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Psychiatrists are often called when there is a complicated case without an obvious answer. Since symptoms of medical disorders can mimic neuropsychiatric disorders, it takes a careful history and some detective work to ascertain the correct diagnosis. In this case, a relatively young man was admitted to the hospital with perplexing psychiatric and neurologic symptoms. (The identifying details of the patient have been changed to protect the patient’s identity.)

“Roger,” a 34-year-old single Hispanic male, presented to the emergency department with severe depression, difficulty getting up in the morning for work, crying spells, chronic insomnia, and passive suicidal ideation—all worsening over the past 6 weeks. He also complained of auditory and visual hallucinations. He reported he “often heard voices muttering in the background,” although he could not decipher what they were saying. He also “sometimes saw shadows in the corner of the room.” He was concerned about “missing a lot of work and forgetting things.”

Roger explained he had been well until approximately 3 years ago when he began experiencing depression. He had already had 2 prior psychiatric admissions at another hospital (each hospitalization lasted 2 weeks apiece and were about 2 months apart). After the second discharge, he was referred back to his therapist in their outpatient clinic.

Roger had been discharged from his second hospitalization 6 weeks prior to this presentation. He was on fluoxetine 20 mg po qAM, risperidone 1 mg po twice a day, and benztropine 0.5 mg po BID. He admitted he was not as careful with medication adherence, noting he takes the medications “some of the time. Sometimes I forget.” He complained that the fluoxetine had sexual adverse effects of reducing frequency of erections, and “also interrupted my sleep.” He complained of ongoing fatigue and memory lapses.

He reported not liking the outpatient clinician, and said, “I never really felt comfortable with her.” He admitted missing a number of follow-up appointments at the mental health clinic. When the symptoms persisted, the patient “decided to try another hospital” and was admitted to our psychiatry unit.

The patient presented with severe depression with insomnia, decreased appetite, anhedonia, and increasing social withdrawal. Roger denied any suicidal plans, but he admitted to having passive thoughts of “not living anymore.” He firmly denied any history of suicide attempts and had no intention of harming himself. He denied any history of violence. He also had the aforementioned auditory and visual hallucinations

Roger He was particularly troubled by his decreased appetite, but he denied dieting or having any kind of eating disorder. He noted that he “didn’t enjoy cooking,” and his diet consisted mainly of take-out and fast-food. He added, “I should really eat better.” He denied taking any vitamins or other supplements.

Roger also complained of worsening memory loss and confusion: “A year or so ago, I started misplacing things: my phone, my house keys…I have trouble concentrating. I even forgot my mother’s birthday. That’s never happened before. I forgot the rent was due and had to pay a late fee.” He also noted that he was having trouble walking, which worsened over the past year or so. He denied any physical trauma. He noted that his legs “felt weaker” and his balance was “off.” He had fallen at home a few times. The patient also presented with vertical nystagmus, which was present for the past year. 

Roger was pleasant upon approach. He said he was glad he had sought admission and was “less lonely now.” He had a fresh-faced look, with good hygiene, and he maintained good eye contact. He said his mood was depressed “a 7 or 8 on a scale of 1 to 10.” The mental status exam was normal except for some difficulty with short-term memory. He scored 22 out of 30 on the Mini-mental state examination, which is consistent with mild cognitive impairment. On the Montreal Cognitive Assessment Test for Dementia (MoCa), Roger scored 18 out of 30, which is consistent with mild dementia. The score can be influenced by factors like fatigue or sedating medications. His long-term memory was adequate.

Regarding substance use history, Roger said he was a social drinker but “had managed to stop entirely over the past year.” He noted he had trouble sleeping most nights and up until a year ago he “would take a couple of shots of tequila or vodka to knock me out.” In the past he felt this was “necessary to cope.” He stopped alcohol use the prior year when he had memory issues and fell at home a few times.

Insomnia, however, was still an issue. He noted he had tried over-the-counter sleep aids, which “did nothing for me.” He volunteered that he had “experimented with mushrooms while in college, which he had enjoyed, but he denied using them since then.” He denied using cannabis or any other street drugs. His urine toxicology on admission was negative.

Roger grew up in Dallas, Texas, but both parents were from Mexico. He had a younger sister and brother, with whom he was close. The family still lived in Dallas. He “was the only one on the East Coast,” where he had moved for his job as an administrative assistant at an art museum. He mentioned that he was “homesick and missed them very much.” He had had some friction with his father that started a decade earlier after the patient came out as gay. He stated his father was macho, and “had real trouble accepting it. Everyone else is fine with it.” It pained him that sometimes his father would not come to the phone when the patient called home. He felt rejected and had not gone home for the past year.

Basic admission bloodwork results were normal. Thyroid function tests were normal. Chest X-ray was negative.

On the inpatient unit, Roger was initially placed on risperidone 1 mg po BID, benztropine 0.5 mg po BID, and bupropion 75 mg one tab orally a day. He was started on desyrel 50 mg po qHS, as needed, for the insomnia, which he said helped him sleep. He participated in many activities and groups on the unit. He was observed chatting with peers in a friendly way.

