Sciences showed that glutamate neurotransmitter could be derived from the the department. In the research arena, antioxidant molecule glutathione. Sulforaphane was also found to turn on a the hottest areas for federal funding gene that increased glutathione in rat neurons. A third pilot study, in the April are the opioid crisis and Alzheimer’s 2018 issue of Molecular Neuropsychiatry, found that healthy volunteers who took disease. So, it’s not surprising that sulforaphane capsules for a week had a 30% rise in glutathione levels in their our biggest recent grants involve the white blood cells, with smaller increases suggested in the brain. opioid field, with three federal grants “Schizophrenia means ‘split mind,’ and we are of two minds about this,” worth a total of $16 million. They will cover areas such as better ways to use says Sedlak. “One is thinking of developing an intervention for schizophrenia, buprenorphine and strategies to treat but the other is that we found that sulforaphane increases glutathione — withdrawal so that patients in detox and perhaps there are other conditions that may benefit from an increase in stick with it rather than drop out. glutathione.” A major National Institutes The work, which came out of a multidepartment coalition focused on the of Health grant also came in for study of first-episode psychosis, raises several questions for future research: Who Alzheimer’s disease, to psychologist are good candidates for a sulforaphane intervention? How much is needed? And Quincy Samus, to fund MEMORI (Making Engagement Meaningful how long would people need to take the supplement to have a lasting effect? Through Organized Routine Akira Sawa, director of the Johns Hopkins Schizophrenia Center, notes Interaction) Corps — a novel way to that investigators need to stratify patients with lower levels of glutathione who support dementia patients and their might benefit most. Even though patients with schizophrenia, on average, have caregivers in the home environment. lower glutathione levels than unaffected people, some have lower levels than We also received private grant others, and those might be the target group. The prodromal period, before the funding of $17 million to create the first episode of psychosis occurs in patients, is a hot area of research, he says. Johns Hopkins Center for Research on Psychedelics and Consciousness, led by Some scientists have been trying to intervene at this stage by providing those at professor Roland Griffiths. This will risk with antipsychotic medications, but only some of these patients go on to allow us to initiate projects examining develop full schizophrenia, leaving the rest exposed to medication side effects the potential of psilocybin to treat such as metabolic syndrome. In addition, Sawa says, the drugs haven’t been conditions such as anorexia nervosa shown to prevent schizophrenia from developing. and post-traumatic stress disorder. “We have some opportunities here to explore using natural compounds On the education front, U.S. News for this preventive stage,” he says, “either to help stave off disease or as & World Report has a new ranking of medical schools for their educational additive therapy, along with lower doses of antipsychotic drugs, potentially quality in psychiatry, and we come hitting symptoms like cognition difficulties not now helped by standard in at #2 in the country. This is a antipsychotics.” wonderful validation of the caliber of The volunteers tolerated sulforaphane well, though some felt gassy. “This is our program, which will be further derived from broccoli,” Sedlak explains. n strengthened by a substantial gift to enhance opportunities on the clinician- educator track within the residency. The big clinical news is that the school of medicine has created a clinical faculty track. Johns Hopkins has always had only a single track throughout its 125 years, and we were the last medical school to maintain that approach. The new track gives us greater opportunity to reward Psychiatry clinically oriented faculty, which should researchers help with recruitment and retention. Akira Sawa and This is a very positive turn of events Thomas Sedlak for our department, especially given have found that clinical excellence has always been that glutamate central to our identity. The response of (shown traveling many of our leading faculty: “Brilliant!” between neurons above) in broccoli sprouts may improve chemical imbalances in people with schizophrenia.

