Board-certified psychiatrist and founder and CEO of Actify Neurotherapies (formerly Ketamine Treatment Centers), 

The hottest subject in psychiatry right now is the clinical use of an old anesthetic (and sometimes party drug), ketamine, as the most rapidly acting and effective antidepressant the field has ever seen.

Ketamine stepped out of the shadows to fill an innovation void and address the growing problems in the United States of depression, post-traumatic stress disorder, and suicide, for which there are few effective treatments. It holds the promise of quickly repairing damage caused by depression in the brain, rather than vaguely masking symptoms. For the past 50 years, we have been stuck with dozens of look-alike drugs that are only moderately effective for severe depression, detrimental to 30% of patients, chock-full of adverse effects, and all based on the flawed “chemical imbalance” theory of depression. 

Ketamine is not approved by the FDA for these indications. It was approved in 1970 as a general anesthetic and is included on the World Health Organization’s list of essential medicines for use around the world to assist in surgery and manage pain. Therefore, its use as an antidepressant is considered “off-label,” a common and permitted practice for physicians that acknowledges that most medications have numerous research-proven therapeutic benefits beyond the narrow scope of what the FDA has approved. 

What is unique about the psychiatric use of ketamine is that it is an old, generic manufactured drug that is already available, so widespread use has progressed in an unregulated market outside the typical FDA approval process. This does not sit well with many in the academic world, who are now voicing concerns about the proliferation of ketamine clinics.

The tide has turned quickly. Media coverage over the past decade had been mostly positive. The formulaic articles typically presented the story of a patient with long-standing depression, the maverick doctor who stuck his neck out to make this treatment available, and the resulting dramatic outcome of a life restored. More recently—and perhaps linked to the imminent arrival of new, brand-name, pharmaceutically produced medications that are based on the mechanism of ketamine in the brain, i.e., ketamine copycats&mdash;the tone has become darker. 

A recent Time cover story on this subject titled “New Hope for Depression,” which highlighted the dire state of depression treatment and the breakthrough of intravenous ketamine, painted the private practice world with a broad, cynical brush: “These clinics have pitched themselves to doctors as get-rich-quick side businesses.…”

 An editorial by Jeffrey A. Lieberman, MD, a past president of the American Psychiatric Association, warned that this treatment is “driven by the profit motive.”

Physicians are playfully mocked as poor business people but then shamed when building responsible businesses that threaten to disrupt the status quo. We accept a pace of innovation in health care that would destroy any other industry. We also operate under the delusion that academia is free from the biases of for-profit private practice—academic department chairmen get to keep their jobs if they are not raising money, and investigators get to do cool science regardless of whether their studies “work” and they are awarded grant money. I apologize if my dripping sarcasm has fried anyone’s eyes.

It is an uncomfortable truth that medicine is a business, and you do not get to stay in business, pay employees, and treat patients unless that business turns a profit at some point. A free market system that gives patients choices, coupled with much-needed regulation aimed at basic safety standards rather than stifling learning and innovation or restricting access to care, breeds a healthy path to move the field forward. 

1. Lieberman JA. One doctor’s concern. 

 website. medscape.com/viewarticle/886547. Published October 6, 2017. Accessed January 11, 2018.

2. Oaklander, M. New hope for depression. Time website. time.com/4876098/new-hope-for-depression/. Published July 27, 2017. Accessed January 11, 2018.

Articles

Features

Column: Are Ketamine Clinics Profiteering or Leading Innovation?

ZTlido, a lidocaine patch 1.8% developed by Scilex Pharmaceuticals, a Sorrento Therapeutics subsidiary, is attempting to redefine this type of nonopioid treatment for patients with postherpetic neuralgia (PHN).

Traditionally, these patches are effective but raise concerns regarding safety, as the method of delivery requires that high amounts of the drug be included in the patch but allows just a limited amount to be administered. Usually, these products are aqueous gel face patches—the therapy is diluted into a gel matrix, then added to the adhesive layer and put onto the patch.

Uniquely, ZTlido uses a nonaqueous system that requires lower levels of heat to release the drug, reducing the amount of drug that needs to be delivered to the skin. “ZTlido is a next-generation, branded lidocaine 1.8% patch,” Jeff Gudin, MD, the director of pain management and palliative care at Englewood Hospital and Medical Center in New Jersey and a scientific advisor for Scilex, told 

®. “As a single-layered anhydrous patch, the product contains only 36 mg of lidocaine versus 700 mg in the reference 5% patch.”

ZTlido’s smaller dose per patch, compared with both Endo Pharmaceuticals’ Lidoderm (lidocaine patch 5%) and Grunenthal’s Versatis (medicated plaster 5%), allows for an estimated 30-fold reduction in residual dose of the drug. This can reduce both drug waste and safety risks for pets and children after the product is discarded.

Additionally, at a time when the United States faces an opioid crisis, a nonopioid treatment for any type of pain comes as a welcome sign. “In this era of opioid abuse, misuse, and diversion, I look forward to clinical trials with topical analgesic products for other types of neuropathic and nociceptive pain so that clinicians can use evidence-based medicine to offer effective treatments for chronic pain,” Gudin said.

In a 2016 study that measured the therapy’s absorption and was led by Gudin, investigators examined the plasma concentration of medicine that the patch administered over time under normal conditions, with heating, and with physical exercise. Levels were lower with exercise than under normal conditions, both peaking around 9 hours postadministration. Absorption levels spiked above 160 mg/mL when heat was applied but were shown to be reversible, returning to baseline after 20 minutes.