To further explore the diagnostic differential, a neurology consult was completed. The neurologist found no physical explanation for the nystagmus and ataxic gait. He concluded that both symptoms were psychogenic.

Since Roger believed he had a computed tomography (CT) scan during a prior hospitalization without any reports of abnormalities, one had not been immediately completed on admission. The team requested records for the 2 prior psychiatric hospitalizations and ordered a CT scan to be thorough.

Similarly, an ophthalmology consult was ordered. It revealed normal healthy eyes except for the vertical nystagmus.

This triad—the combination of an eye disorder (in this case, vertical nystagmus, but it could be another ocular disturbance), and a broad-based, ataxic gait in the context of memory decrease and mood and psychotic symptoms was suggestive of 

Wernicke’s encephalopathy or Korsakoff psychosis (WE)

 Although this syndrome usually occurs in the context of heavy alcohol consumption, Roger noted upon admission that he was merely a social drinker. Upon physical examination, he had no signs of chronic or advanced alcohol use, eg, broken facial capillaries (“gin blossoms”), palmar erythema, or jaundice. The liver function tests on his admission chemistry labs were elevated but still within normal limits. There were no signs of alcohol withdrawal on the unit.

To further explore this possibility, there was a further discussion with Roger about his alcohol use, this time looking for more details. For instance, Roger had noted that a long history of sleep issues for which he drank “several glasses (not shots) of vodka or tequila nightly since about the age of 22 or 23.” He was now 34. Clarification of the term “several” was also pursued. Roger explained that meant “4 or 5 regular glasses; it takes that much to calm me down so I can finally sleep. I drink a lot of coffee during the day.”

Roger also added that this was his nightly routine, not just an occasional thing. He denied ever having any blackouts or withdrawal tremors. He explained, “I’ve always had a high tolerance for booze. It runs in my family.” He did not share this degree of 

 He further noted he decided to stop drinking about a year ago: “I was forgetting too much stuff, over-sleeping sometimes, falling at home. I didn’t want to get fired.” Roger said he “had stopped on his own” without going to an inpatient detoxification or rehabilitation facility. He denied having any withdrawal seizures. He said he “had gone to a couple of Alcohol Anonymous meetings but stopped” because “I didn’t like the people there. It had a ‘homeless’ vibe.”

An Answer to the Mystery—and a Treatment Plan

The head CT with contrast showed changes in the thalamus consistent with WE. There were abnormalities noted in the cerebellum consistent with ataxia. Perhaps the head CTs at the prior hospital had not been interpreted properly.2 We ordered a serum thiamine (vitamin B1) level, which showed that he was severely deficient in thiamine. He now met the criteria for WE.

His loss of appetite and eating habits suggested the possibility of other vitamin deficiencies. We tested for serum vitamin B12 and vitamin D; he was severely deficient in both. This may well have contributed to his depressed mood.

To correct these vitamin deficiencies, the patient was transferred to a medicine inpatient unit. He received an IV bolus infusion of thiamine 500 mg TID for 2 days, then 250 mg IV daily for 

In addition, Roger was started on vitamin B12 injections and high-dose vitamin D tablets. Within about 2 weeks, all of his vitamin levels were restored to the normal range.

His vertical nystagmus stopped completely. His ataxic gait resolved. The depression lessened considerably, and his hallucinations ended.

Roger was discharged on the same psych meds: bupropion, 75 mg po qAM, risperidone, 1 mg po BID, benztropine, 05 mg po BID, and desyrel, 50 mg po qHS prn insomnia. He was also prescribed vitamin supplements of thiamine, vitamin B12, and vitamin D, as well as a therapeutic multivitamin. A nutrition consult was done for him to learn how to improve his eating habits. He was referred for supportive psychotherapy to an outpatient mental health clinic that specializes in treatment of the LGBQT+ community.

Wernicke’s Encephalopathy-Korsakoff’s Psychosis Considered

In general, WE is reversible with thiamine infusions. However, failure to diagnose WE can lead to a serious amnestic syndrome (Korsakoff syndrome). Korsakoff psychosis is generally irreversible. Therefore, it is extremely important that such patients are diagnosed and treated as 

When a patient admits to social drinking, it is helpful to pinpoint the exact extent of alcohol use in terms of type of alcohol, quantity, and 

 An assessment of a patient’s eating habits and nutritional intake (or lack thereof) can also contribute to the diagnosis and treatment of common psychiatric disorders.

There are a variety of evidence-based cognitive 

 Heirene et al compared the neuropsychological tests used to assess alcohol-related cognitive impairment and compared it with tests that screen for alcohol-related dementia and Korsakoff syndrome.

 They concluded that there is a heterogeneity in presentation and suggested using the more broad and inclusive diagnostic conceptualizations of alcohol-related cognitive impairment instead of the discrete diagnoses of Korsakoff syndrome and alcohol-related dementia.

Meanwhile, Sgouros et al has pursued the development of a Thiamine Deficiency Questionnaire (TDQ) to assess thiamine deficiency in patients with 

 Unfortunately, they concluded that further refinement and evaluation was needed before endorsing TDQ’s validity.