2 • HOPKINS BRAIN WISE • WINTER 2019 THE OPIOID CRISIS What do you FEEL Low-Cost Intervention during an OPIOID Reduces Risk of overdose? Opioid Overdose SLOW Pulse sychiatry associate professor and researcher NOT RESPONDING when touched Kelly Dunn is taking aim at a serious Pproblem: the opioid overdoses that claim COOL, MOIST Skin about 130 American lives every day. We saw a gap in the way people were thinking CLAMMY Skin about addiction and overdose,” says Dunn, who has been studying the opioid epidemic since 2011. Until now, she says, much of the prevention effort has focused on people who use opioids illegally and not on patients treated for pain. What’s more, she says, prevention “was really Kelly Dunn and colleagues Cecilia Bergeria and Andrew Huhn have developed an online, self-paced tutorial that about giving (overdose-reversing medication) improves knowledge and reduces risky behaviors around opioids. It emphasizes risk factors for and symptoms of naloxone, but there was little available to empower overdose and explains what to do when an overdose happens. people to prevent them from getting to the point of overdosing and needing it.” and dispels potentially deadly misconceptions, such The authors say their investigation is the first to Now, Dunn and colleagues Cecilia Bergeria, as the popular myth that injecting someone with show “meaningful and sustained increases in opioid postdoctoral fellow in the Behavioral Pharmacology saltwater will stop an overdose. overdose knowledge and to simultaneously target Research Unit; and Andrew Huhn, assistant A study, authored by Bergeria, Dunn and Huhn, three unique populations of people exposed to professor of psychiatry, have created an intervention in the journal Preventive Medicine, examines the opioids who may be at heightened risk of overdose.” they believe can prevent some of those overdoses effects of web-based interventions on three groups They are now working to make the intervention from happening in the first place. of opioid users: people who are prescribed opioid available to clinicians and patients. “We like this They developed an online, self-paced tutorial medication for acute pain, patients prescribed approach because staff members are very busy and about opioids, risk factors for and symptoms of opioids for chronic pain and people without pain don’t necessarily know how to teach interventions,” overdose, and what to do when someone overdoses. who take opioids illicitly. says Dunn. The intervention improves knowledge and reduces The research shows that the intervention is The study also looked at two formats for the risky behaviors — such as mixing opioids with effective for all three groups. What’s more, all three intervention: a “mastery” style, with periodic quizzes alcohol or taking them when alone — among pain showed improved opioid knowledge immediately, that require correct answers in order to continue; patients as well as those who use the drugs illegally. as well as 30 days later. The researchers found that and a “presentation” style, without the quizzes. With just a few words each on 33 slides, the the acute pain group had the least opioid knowledge intervention provides straightforward information before the intervention. continued on page 4

PSYCHIATRY TRAINING

New Psychiatry Residency Tracks: More Mentorship and Career Development

ince its 1913 origins, Johns Residents will be given dedicated peers who are earlier in their training. see the tracks as a vehicle for helping Hopkins’ Department of time each year to pursue independent Also built into the tracks are monthly make that happen.” n SPsychiatry and Behavioral activities: one month in the first meetings during which residents can Services has been known for year, two months during the second meet faculty, discuss their interests providing trainees with a clinically and third years, and seven months and ongoing work, and receive rigorous program and cutting- during the fourth year. The goal is feedback. Four new scholarly tracks edge academic opportunities. The for residents to develop an area of The program was rolled out during offer dedicated department has trained leading expertise and produce a scholarly the 2018–2019 academic year, with mentorship for psychotherapists such as Irving product — such as a research paper interns given elective time. All four residents as they Yalom develop projects, and eminent neuroscientists or educational curriculum — by residency classes will have protected says residency like Solomon Snyder. But a graduation. Each resident is paired time for scholarship this academic education changing landscape because of factors with one or more mentors. year. Trainees have used the time to director Graham such as medical documentation “We have tried to emphasize to develop research projects, finish papers Redgrave. demands has meant less time for applicants and residents that the begun in medical school with the residents to pursue scholarly efforts first two years are exploratory,” help of Johns Hopkins mentors, and and career development. says Graham Redgrave, director pursue adolescent mobile treatment, Education leaders felt it was time for residency education. “We want among other opportunities, Redgrave for a change. them to meet a ton of people in says. Starting this academic year, the the department, do a lot of reading “We’ve gotten a lot of very positive psychiatry residency program will offer and have a lot of short- and longer- feedback,” says Jimmy Potash, four scholarly tracks with dedicated term exposures to help them make director of the psychiatry department. faculty mentors: public mental health, decisions, so during the second two “The residents are really quite excited led by Jin Joo; child psychiatry, by years they can start building toward a about it for all kinds of reasons. For Esther Lee and Hal Kronsberg; project.” one thing, they really like the closer research, by Christopher Ross, A big part of the program is peer mentorship experience with faculty. Kellie Tamashiro and Russell mentorship, he adds. As third- and We want the residency to be a place Margolis; and clinician-educator, by fourth-year residents’ projects come where we train the future leaders Karen Swartz. to fruition, those residents can help in the field of psychiatry, and we HOPKINS BRAIN WISE • FALL 2019 • 3 Low-Cost Intervention Reduces Risk of Opioid Overdose continued from page 3