“The thinner topical system showed improved adhesion, which is obviously necessary for efficacy and should more readily adhere to curved [joint] surfaces,” Gudin said. “The [FDA-]approved indication will be similar to the legacy patch post-PHN.”

In June 2017, Scilex announced positive results from a comparative study of its lead product. The trial, which compared ZTlido with Veratis (a similar European product), reported that the European Medicines Agency adhesion scores for the Scilex product were 5.35, compared with 3.59 for the medicated plaster 5% (

 <.001). After a 12-hour dosing period, the mean scores were 5.006 and 2.268, respectively (

 <.001). The scores were assessed in 44 healthy participants at hours 0, 3, 6, 9, and 12.

During the trial, 2 patients experienced complete detachments of Veratix compared with none with ZTlido, which also produced equivalent dermal irritation scores (

 = .1656). Both patches resulted in 7-point dermal irritation scale scores lower than 1.

“It is very frustrating for patients to use a patch that doesn’t have good adhesive properties,” Kip Vought, vice president of development for Scilex, said.

 “If it is ripping or falling off, that’s a challenge, because in addition to the patient not receiving the right amount of the drug, they will have to keep reapplying the patch. Therefore, improving the adhesive properties was critical. We tested the patch clinically to ensure it would stay in place throughout the administration period.”

Just 2 months later, in August 2017, Scilex submitted a new drug application (NDA) to the FDA for the product. “We are excited about the opportunity to bring to the market a product that will adhere during the full prescribed treatment period, as well as be able to be worn during exercise,” Anthony Mack, the president of SCILEX Pharmaceuticals, said in a statement.

 “As a company, our desire is to help patients by developing better products to treat pain.”

This is the therapy’s second go-round with the FDA. An NDA was previously filed in March 2014, with bioequivalence data from 2 pharmacokinetic trials comparing it with Lidoderm, and accepted by the FDA in September 2015. In May 2016, the therapy met a setback—the FDA sent Scilex a complete response letter (CRL), citing a need for additional data from a pharmacokinetic trial; a 3-month toxicity study; and information regarding the quality, management, design, and purchasing controls related to the drug.

New data were collected, and the August 2017 NDA filing was considered a complete class 2 response to the CRL. It was accepted, and the FDA set a Prescription Drug Fee User Act action date for February 28, 2018. The FDA approved the patch for an indication of relief of pain associated with PHN.

“The patch, [with] market approval, may offer possible advantages over the 5% lidocaine patch, including more efficient delivery of lidocaine, superior adhesion, and less residual left in the patch after normal use,” Gudin said.

1. Gudin J, Vought K, Shah M, Patel K. Adhesion characteristics of a topical lidocaine patch 8% (36 mg). Poster. Simul Europe website. simul-europe.com/2016/wip/Files/(kpatel@scilexpharma.com)WIPGudin.Voght.Shah.Patel_v4_5.16.16.pdf. Published May 2016. Accessed February. 14, 2018.

2. Miseta E. New patch technology will help Scintilla treat pain. 

. August 16, 2016. clinicalleader.com/doc/new-patch-technology-will-help-scintilla-treat-pain-0001. Accessed February 14, 2018.

3.Sorrento Therapeutics, Inc. submits NDA for 

 next-generation lidocaine patch [news release]. San Diego, CA: Sorrento Therapeutics, Inc; August 29, 2017. drugs.com/nda/ztlido_170829.html. Accessed February 14, 2018.

Clinical Pipeline

ZTlido, a lidocaine patch 1.8% developed by Scilex Pharmaceuticals, a Sorrento Therapeutics subsidiary, is attempting to redefine this type of nonopioid treatment for patients with postherpetic neuralgia.

ZTlido Lowers Doses While Raising Efficacy

Depression is often daunting for patients to go through and for their physicians to treat. About 13% of pregnant women and new mothers have depression, according to the Office on Women’s Health of the US Department of Health & Human Services (HHS).

The CDC clarifies that the number of women suffering from postpartum depression varies from state to state and that as many as 1 in 5 women reports the condition.

Lauren M. Osborne, MD, assistant director of the Johns Hopkins Women’s Mood Disorders Center and assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, is an expert in the diagnosis and treatment of mood and anxiety disorders during pregnancy and postpartum. Her research focuses on the biological pathways that contribute to mental illness during times of reproductive life cycle transition, with an emphasis on the immune system’s role.

“The diagnostic is not well defined; the [

Diagnostic and Statistical Manual of Mental Disorders

] does not even really acknowledge postpartum depression in this current iteration,” Osborne told 

. “They have a specifier that says ‘Major Depressive Disorder With Peripartum Onset,’ but that refers to anything beginning in pregnancy or afterward. We think that people who are depressed in pregnancy and people who are depressed postpartum are in biologically distinct states because there’s a very different biological environment going on during those 2 periods.”

Catherine Birndorf, MD, medical director of The Motherhood Center in New York, New York, and board member of Postpartum Support International (PSI), clinical associate professor of psychiatry and obstetrics/gynecology, and founding director of NewYork-Presbyterian Hospital’s Payne Whitney Women’s Program, believes part of the problem of defining postpartum depression is that “depression” is not what many women feel they experience.

“Many patients say, ‘I do not have postpartum depression because I’m not depressed!’” Birndorf told 

. “People get very confused because it’s the only term we have, but they do not feel sad; they feel anxious. So the new term—and we’re really trying to get it out there&mdash;is PMADS, perinatal mood and anxiety disorders. It’s a much more inclusive and descriptive acronym.”