Alcohol use (as well as the use of other street drugs) is 

 According to Livingston and Callinan, “population surveys typically produce underestimates of alcohol consumption of approximately 40%-50%.”

 Thus, it is critical to be as specific as possible regarding what kind of alcohol is being consumed, how much at a drinking session, and how often in the initial patient interview. If the patient admits to “a couple of beers,” ask if those are 12-ounce, 16-ounce, or 24-ounce drinks. Ask for the pattern: are they drinking more on weekends than on weeknights when they have to get to work the next day? Listen for words like 

 as these can be common triggers for high levels of alcohol consumption.

Alcohol use disorder is not the only cause of WE. Any condition that compromises the body’s access to vitamin B1 (thiamine) can 

is a board-certified psychiatrist. She is on the staff of Manhattan Psychiatric Center and works in their mental health outpatient clinic. Her new book 

1. Chandrakumar A, Bhardwaj A, 't Jong GW. Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis. 

2. Wijnia JW, Oudman E, Bresser EL, et al. Need for early diagnosis of mental and mobility changes in Wernicke encephalopathy. 

3. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff-syndrome: under-recognized and under-treated. 

4. Livingston M, Callinan S. Underreporting in alcohol surveys: whose drinking is underestimated? 

5. Boniface S, Shelton N. How is alcohol consumption affected if we account for under-reporting? A hypothetical scenario. 

6. Boniface S, Kneale J, Shelton N. Drinking pattern is more strongly associated with under-reporting of alcohol consumption than socio-demographic factors: evidence from a mixed-methods study. 

7. Heirene R, John B, Roderique-Davies G. Identification and evaluation of neuropsychological tools used in the assessment of alcohol-related cognitive impairment: a systematic review. 

8. Sgouros X, Baines M, Bloor RN, et al. Evaluation of a clinical screening instrument to identify states of thiamine deficiency in inpatients with severe alcohol dependence syndrome. 

9. Choi EY, Gomes WA, Haigentz M Jr, Graber JJ. Association between malignancy and non-alcoholic Wernicke’s encephalopathy: a case report and literature review. 

10. Hutcheon DA. Malnutrition-induced Wernicke’s encephalopathy following a water-only fasting diet. 

11. Shible AA, Ramadurai D, Gergen D, Reynolds PM. Dry beriberi due to thiamine deficiency associated with peripheral neuropathy and Wernicke's Encephalopathy mimicking Guillain-Barré syndrome: a case report and review of the literature. 

12. Togay-Işikay C, Yiğit A, Mutluer N. Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised condition. 

Psychiatrists face diagnostic puzzles almost every day. Find out how one clinician cracked a tough case.  

A Young Man Presents With Perplexing Symptoms: What Is Going on Here? 

Robert DeLuca, RPh, president of Orexo US, talks about the new and upcoming digital therapeutic, 

, and its aim to help close the gap in care for patients with opioid use disorder. You can learn more by visiting 

. Modia™ is expected to be available later this year.

is President of Orexo US and has more than 25 years of industry experience at several multinational pharmaceutical companies. In addition to his demonstrated track record of success in the pharmaceutical industry with a combined background in global commercial operations, marketing, market access, and sales, DeLuca is also a New Jersey licensed pharmacist. He practiced retail pharmacy for 3 years post licensure prior to entering the corporate arena. DeLuca also is on the St. John’s College of Pharmacy Advisory Board and has memberships in the Academy of Managed Care Pharmacy (AMCP) and in the American Pharmacists Association.

What digital therapeutic treatment for opioid use disorder will soon be available to complement psychiatric care? 

Effectively Treating Opioid Use Disorder

Adial Pharmaceuticals, Inc. is filing an application for Fast Track with the US Food and Drug Administration (FDA) for its lead drug candidate, AD04.

Adial previously requested AD04, a therapeutic agent for the treatment of alcohol use disorder (AUD) in patients with target genotypes, be considered for the FDA expedited review program.

“We are working with our regulatory counsel to prepare our Fast Track submission after consultation with the FDA,” Adial’s CEO, William Stilley, said to the press “Following our submission, the FDA is expected to review the request and make a decision within 60 days.”

When a Fast Track application is reviewed, the submitted drug must demonstrate advantages over the currently available and approved therapy, thus meeting an unmet medical need. Advantages Adial believes AD04’s advantages include the following: 1) AD04 had a significant effect in patients with AUD who did not tolerate available therapy or failed to respond to said therapy; 2) AD04 saw a decrease in clinically significant toxicity of a common available therapy that often causes discontinuation of treatment; 3) AD04 has a safety and efficacy profile similar to that of available therapies, but is expected to enhance improvement in serious cases of AUD; 4) AD04 addresses the anticipated public health need.