They found that the mastery format caused more “It could have significant public health impact NEW BOOKS Peris Exposure Therapy for Children with Anxiety and OCD Storch participants to drop out, without leading to any by reducing opioid overdose risk in people who are Clinician’sBY Guide FACULTY to Integrated Treatment McGuire Exposure Therapy for Children with Anxiety and OCD Edited by advantage in improved knowledge as compared to managing their acute or chronic pain with an opioid Tara S. Peris, Eric A. Storch and Joseph F. McGuire Exposure Therapy for Children Exposure-based cognitive-behavioral therapy is the leading treatment for youth with anxietyExposure and obsessive-compulsive disorder Therapy (OCD). However, many providers for have the presentation format. prescription, or who have no pain and are using difficulty in understanding how best to implement this approach.Exposure Therapy for with Anxiety and OCD Children with Anxiety and OCD: Clinician’s Guide to Integrated Treatment provides a step-by-stepChildren framework about how to best with apply exposure Anxietytherapy to meet the needs of n children and adolescents with anxiety and OCD. Chapters are written by content leaders Clinician’s Guide to Integrated Treatment “The presentation version of this intervention opioids illicitly.” in the field in such a format that provide readers with relevant background information, empirical support, and a practical discussion on the nature and implementation of exposuresand for specific OCDconditions. Tables of sample exposures and case illustrations are provided throughout the book. Furthermore, key chapters address common challenges may be of particular value because it is brief, that complicate the implementation of exposure therapy for youth. Chapters provide clinical excerpts to illustrate techniques in an easy “how-to” format so that readers can Access the intervention at directlyClinician's incorporate into their own practice. Guide to Integrated user-friendly, well-accepted and recommended This book brings together a multidisciplinary team of treatment experts to explore the many recent advances in basic science and experimental research that can and should bit.ly/opioidEd be usedTreatment in exposure therapy. by participants, low-burden and scalable,” the Key Features • Describes the application of exposure therapy for common anxiety disorders and OCDEdited by Tara Peris, Ph.D., • Chapters are written and edited by key content leaders in the field researchers wrote. • SummarizesEric empirical Storch, support for exposure Ph.D.treatment efficacy and • Recommends how to develop and implement exposure therapy treatment • Offers separate treatment guidelines for children and adolescents Edited by • IntegratesJoseph exposure therapy McGuire, with other therapy modalities Ph.D. • Includes case studies and clinical excerpts illustrating techniques Tara S. Peris • Provides guidance on overcoming common challenges when implementing exposures in practice Eric A. Storch Academic Press Joseph F. McGuire “There was little available to empower ISBN 978-0-12-815915-6 Release date January 2020 people to prevent them from getting to the 9780128 159156 point of overdosing and needing naloxone.” — KELLY DUNN

Hopkins Non-Profit Org. This newsletter is published for the Department of Psychiatry and U.S. Postage Department of Psychiatry and Behavioral Behavioral Sciences PAID Sciences by Johns Hopkins Medicine James “Jimmy” Potash, M.D., M.P.H. Permit No. 5415 Marketing and Communications. Director 901 S. Bond St., Suite 550 Baltimore, MD Baltimore, MD 21231 Marketing and Communications Suzanne Sawyer, Senior Vice President, Some of the research in this newsletter Chief Marketing and Communications has corporate ties. For full disclosure Officer information, call the Office of Policy Coordination at 410-223-1608. Judy F. Minkove, managing editor Karen Blum, Judy F. Minkove, To make a gift, contact Karen Hussey, Karen Nitkin, writers Director of Development Lori Kirkpatrick, designer Johns Hopkins Department of Keith Weller, photographer Psychiatry and Behavioral Sciences Fund for Johns Hopkins Medicine 550 N. Broadway, Suite 914 © 2019 The Johns Hopkins University and Baltimore, MD 21205 The Johns Hopkins Health System 410-955-8159 Corporation If you no longer wish to receive this newsletter, please email [email protected].

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FALL 2019

HopkinsTHE NEWSLETTER OF THE JOHNS HOPKINS DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES

Esketamine: Lab Studies New Psychiatry A New Dive Headfirst Residency Tracks: Approach for into Pathways More Mentorship Patients with Touched by and Career Treatment- Schizophrenia Development Resistant PAGE 3 Depression PAGE 2

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4 • HOPKINS BRAIN WISE • FALL 2019