“We see more anxiety here than mood disorders,” Sarah Homitsky, MD, a psychiatrist with clinical expertise in perinatal psychiatric services, including postpartum depression, and medical director of the Women’s Perinatal Psychiatry Program at West Penn Hospital, told 

Homitsky also pointed out that depression is not the only piece of the postpartum puzzle. Her team screens for bipolar illness along with postpartum depression.

“I think that is important because 60% of the time, a woman who has bipolar disorder could present a positive depression screen and therefore be misdiagnosed; if you are diagnosed with depression but actually have bipolar illness, a medication for depression can sometimes make the symptoms worse,” Homitsky said. “So we screen all women during their initial prenatal visit in their third trimester and then again postpartum for both because that way, we can identify the roughly 20% of women who have bipolar disorder and screened positive in [bipolar screening].”

Historically, hormones have been blamed for postpartum depression. During pregnancy, levels of estrogen and progesterone are highly elevated; within 24 hours of childbirth, however, those levels crash down about 1000-fold.

“The problem is, that crash happens to every woman, but not every woman gets postpartum depression. There has been some really interesting work that has clarified that instead, there is a certain group of women who are vulnerable to that change in hormones,” Osborne noted.

Postpartum depression has biological roots, but it is also characterized by psychosocial risk factors.

“It’s an enormous transition from being a free person to being a person with a child,” Osborne said. “The biggest risk factor for developing postpartum depression is depression during pregnancy, but other risk factors are poor social support, high rates of trauma or adverse life events, and lack of sleep.”

People joke about missing sleep all the time, but it is a huge risk factor, Osborne stressed.

“One of the things I do clinically is make every pregnant patient come in and bring her partner or some supporter at 36 weeks to create a sleep plan because it has an enormous impact,” she said.

Because research has now indicated that some women are more vulnerable than others to the hormonal transition that marks the postpartum period, investigators in this area are attempting to tease out the other biological factors contributing to the illness. Osborne’s work focuses on the immune system and how the hormonal and stress response systems interact with it; other recent work from her colleagues describes the hormonal environment.

“One of the studies that my group did recently was on allopregnanolone, a metabolite of progesterone that is also sometimes called the antianxiety hormone,” Osborne said. “It’s a very calming hormone and has the same effect on the brain as alcohol or benzodiazepines like [lorazepam] and [diazepam]; it attacks the same receptors.”

Osborne noted that results from a 2017 study showed that pregnant women who went on to develop postpartum depression had lower levels of allopregnanolone in early pregnancy. “Every additional nanogram per liter of allopregnanolone reduced the odds of developing postpartum depression by 63%, which is huge,” she said.

Jennifer L. Payne, MD, and Zac A. Kaminsky, PhD, colleagues of Osborne’s, are searching for something in the epigenetic signature of women with postpartum depression that is making them vulnerable.

“They have discovered epigenetic biomarkers that predict the development of postpartum depression with an accuracy of about 82%, and we do not know what these genes really do,” said Osborne. “There’s a different pattern of DNA methylation in these genes in the women who go on to develop postpartum depression, and we’ve now replicated that several times, so that’s a promising avenue.”

Another new treatment that was given Breakthrough Therapy designation by the FDA is brexanolone, which is being developed by Sage Therapeutics. It is an intravenous (IV) infusion that is a synthetic version of allopregnanolone. Initial trials for brexanolone showed a dramatic effect: remission symptoms within 3 days for 70% of the women.

While results from the most recent studies showed that the difference between the placebo and experimental groups was not as statistically significant, investigators like Osborne are hopeful.

“We do not yet know whether it is going to be able to be turned into something reasonable,” Osborne said. “Right now, it requires the woman to stop breast-feeding and have an IV infusion, come into the hospital, and be in a clinical trial. But a lot of us in the field are excited about the possibilities of this drug, if the results hold.

“It’s really the first drug in ages that people have tried specifically for postpartum depression and the first new thing to come along,” she added.

In her work at PSI, Birndorf is focusing on rolling out resources for people providing care to patients with postpartum depression. The PSI education committee is currently creating a frontline training program for any health care professional who treats these patients but is not a specialist in the field.

“In most places in the country, there really are not any specialists in this area,” Birndorf said. “The program is called Expert Provider Training in Perinatal Mood and Anxiety Disorders, and it is 5 different hour-long webinars of training, or there is a 1-day live version. Each includes everything from what is PMADS and how to screen for it to psychotropic medications during the perinatal period.”

Birndorf also wants to expand the ways in which professionals in the field can assist one another day to day. She noted another project she is helping to develop, a national consultation service.

“This is going to be provider to provider across state lines—no patient care, no money exchanged, just giving advice,” she said. “It’s not about a specific patient; it’s education for people who are far away from experts in the field and need expert advice on prescribing and other issues.”

One of the challenges of treating postpartum depression is that many pregnant women are reluctant to take any medication and feel they should grin and bear feelings of depression rather than put their babies at risk. However, experts say that this is a misconception of the actual risks.

“The reality is, we know that untreated depression and anxiety in pregnancy can actually affect the baby,” Osborne said. “Untreated depression and anxiety are associated with preterm birth, a higher rate of miscarriage, and deleterious effects on the baby, such as higher rates of depression, anxiety, and attention problems in that child eventually.”

“If you do not treat the depression, there’s a risk of untreated illness,” Birndorf noted. “And it hurts the fetal environment because the baby is bathing in cortisol because you’re so depressed or anxious. That’s also not good for a developing person.”