“Adial’s correspondence and consultation with the FDA following its expedited review filing in September 2020, leads us to believe that AD04 qualifies for Fast Track consideration,” Adial’s Head of Regulatory, Jack Reich, PhD, commented to press. “I am confident Alcohol Use Disorder qualifies as a serious condition and that there is an unmet medical need, based on our communication with the FDA and as set forth in the FDA’s 

Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics

Cornel N. Stanciu, MD, MRO, had this to say: "You can look at the issue of pharmacotherapy for alcohol use disorders in two ways. On one hand, currently only 6% of those with an alcohol use disorder receive any of the FDA approved medications for relapse prevention, so we are not making use of what is available. On the other hand, addictionologists like myself need more tools to be able to tailor and personalize treatments for individual sufferers as one size does not fit all. This development presents a step forward towards a novel type of drug development to address an unmet medical need."

1. Adial Pharmaceuticals. Adial to file Fast Track application for AD04 with the FDA. News release. February 23, 2021. 

https://ir.adialpharma.com/press-releases/detail/112/adial-to-file-fast-track-application-for-ad04-with-the-fda

An alcohol use disorder treatment has 4 potential advantages over existing treatments.  

Hitting the Fast Track: Alcohol Use Disorder Treatment Filing with FDA

In the midst of a nationwide opioid epidemic, there is a population that is largely being ignored. According to a large cohort study, only a small percentage of teens receive proper aftercare following near-fatal overdoses. 

 examined data from more than 4 million Medicaid enrollees (N = 4,039,216) and found that only 1 in 54 youths aged 13 to 22 years received evidence-based pharmacotherapy after an overdose. Unfortunately, it appears that proper care in this patient population is given in very few cases (

 invited lead author Rachel H. Alinsky, MD, MPH, to share insights from the study. Alinsky is an adolescent medicine and addiction medicine fellow at 

Johns Hopkins University School of Medicine

: Your research highlights the need for quality treatment, especially for younger patients. What insights can you provide about interventions and obstacles to treatment?

We need to find effective interventions that can link adolescents and young adults directly into treatment after an opioid overdose. We also need to evaluate the barriers to accessing care at the time of overdose (such as insurance restrictions, lack of community providers or treatment centers, and stigma), and find strategies to mitigate these barriers. System-level changes are necessary, such as targeting federal funding for research and treatment for youth, decreasing insurance barriers, and increasing the availability of youth-serving physicians and addiction treatment centers.

 In the study, you and your colleagues noted, “Nonfatal opioid overdose may be a critical touch point when youths who have never received a diagnosis of opioid use disorder can be engaged in treatment.” Is that because these youths have hit rock bottom?

In the addiction treatment field, we do not abide by that old adage—that people have to hit rock bottom before they are ready to get treatment. That is somewhat of a myth. What we are trying to emphasize in our article is that overdose is a particularly crucial time when we can draw someone into treatment because they are presenting into the medical setting, seeing doctors, and we have this opportunity to interact with them and offer them treatment. Coming into the emergency department with an overdose may be the only time this person is sitting face-to-face with a doctor, and we want to capitalize on this opportunity to offer the best care we can to the patient.

Of course, that does not mean they did not want treatment a month ago or a week ago—they very well might have wanted treatment but did not know how to access it in our very difficult-to-navigate addiction treatment system. So when the patient is physically with us after an overdose, we have the chance to help them gain access to lifesaving treatment.

PT: What are the key takeaway points from the study?

Prior to this study, we knew that teens and young adults were about one-tenth as likely as adults to receive treatment for opioid use disorder in general.

 And while we knew that more than 4000 adolescents and young adults between the ages of 15 and 24 die from an 

 very little was known about health care use following nonfatal opioid overdose in youth. We were interested in figuring out the extent to which adolescents and young adults are receiving evidence-based treatment after a nonfatal opioid overdose.

We found that fewer than 1 in 50 adolescents and young adults who had an opioid overdose received the standard-of-care medication treatment that is recommended by the American Academy of Pediatrics.

 We also found that youths with opioid overdose have a 

; more than 8% of youths with heroin overdose experience another overdose within 3 months.

When an adolescent or young adult goes to the hospital with an emergency, you expect them to get the treatment they need. But here we see that less than 2% are getting that treatment, which would not be acceptable for any other medical condition. In pediatrics, it would be unacceptable if only 1 in 50 youths with asthma [received] the standard treatment when they came into the emergency department, or if 1 in 50 youths with diabetes [received] the standard treatment when they were hospitalized with diabetic ketoacidosis. Pediatricians would not find that treatment gap acceptable. Yet this is where we are now with the treatment for youths who have an opioid overdose—and we need to do better for them.

Additionally, with such high rates of recurrent overdose, it is even more important to get these youths into effective treatment as soon as possible, so we can try to prevent another overdose.

Finally, prescribing practices should be closely monitored in young people; they are a critically neglected patient population when it comes to addiction monitoring. As verified in an earlier study of 2,752,612 adolescents: “Safe opioid prescribing practices are critical to mitigate the risk of prescription opioid overdose in adolescents and young adults.”

PT: What are the key issues in recognizing opioid use disorder in youth?