Treating depression with medication during pregnancy has a great track record for safety—but getting this across to patients is not always easy.

“There is a huge amount of literature available, and most of it is incredibly reassuring that antidepressants are extremely safe drugs to take in pregnancy,” Osborne said. “If you have a woman who you know is at high risk and who has severe depression, it makes sense to treat that depression in pregnancy. Remember, the biggest risk factor for postpartum depression is depression in pregnancy.”

Another common problem that Osborne and Birndorf see regularly is undertreatment in women for their depression because they are pregnant.

“I think that’s largely because doctors believe they should give pregnant patients a lower dose, when in fact what we know about the pregnant body is that it metabolizes the drugs at a higher rate,” noted Osborne. “So actually the effective dose that the mom is getting even if she stays at the same dose is going to be lower by the end of pregnancy.”

Despite the impressive progress being made in the treatment of postpartum depression, notable challenges remain for every doctor involved. Lack of access to care and insurance is one.

“Access to care is a challenge for every mental health clinic,” said Homitsky. “We are diligently thinking of ways to provide care to people who have a barrage of barriers, whether those are a lack of insurance, a lack of transportation, or multiple other children, and I think a big part of the whole treatment in the future will be figuring out how to bring the care to patients instead of having them have to conform to the traditional outpatient setting.”

Osborne noted that the most important facet of postpartum depression is that it is a treatable condition, despite its high prevalence.

“Even so, it’s misunderstood, mistreated, and misdiagnosed,” she said. “Health care professionals should be asking women in postpartum questions in a nonjudgmental way to see how they’re feeling because if you do not catch it—if you do not diagnose and treat it&mdash;it affects not only that mom but also that child, the next generation. Then it affects that generation’s risk for passing something on to their kids.

“If we’re not aware of it and do not look for it, we’re not going to find it,” she added.

Birndorf also feels strongly about simply taking the time to look for the problem and reaching out for help from other health care professionals if needed.

“I think most important, we can recognize it if we ask women, if we look them in the eye and hold their gaze and ask them how they’re doing,” Birndorf added. “I mean, it’s not that hard to diagnose. But the reason people do not always ask is they do not know what to do with it or where to send people for treatment because there’s a dearth of treatment options out there.”

1. How common is depression during and after pregnancy? Office on Women’s Health website. womenshealth.gov/a-z-topics/depression-during-and-after-pregnancy. Updated June 12, 2017. Accessed January 20, 2018.

2. Depression among women. CDC website. cdc.gov/reproductivehealth/depression/index.htm. Updated December 13, 2017. Accessed January 20, 2018.

Cover Story

Depression is often daunting for patients to go through and for their physicians to treat. About 13% of pregnant women and new mothers have depression.

Perinatal Mood and Anxiety Disorders: Redefining Postpartum Depression

Howard Fillit, MD, the founding executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation (ADDF), sat with 

to discuss the state of therapies for Alzheimer disease (AD), including funding-related struggles and the burden faced by physicians who treat patients with AD.

Despite the potentially huge clinical implications, producing AD therapies is often risky and expensive, so AADF plays a role in helping these ventures get off the ground, Fillit said. “The pharmaceutical companies have big dollars. They can come in phase 3—a phase 3 trial in Alzheimer’s costs $300 to $400 million, and you are going to need 2 or 3 of them, maybe 4, to get FDA approval,” Fillit told 

. “That is a big risk. You cannot take many of those bets without going out of business, and a lot of Big Pharma companies have left not just Alzheimer [disease] but [also] the whole central nervous system space because it is so risky. You cannot run a company with such large risks, financial and scientific.”

There have even been struggles related to clinical trial funding by venture capitalists, he said: They often operate with decade-long funds, Fillit said, but developing a drug usually takes between 12 and 15 years—a small difference in the long run but enough to keep funders away.

“They are tending to step in late,” Fillit said. “They want to see, generally speaking, phase 2 data. There are some funds that will step in earlier into the preclinical space, but most of them won’t—again, for the same reason. They have obligations to their investors to make money, and that is a good thing, because if a drug is brought to market, everybody wins. But where they can put their money is in a different place than the pipeline.”

Despite those struggles, more than 250 clinical trials are underway for AD therapies, with 126 drugs in the pipeline, according to Fillit. “It is amazing, because when I started in the field in 1980, there were no drugs in clinical trials,” he said.

The ADDF has supported about 25% of the therapies being developed. Fillit expressed his excitement about the ADDF’s ability to help, as well as the availability of so many targets that biologic part of the condition—and the ability to repurpose them.

Of the 126 therapies in clinical development, 17 are repurposed drugs that are on the market for other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease. A number of trials are expected to report out in the next year or so, and Fillit stressed the pressing need for these drugs, which could be used sooner rather than later to help patients with AD. Despite multiple advances and some promising therapies, Fillit acknowledged, none offer a cure for the neurodegenerative condition, making those that slow the progression of cognitive impairment more and more important.

“What we need—like in cancer, like in diabetes, like in hypertension, like in HIV/AIDS&mdash;[is] combination therapy, because the way this disease evolves is multifactorial,” Fillit said. “You have inflammation, epigenetic changes, neuronal energy failure, mitochondrial dysfunction, hypoxia and ischemia from microvascular disease, protein chaperone misfolding and failure, so we are going to need a combination of drugs to attack this disease.”