The diagnosis of opioid use disorder is straightforward and is based on how many criteria an individual meets from a set of 11 criteria defined in DSM-5. In the case of youths who are presenting with opioid overdose, there is a chance that clinicians may view this as a standalone incident, and not recognize it as a manifestation of an adolescent’s underlying opioid use disorder. Thus, clinicians should be thinking about, and evaluating for, opioid use disorder in any youths that present with an overdose. Clinicians should probe for issues such as taking the opioid in larger amounts than intended, unsuccessful efforts to cut down use, cravings, recurrent use despite failure to fulfill obligations at school or home, or recurrent use in physically hazardous situations.

In terms of treatment, psychiatrists and other providers should offer medication for opioid use disorder as first-line treatment, consistent with recommendations from the 

. These medications include buprenorphine, methadone, and naltrexone. Pharmacological interventions can be combined with behavioral health services such as therapy or counseling. The provider will need to determine the level of care that will best support the patient in their current stage of treatment—inpatient hospitalization, residential treatment, intensive outpatient, or outpatient treatment.

We know that medication is effective and lifesaving for opioid use disorder; large studies in adults have found that medication cuts the risk of death in half.6,7 We also know that youths who are on medication stay in treatment longer.8 Because so few youths actually ever receive this effective addiction treatment, an overdose can be an ideal opportunity to link someone into care who has not been able to access it previously.

How can clinicians advise their patients and families on finding the most appropriate care?

Patients and their parents can advocate for treatment by asking their doctors about treatment when they are in the emergency department with an overdose. Some emergency departments have programs where patients can immediately start on medication treatment; the programs can then link them to a provider in the community. These programs have been shown to be extremely effective, with much higher rates of individuals entering and staying in treatment than if someone is simply handed a phone number to call to set up treatment.9 If that sort of linkage is not available, families should ask to be referred so their teen or young adult can receive treatment in their community as soon as possible.

Clinicians or patients and families who want to find available treatment resources within their community can use the treatment locator provided by the Substance Abuse and Mental Health Services Administration (

). Here you can enter your zip code and find all the available addiction treatment centers, sorting by services offered. It is also possible to specifically look for buprenorphine prescribers or methadone programs from that web page.

1. Alinsky RH, Zima BT, Rodean J, et al. 

Receipt of addiction treatment after opioid overdose among Medicaid-enrolled adolescents and young adults

2. Chua KP, Brummett CM, Conti RM, Bohnert A. 

Association of opioid prescribing patterns with prescription opioid overdose in adolescents and young adults

3. Overdose death rates. National Institute on Drug Abuse. Updated March 10, 2020. Accessed November 30, 2020, 2020. 

https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates

4. Committee on Substance Use and Prevention. Medication-assisted treatment of adolescents with opioid use disorders. 

5. Feder KA, Krawczyk N, Saloner B. Medication-assisted treatment for adolescents in specialty treatment for opioid use disorder.

6. Larochelle MR, Bernson D, Land T, et al. Medication for opioid use disorder after nonfatal opioid overdose and association with mortality: a cohort study. 

7. Medications for Opioid Use Disorder Save Lives. The National Academies Press. Accessed November 30, 2020. 

http://www.nationalacademies.org/hmd/Reports/2019/medications-for-opioid-use-disorder-save-lives.aspx

8. Hadland SE, Bagley SM, Rodean J, et al. Receipt of timely addiction treatment and association of early medication treatment with retention in care among youths with opioid use disorder. 

9. D’Onofrio G, O’Connor PG, Pantalon MV, et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. 

With opioid use disorder, a tiny fraction of young patients are getting treatment, which would not be acceptable for any other medical condition. 

Improving Care in Teens With Opioid Use Disorder

In an attempt to remove a potential barrier to opioid use disorder (OUD) treatment, the Department of Health and Human Services (HHS) announced a plan

Organizations like the American Medical Association (AMA) welcomed the revision. Patrice Harris, MD, chair of the AMA’s Opioid Task Force and the organization’s immediate past president, said the following in the AMA’s released statement: “With this change, office-based physicians and physician-led teams working with patients to manage their other medical conditions can also treat them for their opioid use disorder without being subjected to a separate and burdensome regulatory regime.”

The newly unveiled practice guidelines include an exemption from current certification requirements. The exemption applies to physicians already registered with the Drug Enforcement Administration.

The new HHS policy potentially limits physicians to treating no more than 30 patients with buprenorphine for OUD at any single time. The HSS will make exceptions to this limit for hospital-based physicians, such as those working in emergency departments.

Additionally, the policy change only applies to the prescription of drugs or formulations covered under the X-waiver of the Controlled Substance Act, such as buprenorphine. It does not apply to methadone. The effectual date of the new guidelines will be added after publication in the Federal Register.

The X-waiver has received criticism for years, with one group of doctors writing a 2018 Viewpoint article in 

, titled “Buprenorphine Deregulation and Mainstreaming Treatment for Opioid Use Disorder: X the X Waiver.”

 Deregulating buprenorphine, in the opinion of the authors, might be a way to mainstream an effective treatment for OUD.

“Federal policies surrounding buprenorphine constrain its wider use through separate US Drug Enforcement Agency (DEA)–amended licenses (‘waivers’) after approved training,” wrote Fiscella et al. “Removing buprenorphine prescribing regulations in France yielded increases in its use by persons with OUD. Notably, deaths from opioid overdoses in France declined 79% over the subsequent 3 years.”