Repurposing therapies gives physicians that treat AD a huge advantage: If trial results are positive, Fillit said, then he can start prescribing a drug off-label the next day. “I do not have to wait for FDA clearance. The big opportunity when you discover a repurposing drug that works is that then we can go back and do new chemistry, create new chemical entities, get new indications for unique drugs, and build the space, because we have a proof of concept,” he said.

For example, riluzole, the only drug that has shown an ability to slow the course of ALS, is being repurposed for patients with AD. Fillit expects the trial to wrap up in about 2 years, which is “pretty quick,” he noted. “We are going to have an answer [soon], unlike when new chemical entities have to go through a regulatory environment that takes 12 to 15 years,” Fillit said. “Once these trials come out, it opens up a new area, but the drugs can be used off-label immediately.”

Treating patients with AD is difficult not just because of the lack of options, Fillit said, but also because it places a burden on physicians who provide the hours of care, education, and testing required by patients and their caregivers. That takes a toll on physicians both in their ability to give so much care in a limited amount of time and, due to complications with the health care system, in their reimbursement.

Fillit, who has been working with patients with AD for almost 40 years, understands this all too well. “When you’re treating a person with Alzheimer’s, you’re also treating their caregiver,” he said. “There is always a dyad of the caregiver—the spouse, the daughter, the son, a home aide&mdash;there is almost always a caregiver, [because] it is very hard for a person with Alzheimer’s to live alone and not have any services.”

There is no magic bullet for AD, he said—no biomarker like cholesterol or hemoglobin A1C that physicians can use to measure progression. “We are measuring cognition as the primary outcome and function, and it is hard&mdash;there is no number,” he said. “It takes an interview or a mini-mental exam or some kind of gestalt about how a patient is doing.”

In addition, patients require education and counseling, which takes a long time. “There are reimbursement problems for payment for a physician to spend an hour with a patient and, after taxes and overhead and rent, to literally come home with $30 to $40 because all these people have Medicare,” Fillit said.

The result: disincentives for doctors to spend time on education, counseling, and arranging the services and long-term care that patients need. “I really think that the problem is sort of structural. I hope that, with the way that medicine is changing, maybe the financial incentives can change so that doctors can take better care of Alzheimer patients,” Fillit said. “But right now, I get patients referred to me who are seeing neurologists and primary care doctors at some of the major academic medical centers—they are just not getting care.”

Fillit likes to quote Hippocrates, who said that the role of the physician is sometimes to treat and often to relieve pain, but always to comfort. Those words apply perfectly to physicians who treat patients with AD: “These patients are suffering. Most of them are not having a good time. It is a long day. Caregivers need, really, a lot of education and counseling on how to deal with the thing…These are people [who] are often 75, 80 years old taking care of someone who is totally dependent or keeps asking them 5 times every minute, ‘Where are we going later?’ And that drives you crazy.

“The challenges [with AD] are enormous,” Fillit said. For physicians, AD is a very difficult illness to treat, and “the right paradigm for care has not been figured out,” he said.

's new sister site, provides even more extensive coverage from the Alzheimer’s disease space, as well as updates pertaining to dementia and the latest from the field’s most prominent conferences.

Howard Fillit, MD, the founding executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, sat with MD Magazine to discuss the state of therapies for Alzheimer disease (AD), including funding-related struggles and the burden faced by physicians who treat patients with AD.

Peer Insight: Funding and Treating Alzheimer Disease With Howard Fillit, MD

Underscoring a commitment to make health care accessible to all populations, the Kraft Center for Community Health at Massachusetts General Hospital recently launched CareZone—a mobile clinic aimed at engaging and treating those struggling with opioid use disorder and related health issues.

GE Foundation, Ford Motor Company, Boston Health Care for the Homeless Program (BHCHP), and the Boston Public Health Commission’s harm reduction and needle exchange site, AHOPE, CareZone delivers addiction treatment services to the vulnerable members of the population who need them most but often have the greatest difficulty accessing them.

“I think that we have decades of science now showing us what works from a research perspective, which is really ready and immediate access to treatment that involves some combination of medication treatment, behavioral treatment, and ongoing follow-up and having all of that delivered in a way that’s welcoming and nonjudgmental and patient centered,” Sarah Wakeman, MD, medical director of the Substance Abuse Disorders initiative and program director of the Addiction Medicine Fellowship at Massachusetts General Hospital in Boston, told 

Wakeman added that despite the extensive knowledge of what is needed in addiction medicine, what is often offered in the addiction treatment system does not match that need. “Care is often delivered in a somewhat punitive approach where people are kicked out of treatment if they continue to struggle,” she said.

“They make it very hard for people to access addiction treatment,” Wakeman added. “They have to navigate complex waiting lists and lots of requirements and rules. And if you think about the current crisis where heroin and fentanyl are readily available in every city, there’s this mismatch where we make treatment really hard to get, and yet we make ongoing opioid use and the harm that goes along with that incredibly easy to access. Then we wonder why people continue to die.”

The goal of CareZone is to remedy this flawed system by bringing care directly into the communities that need it most. Massachusetts is currently facing a morbidity rate of 6 people per day because of opioid overdose, according to the Massachusetts Department of Public Health

“The fundamental cause of these deaths is the disease of addiction. Effective, lifesaving treatments are available now, but there is substantial lack of access to treatment, particularly among our most vulnerable populations,” Elsie Taveras, MD, MPH, executive director of the Kraft Center said in January.

 “There is also reluctance of many people to use traditional clinics or hospitals out of fear of stigma. That is the space we hope to fill with the 

In the first 9 months of 2017, there were 932 confirmed opioid-related overdose deaths in the state, according to a DPH data brief.

 The DPH estimated that there would be an additional 491 to 582 opioid-related deaths in the last 3 months of the year.

Despite a slight dip in 2017, opioid-related overdose deaths have steadily increased since 2014, with a total of 2094 deaths in 2016, 1687 in 2015, and 1364 in 2014, according to the DPH.

“Boston, just like many cities and towns across the nation, has been hit very hard by the opioid epidemic, and most recent numbers show that it’s only gotten worse,” Taveras told 

. “No Boston neighborhood has been entirely spared. We are fortunate [here] to have such great community health centers and hospitals. However, the problem is so vast that we’re all playing catchup to try to get ahead of the epidemic.”

Launched on January 9, CareZone targets Boston’s most vulnerable neighborhoods and consistently engages the public in order to forge relationships, establish trust, and deliver proper care.

“We’re trying to build relationships with a group of people who are really not accessing care in traditional ways, in brick-and-mortar health care programs or addiction programs,” Jessie Gaeta, MD, chief medical officer of BHCHP and medical director for CareZone, told 

Gaeta noted that the patients who most need the treatment often have a sense of mistrust for the system that seeks to treat them, making the relationship-building process both sensitive and tedious—but still necessary.

“The most important thing we are doing right now is showing up, being when and where we said we were going to be on a regular basis every single week, and we’re engaging dozens and dozens of individuals and trying to build relationships,” Gaeta said.

The CareZone van is staffed with a physician and a team of public health outreach workers who go into the neighborhoods they serve to engage those in need of treatment.

“We walk around alleyways all through the neighborhood, and we find a lot of people who are pretty hidden, actually,” Gaeta said.

Patients can access not only treatment for opioid use disorder through CareZone in the form of medication addiction treatment (MAT) but also treatment or referrals for a variety of other health issues, ranging from vaccinations and screenings to treatment for chronic conditions like hypertension and diabetes.

“We can test for things that this population is at higher risk for, like HIV and hepatitis B,” Gaeta said. “We can offer treatments for those diseases or connections or referrals to specialists. [We can do] just about everything you might do in an outpatient [setting].”

For those patients who are not yet prepared to enter into treatment, be it MAT or rehabilitation, CareZone also offers harm reduction services.

“We’re hoping to engage people who are experiencing overdoses, have opioid use disorder, and are otherwise not able or not wanting to access treatment for opioid use disorder right now. We’re hoping to at the very least provide harm reduction services if they don’t want treatment right now, so we are distributing [naloxone HCl spray] and even clean syringes and teaching people safer injection techniques,” Gaeta said.

When patients are ready to enter into treatment, the CareZone team works to “lower every possible barrier,” Gaeta said, to either connect them to treatment or provide it directly in the van.

According to Wakeman, opioid abuse disorder generally comes with a good prognosis—one she considers “the most treatable of any type of drug use disorder.”

The prognosis is good, she says, because as long as patients receive the proper treatment, it is effective, and there are multiple treatment options available.

“For most substance use disorders, effective treatment is usually a combination of medication treatment, behavioral intervention, and ongoing follow-up and support,” Wakeman said. “So while we have effective medication for alcohol use disorder and for tobacco use disorder, our medications for opioid use disorder are far more effective. [Conversely], we don’t have any effective medications for something like cocaine use disorder—at least not yet.”

However, the problem with treating patients with opioid use disorder is that most people who have the disorder never become patients in the first place. They simply don’t receive treatment.

“Some of our most effective treatments are some of our least utilized,” Wakeman said. “There’s this huge gap between what we sort of know works from science and what actually is available for people in clinical practice.”

While CareZone is still in its infancy and is currently operating as a pilot program, officials project the program can engage as many as 450 individuals in care within its first 6 months.

“That doesn’t necessarily mean that all of them are going to want treatment per say,” Gaeta said. “But that is at least 450 people we’re going to engage, have a relationship with, and make sure we’re providing harm reduction services for at a minimum—which I think is really important&mdash;including overdose prevention and syringe exchange and HIV testing and hepatitis B testing. All those things.

“I think even if we were able to engage as many as 50 people in treatment in the 6-month period, I would consider that a really big success,” Gaeta added.

The Kraft Center for Community Health at MGH mobilizes care for opioid use disorder to Boston’s most vulnerable [news release]. Boston, MA. Mass General Public Affairs; January 11, 2018. massgeneral.org/News/pressrelease.aspx?id=2200. Accessed January 20, 2018.

Massachusetts Department of Public Health. Data brief: opioid-related overdose deaths among Massachusetts residents. mass.gov/files/documents/2017/12/04/Opioid-related%20Overdose%20Deaths%20among%20MA%20Residents%20-%20Revised%20December%202017.pdf. Revised December 2017. Accessed January 20, 2018.

Underscoring a commitment to make health care accessible to all populations, the Kraft Center for Community Health at Massachusetts General Hospital recently launched CareZone&mdash;a mobile clinic aimed at engaging and treating those struggling with opioid use disorder and related health issues.

Mass General's CareZone Treats Opioid Use Disorder Where It Lives

Physicians have used neurofeedback therapy to effectively treat anxiety, depression, mood disorders, posttraumatic stress disorder, and, more recently, attention-deficit/hyperactivity disorder (ADHD). Relying on quantitative electroencephalography (qEEG) to map the grid of brain waves, physicians can use neurofeedback therapy to train themselves to improve behavior outcomes, such as sharper focus and reduced distractibility.