By removing this waiver, the HHS has hopefully taken a step toward reducing opioid overdose in the United States.

1. Department of Health and Human Services. Announcement of practice guidelines for the administration of buprenorphine for treating opioid use disorder. January 12, 2021. Accessed January 18, 2021. 

https://www.hhs.gov/sites/default/files/mat-physician-practice-guidelines.pdf

2. Young KD. HHS will drop buprenorphine waiver rule for most physicians. 

https://www.medscape.com/viewarticle/944208

3. Fiscella K, Wakeman SE, Beletsky L. Buprenorphine deregulation and mainstreaming treatment for opioid use disorder: X the x waiver. 

The Department of Health and Human Services moves to reduce administrative procedural barriers to OUD treatment. 

Dropping the X-Waiver for Buprenorphine

The Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder study, or ADAPT-2 study, discovered that a combination of injectable naltrexone and oral bupropion was safe and effective for treating adults with moderate to severe methamphetamine use disorder. This combination therapy may be a potential treatment addition for those struggling to overcome addiction to methamphetamine.

“The opioid crisis and resulting overdose deaths in the United States are now well known, but what is less recognized is that there is a growing crisis of overdose deaths involving methamphetamine and other stimulants. However, unlike for opioids, there are currently no approved medications for treating methamphetamine use disorder,” National Institute on Drug Abuse (NIDA) Director Nora D. Volkow, MD, said to the press. “This advance demonstrates that medical treatment for methamphetamine use disorder can help improve patient outcomes.”

The research was conducted from 2017 to 2019 at multiple sites within the NIDA Clinical Trials Network (NIDA CTN). The study enrolled 403 adult participants aged 18 to 65 years with moderate to severe methamphetamine use disorder for stage 1, and 225 participants in stage 2. All of these participants wanted to reduce or cease use of the drug.

The study was broken down into 2 stages, 6 weeks each. Participants in the treatment group were given an injection of extended-release naltrexone every 3 weeks and extended-release tablets of bupropion daily. Participants in the control group were given injectable and oral placebos over the same time periods. Adverse events within the naltrexone–bupropion treatment group included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants who received naltrexone–bupropion during the trial.

At the end of each stage of the trial, researchers gave 4 urine drug screens. If at least 3 of the 4 urine screens were negative, the participant was considered to have responded to treatment.

Over a 12-week period, responses among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low; however, it was higher than that of the participants who received placebo.

“Long-term methamphetamine misuse has been shown to cause diffuse changes to the brain, which can contribute to severe health consequences beyond addiction itself,” trial leader Madhukar H. Trivedi, MD, of the University of Texas Southwestern Medical Center, Dallas, said to the press. “The good news is that some of the structural and neurochemical brain changes are reversed in people who recover, underscoring the importance of identifying new and more effective treatment strategies.”

1. National Institutes of Health. Combination treatment for methamphetamine use disorder shows promise in NIH study. News release. January 13, 2021. 

https://www.nih.gov/news-events/news-releases/combination-treatment-methamphetamine-use-disorder-shows-promise-nih-study

2. Trivedi MH, Walker R, Ling W, dela Cruz A, et al. Bupropion and naltrexone in methamphetamine use disorder. N Engl J Med. 2021;384:140-153.

In an ADAPT-2 study, a combination of injectable naltrexone and oral bupropion showed promise for methamphetamine users.  

Medicine Combination With the Potential to Beat Methamphetamine Use Disorder

Major depressive disorder (MDD) is the leading cause of global disease burden.

 of MDD in the United States has continued to increase among all age groups.

 Patients with these disorders are twice as likely to suffer from a comorbid substance use disorder (SUD) compared with the general population, and the severity of the S6UD parallels that of MDD.

 The comorbidity poses treatment challenges, and patients have been found to have poor outcomes (eg, increased substance use, more severe disease burden, higher rates of suicide attempts and behaviors), as well as an overall increased mortality.

The tight association between MDD and SUD does not necessarily hint at causation, as substance use can lead to mental health symptoms and conditions; mental illness can lead to self-medicating with substance use; and both conditions may co-occur independently as in the case of overlapping predisposing genetic factors. For patients with the comorbidity treatment gaps exist. 90% of those with SUD do not get MDD treatment, and 55% of those with MDD do not get SUD treatment when addressed independently, while 33% of them get no treatment at all.

Both MDD and SUD are in the DSM-5 and hence it is our responsibility to treat them as part of our routine psychiatric practice. Treating depression and substance use independently and in isolation of each other is incongruent with 

 Guidelines recommend simultaneous and integrated treatment with pharmacotherapy and/or psychotherapy for MDD depending on disease severity.

As for how closely these guidelines are followed, no study to date has investigated whether those with the SUD comorbidity receive similar MDD care to those without SUD among the pharmacotherapy and psychotherapy-based treatment modalities, or the degree to which specific SUDs are differentially associated with the receipt of guideline-specific MDD treatment. 

 Do patients with MDD and comorbid SUD receive similar, guideline-concordant, care as those without SUD?

 of 53,034 patients in whom MDD was diagnosed in the 2017 fiscal year in the US Veterans Health Administration (VHA).