“It is a very different way of thinking about people’s problems,” Robert Reynolds, PhD, founder of The Reynolds Clinic in Middletown, Connecticut, told 

. “As therapists, we’re often trained to think about problems psychodynamically, not neurophysiologically. This is a paradigm shift in terms of understanding what causes problems.”

Clinical studies using qEEG to produce brain wave maps have shown a correlation between patterns of abnormal brain waves and certain behaviors. Patients with ADHD show a greater ratio between the resting theta waves and the faster beta waves compared with their age- and sex-equivalent peers without ADHD, with less ability to stay focused on a task. These quantitative data are an objective indicator of cortical dysregulations that can be improved through training patients to create better pathways through physician-guided operant conditioning.

“The patient comes into the office and does the qEEG, and the doctor sets the protocol based on the results of the qEEG,” Robert Reiner, PhD, executive director and founder of Behavioral Associates in New York, New York, told 

. “It’s [an interactive video of] 2 people running a race, and the more your brain is going into a ‘good spot,’ the more it is producing beta waves, and you’re less distracted. So it is really great for kids—they do not even know they are being treated sometimes.”

“The overall benefit of neurofeedback amounts to increased self-regulation,” Reynolds said, “whether that is better regulation of anxiety, emotional states, attentional issues, or behavioral issues. If you can identify which parts of the grid are not operating optimally, then you can begin to train those parts of the brain to come online more effectively, and it basically strengthens the entire grid.”

Visual, auditory, and tactile feedback provides affirmation to patients using neurofeedback devices, such as Deymed Diagnostic neurology-grade equipment, while under supervision from their physician in the office. The patient progresses through the treatment and continues to receive rewards for attention, thus creating stronger neurological pathways for improved performance.

“When the mind goes off the protocol, which is a sign of distractibility and impulsivity, I’m able to fine-tune and maybe adjust that person’s protocol,” David Sitt, PsyD, a clinical psychologist, the founder and president of the Mindful Consulting Group, and a lecturer in the Department of Psychology at Baruch College in New York, New York, told 

. “Maybe instead of inhibiting distraction, I might decide to use a protocol that has to do with rewards. I could tweak in theory the protocol for different types of brains [of patients with ADHD].”

Newer technological advances allow physicians the option of treating patients with ADHD with home-based neurofeedback. The Muse is a 3-channel headband that, when placed over the forehead, produces EEG feedback. Used with Myndlift software, this allows a clinician to give the Muse to a client and monitor the feedback and create a protocol for that client based on their ADHD and their specific type of ADHD symptomology. A fourth electrode can be added to produce more sensitive EEG feedback.

“It wasn’t until hardware developers started using a qEEG cap that you’d have a 19-channel EEG reader and could get a full mapping of various electromagnetic movements in the brain,” Sitt, who has incorporated home-based neurofeedback into his practice with positive results, said. Sitt finds that his patients are more compliant with home-based treatment, as it reduces the number of office visits they must make.

“Patients know that their doctor can see everything they do,” Reiner said. “We can see who’s not being compliant. With the dashboard, we can follow every patient, tweak their protocol as they progress, and have them come in every 2 months for another qEEG. It has completely transformed the way we work. The idea that people can do this at home right now speeds up the progress tremendously. It’s been very clear to me that patients are better off doing four 10-minute sessions every other day than coming into a therapist’s office once a week and doing 40 minutes of neurofeedback/biofeedback.”

Home-based neurofeedback devices can be used by children, adolescents, and adults with ADHD. Patients are trained in the office, and physicians are alerted when they log on to the program (usually from an app on their phone). Information about the patient’s session length and results and any technical difficulties are also accessible to the physician, who has capability to adjust treatment settings. Some physicians prefer to conduct neurofeedback therapy in the office, for increased supervision, especially for pediatric patients.

“The problem I have with [home units] is that I cannot monitor them; they are dependent on parental administration,” said Reynolds. “I think it puts them in an unfair position. I think the issue is one of sensitivity, and I’ve found the Deymed system to be the most sensitive.”

Relying on qEEG to map the grid of brain waves, physicians can use neurofeedback therapy to train themselves to improve behavioral outcomes, such as sharper focus and reduced distractibility.

Neurofeedback Therapy Improves Behavior Outcomes in Patients With ADHD

Although the causes of multiple sclerosis (MS) remain unknown, a variety of factors have been linked to exacerbations and relapse—and several that have recently been associated with increased risk of onset are avoidable.

Findings from the largest study to examine whether concussive head injury increases the risk of developing MS revealed an association with concussion occurring in adolescence and an increased risk of multiple concussions. The risk was not seen in younger children.

It is not yet clear, however, whether MS should be included with conditions such as chronic traumatic encephalopathy (CTE) in warnings about the dangers of concussions, according to the study’s lead author, Scott Montgomery, PhD, the director of the Clinical Epidemiology Group in the Department of Epidemiology and Biostatistics at the School of Medical Sciences at Örebro University in Sweden. “As only a very small proportion of those with head injuries in adolescence will develop MS, listing MS as an outcome might be considered alarmist without more detailed qualification of the risk,” he said.

Montgomery and colleagues used the national Swedish Patient Register of hospital diagnoses and the MS Register through 2012 to identify over 7000 patients with MS who were born since 1964. Each was matched to 10 patients with similar demographics but no MS diagnosis, producing a study cohort of over 80,000 individuals.

The investigators then examined medical records for prospectively recorded diagnoses of concussion from birth to age 10 years or from age 11 to 20 years. The data were further stratified for single and multiple episodes of trauma, to consider the possibility of a dose-dependent association. A matched control group consisted of those with broken limb bones but no traumatic head injury.

Although findings of several studies have suggested a link between concussion and MS risk, the pooled results from cohort studies have not been statistically significant, according to Montgomery and colleagues. They also pointed out that previous studies relied on retrospective reporting of earlier trauma, and, although the largest study had 5550 participants, most had substantially fewer than 700 cases and controls.

Few of the studies included trauma up to age 20 years, the investigators said, even though different developmental phases in the central nervous system (CNS) suggest the possibility of age-specific differences in susceptibility. “To the best of our knowledge, this is the largest study of traumatic head injury before age 20 years and subsequent MS risk, and notably, the first to use prospectively recorded data, thus enhancing accuracy,” Montgomery and colleagues wrote.

The investigators found that 1 diagnosis of concussion in adolescence raised the risk of MS, with an odds ratio (OR) of 1.22 (95% CI, 1.05-1.42), and the risk rose further with more than 1 episode, OR 2.33 (95% CI, 1.35-4.04). There was no discernible association of MS with concussion in childhood, or with broken limb bones in childhood or adolescence.

“I would like to see a replication and extension of our study to further quantify the risk for MS associated with traumatic head injury so that more detailed advice can be given. We are currently looking at other measures of susceptibility and exposure to better identify those at risk of MS,” Montgomery told 

Although MS is an immune-mediated disease, the investigators posited how environmental factors such as head trauma could trigger a pathological process leading to the disease. In one scenario, a neurofilament could be released into the cerebrospinal fluid and then to systemic compartments including lymph nodes, provoking an adaptive immune response to the CNS component.

“There are notable differences in the etiology of CTE and MS, but it is plausible that CNS trauma is a risk for both diseases,” Montgomery said. “We believe that several exposures other than this type of trauma may initiate the autoimmune processes leading to the focal inflammation in MS.”

The possibility that certain maternal or perinatal exposures contribute to the risk of pediatric-onset MS was examined in a case control study of 265 children with MS or clinically isolated syndrome and 412 healthy controls.

Cases identified from 16 clinics participating in the United States Network of Pediatric Multiple Sclerosis Centers were median age 15.7 years and 62% girls, and the controls, identified from primary care or other clinics at the same institutions, were median age 14.6 years and 54% girls.

The study’s environmental questionnaire, based on earlier ones used in MS and other autoimmune diseases, tested for wording problems or incomplete response in 30 families prior to the study. The questions referred to the period of 3 months before conception through first year of life. Statistical analysis adjusted for age, sex, race, ethnicity, US birth region, and socioeconomic status.

The investigators reported that maternal illness during pregnancy could be a risk factor for pediatric-onset MS. In contrast to previously reported associations of a deleterious or neutral effect of cesarean delivery on adult-onset MS risk, a cesarean delivery appeared to have some protective effect against pediatric-onset MS in this cohort. The investigators did not confirm that breast-feeding was a protective factor, as has been speculated.

Another Reason to Reduce Childhood Obesity

A notable finding was that exposure to pesticides in the perinatal period appeared to increase MS risk, and the investigators suggest that exposure to petroleum-based organic solvents may be particularly relevant after the first year of life. “While our pesticide results are preliminary and require replication, as well as investigation of the mechanism, this is an important finding because the risk factor is preventable,” lead author Jennifer Graves, MD, PhD, a neurologist at the University of California, San Francisco, Regional Pediatric Multiple Sclerosis Center, told 

. “Even if families can’t control agricultural pesticide practices, they can exercise protective practices, including appropriate hygiene with home use, and select the best produce options with washing.”

Reclassifying 2 avoidable factors that might contribute to pediatric-onset MS—low vitamin D and high body mass index (BMI)&mdash;from the category of “possible association” to “causal” could prompt greater preventative efforts. Milena Gianfrancesco, PhD, MPH, of the Division of Epidemiology at the University of California, Berkeley, School of Public Health and colleagues took up the challenge.

Others have suggested an association between childhood obesity and risk of pediatric-onset MS and an association between low vitamin D status and risk of adult-onset MS, as well as a relationship between the 2, possibly based on reduced circulating levels of fat-soluble vitamin D with increased available storage in adipose tissue with obesity.

The investigators employed Mendelian randomization and meta-analysis to estimate the likelihood of causal associations with pediatric-onset MS using genetic risk scores (GRS) in a study population of over 16,000 in the United States and Sweden.

“We report strong evidence for a causal and independent association between low serum concentrations of vitamin D and increased BMI and risk of pediatric-onset MS after adjusting for sex, ancestry, [genetic risk factor] HLA-DRB1*15:01, and over 100 non-human leukocyte antigen (HLA) MS risk variants,” the investigators wrote. “A causal relationship between low vitamin D and increased BMI has implications for prevention strategies in children.”

Even more resources pertaining to multiple sclerosis can be found on 

1. Montgomery S, Hiyoshi A, Burkill S, Alfredsson L, Bahmanyar S, Olsson T. Concussion in adolescence and risk of multiple sclerosis. 

2. Graves JS, Chitnis T, Weinstock-Guttman B, et al. Maternal and perinatal exposures are associated with risk for pediatric-onset multiple sclerosis. 

3. Gianfrancesco MA, Stridh P, Rhead B, et al. Evidence for a causal relationship between low vitamin D, high BMI and pediatric-onset MS. 

Although the causes of MS remain unknown, a variety of factors have been linked to exacerbations and relapse&mdash;and several that have recently been associated with increased risk of onset are avoidable.

March 2018