 The patients were all veterans receiving care through the US Veterans Health Administration system. They all had a diagnosis of depression made in 2017.

 Electronic medical record data was reviewed to identify patients from both inpatient and outpatient encounters who were diagnosed with depression using ICD-10 codes and Patient Health Questionnaire (PHQ) screens. The PHQ was required to have been documented within a 30-day window of the depression diagnosis in order to capture active depressive episodes. Exclusionary criteria targeted patients with a past depressive diagnosis or who had received prescription antidepressants (except trazodone) or 

 in the past 12 months prior to the index diagnosis date. Also excluded were those with positive PHQ scores documented between 30 days and 12 months before the index depression diagnosis. Patient with comorbid bipolar disorder, schizophrenia, psychosis, personality disorder or developmental disorders, or those with more than 30 days of inpatient treatment in the last year were also excluded. Patients with comorbid SUD were identified as receiving a SUD diagnosis in the year before the depression diagnosis, as identified using ICD-10 codes meant to capture alcohol, opioid, cannabis, cocaine, stimulants, and other SUDs.

The outcomes measure assessed was adherence to treatment guidelines. For this, the authors used 

Healthcare Effectiveness Data and Information Set

 (HEDIS), which is a set of performance measurement tools developed and maintained by the National Committee for Quality Assurance (

) and widely used to assess where improvements can make a difference. HEIDIS is intended to allow comparisons among various health plans, systems, as well as adherence to national benchmarks and guidelines.

Among patients who received an initial prescription for antidepressants within 90 days of the index, depressive disorders to HEDIS based measures related to pharmacotherapy were applied. These resulted in measurements of adequate acute phase treatment (receipt of an antidepressant prescription within 90 days of diagnosis that provides medication for at least 84 of the 114 days following initial prescription); adequate continuation phase treatment (continuing antidepressant for 180 of the first 231 days following initial script).

) was also examined using metrics analogous to HEDIS. Here they evaluated both acute phase treatment (psychotherapy sessions that occurred within 90 days of the index depression diagnosis), as well as continuous phase treatment (at least 3 psychotherapy sessions in the 12 weeks following the first session). Additionally, the authors considered the confounding element that psychotherapy could be delivered for both depressive disorders and SUDs hence, in the analysis-only sessions for whichdepressive disorders were the primary diagnosis were included.

The authors also aimed to adjust for patient demographics (age, gender, race, geographical locality, and distance from the VA) and clinical characteristics (comorbid mental health disorders, measured by the Elixhauser score for severity).

. Sample characteristics across all described covariates were compared between those with and without SUD. Four multivariate logistic regression models were conducted to assess the associations between the presence of a SUD diagnosis and adequate acute and continuous phase antidepressant or psychotherapy treatment. Adjustments for covariates were done for each model.

The authors estimated percentages of those receiving treatment across each of the depression care metrics (those with and without comorbid SUD) as the marginal means of balanced population based on the model. Associations of specific SUDs with depression treatment were examined via the 4 models with each SUD independently analyzed. Authors also descriptively examined the setting where patients with SUD were receiving depression treatment.

Among the 53,034 participants diagnosed with a new episode of depression during the 2017 fiscal year, 52.9% received antidepressant treatment and 34.9% received psychotherapy within 90 days following diagnosis. Of this cohort, 14.2% had a SUD diagnosis in the year prior to the depression diagnosis.

Patients with SUD comorbidity had more visits in mental health and primary care settings in the year following the depressive diagnosis (average of 14.1 visits [SD 18.1] compared with 10.2 visits [SD 10.9] among those without SUD). Unfortunately, despite this higher opportunity for depression treatment, those with SUD received significantly less guideline-concordant depressive treatment across all metrics.

Before adjusting for covariates, observed rates show acute and continuation-phase antidepressants were provided to 59.4% and 36.3% of those with SUD and MDD versus 66.2% and 44.8% of those with just MDD (

. In terms of psychotherapy, 31.6% and 26.8% of those with SUD received acute and continuation-phase treatment respectively, compared to 35.4% and 32.2% of those with just MDD (

). For those with SUD, most received treatment in metal health clinics (47% psychotherapy [N = 1117]; 59.1% antidepressants [N = 2390]); or in primary care/mental health integration clinics (42.7% psychotherapy [N = 1014] and 31.8% antidepressants [N = 1287]). A very small minority received depression treatment in SUD specialty clinics (3.5% psychotherapy [N = 83] and 2.5% antidepressants [N = 102]).

In terms of patient characteristics, those with SUD were slightly younger, male, African American, homeless, and had comorbid psychiatric conditions. Those without SUDs were more likely to be service connected, live in rural areas, and have more comorbid diagnosed medical conditions.

Patients with SUD had lower odds of receiving guideline-concordant care, specifically 21% lower odds of receiving acute antidepressant treatment, 13% lower odds of initial psychotherapy treatment, 26% lower odds of adequate continuation of antidepressant, and 19% lower odds of continuation of psychotherapy.

Based on predicted probabilities of receipt of guideline-concordant depression treatment, an estimated 55% of individuals with comorbid SUD, compared with 61% without, received adequate acute antidepressant treatment, and 27% of individuals with comorbid SUD, compared with 29% without, received initial psychotherapy. As for cotinuation of treatment, 33% of individuals with comorbid SUD, compared with 40% without, received adequate continuation of antidepressants, and 22% of individuals with SUD, compared with 25% without, received adequate continuation of psychotherapy.

In terms of specific SUDs, lower quality depression care was evident across all evaluated substance types. Alcohol and cannabis use disorders were associated with significantly lower odds of adequate continuation of antidepressants (adjusted OR 0.81, 95% CI = 0.75, 0.88, p < 0.001 and adjusted OR 0.74, 95% CI = 0.63, 0.87, p < 0.001 respectively). Alcohol and cocaine use disorders were associated with lower odds of initiation of psychotherapy for depression (adjusted OR 0.86, 95% CI = 0.81, 0.91, p < 0.001 and adjusted OR 0.78, 95% CI = 0.66, 0.92, p < 0.001 respectively). Alcohol use disorders alone were associated with lower odds of adequate psychotherapy continuation (adjusted OR 0.81, 95% CI = 0.72, 0.90, p < 0.001).

There were also several covariates associated with lower odds of guideline-concordant care. These included homelessness, racial and ethnic minority groups, those in rural areas, and those with high psychiatric disease burden living farther away from a health care facility.

This retrospective review study of patients in the Veteran Healthcare Administration system points to a treatment gap in the delivery of guideline-concordant care for depression among those with SUD compared with those without it.

This study assessed an interesting question: do patients with comorbid MDD and SUD receive different care for depression than those without SUD? Consistent with previous data

 in a large national sample of veteran patients within the VHA system, the authors found that having the comorbid SUD diagnosis is associated with lower quality of depression treatment compared with those without it.

 After accounting for various demographic, medical, and psychiatric factors, patients with SUD had lower odds of adequate acute phase treatment (21% and 13% lower for antidepressant and psychotherapy, respectively) and lower odds of adequate continuation of treatment (26% and 19% lower for antidepressant and psychotherapy, respectively) for depression. This discrepancy in guideline-concordant care for depression comes despite patients with SUD having higher health care utilization (more visits and medical encounters) and hence more opportunities for MDD treatment initiation. Knowledge of this treatment gap is important because SUD and MDD affect each other bidirectionally, and the most effective approaches involve concurrent treatment.

There are several limitations to this study. As the authors point out, this sample is limited to veterans in care within the VHA system. The generalization outside this system, and to civilians with various insurance coverages, is unknown. Additionally, the analysis does not include or account for services rendered outside the VHA system, where it is not uncommon for veterans to seek care from.

The diagnosis of MDD as well as SUD is identified here based on ICD-10 codes entered in the electronic health records, which can at times contain errors or not even be entered at all.

There is no mention of how closely providers actually adhere to the use of screening tools such as PHQ-9. It is also necessary to consider that there are other widely available tools that are not accounted for here. It is important to keep in mind that lack of training in the assessment and treatment of complex presentations such as comorbidity leads to inaccurate beliefs and stigmas, an inability to accurately identify co-occurring disorders,

 a lack of awareness of appropriate referral sources,

 and a lack of preparedness to treat co-occurring disorders.

 The providers caring for these patients are not explicitly defined here as to whether they are highly trained physicians or independently practicing nurse practitioners.

The severity of the MDD is not specifically described here via the use of any objective measure.

 Because engagement (or refusal) in treatment represents a patient-specific barrier, having a significant MDD severity, which patients with SUD comorbidity do, can lead to low motivation and lack of interest and future outlook, and hence would make it less likely for patients to be interested in and pursue treatment as well as adhere to it.

The sample selection criteria (new diagnosis of depression in fiscal year 2017 and a positive PHQ depression screen 30 days surrounding time of diagnosis) may lead to limits of generalizability of findings to the degree that these criteria may not capture most patients with depression (ie, preexisting diagnosis, noncompletion or adherence with depression screen).

Worthy of mention is that in the context of certain substances (ie, stimulant or cannabis), MDD may have psychotic features and hence require treatment with nontraditional modalities such as antipsychotics, rather than antidepressants. Within the limits of the study design it is also difficult to determine whether the MDD is due substance use or withdrawal.

The primary outcome measures here were based on the HEDIS, which has been criticized in the past for how its individual measures provide a narrow view of health care quality and interventions. There is also a question about whether attainment of their measures actually indicate better outcomes. In this study, the indicators of adequate acute and continuous phases of care (which are most often used measures of the quality of depression care) certainly do not encapsulate all features relevant to high-quality depression care. Nonetheless, HEDIS is part of NCQA’s accreditation process and attainment is globally used as incentive for many health plans and 

Are patients with depression and substance use disorder getting an appropriate level of care? Our Journal Club piece investigates.

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An Inside Look at Depression Treatment Among Patients With Addictive Disorders

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The Case for Medication-Assisted Treatment: An Ethical Priority