Leah Kuntz

Lyndra Therapeutics announced the positive outcome of an end-of-phase 2 meeting with the US Food and Drug Administration (FDA) suggesting a clear path to approval for its weekly risperidone for the treatment of schizophrenia, LYN-005. This treatment is designed as the first-ever oral, ultra-long-acting, extended-release therapy.

The company plans to initiate its pivotal program for LYN-005 in early 2022.

“We are grateful to the FDA for their guidance as we design this pivotal program. Transforming the patient experience via oral therapies that achieve consistent plasma drug concentrations at target therapeutic levels for an entire week is one of our key goals,” said Patricia Hurter, PhD, Chief Executive Officer of Lyndra Therapeutics. “This pivotal program allows us to deliver swiftly on the unmet need for ultra-long-acting oral therapies that have the potential to have an enormous and positive impact for patients and caregivers. We hope that the availability of an oral, once-weekly risperidone product will provide a valuable option for those who struggle with adherence but prefer an oral formulation.”

Lyndra and the FDA agreed on the necessity of 2 key elements of this program: 1) a 90-person pharmacokinetic comparability study that builds on the previously established safety and efficacy profile of risperidone, and 2) a 6-month double-blind safety study to characterize the safety profile of the dosage form. Both studies will evaluate LYN-005 at weekly doses ranging from 2 to 6 mg daily, and will support indications in schizophrenia, bipolar mania, and bipolar 1 disorder.

“The FDA provided valuable feedback during the end-of-phase 2 meeting on trial design, manufacturing and control strategy and Lyndra’s path forward as we pursue the pivotal program,” said Chief Medical Officer of Lyndra Therapeutics, Richard Scranton, MD, MPH. “The productive and collaborative nature of these meetings has allowed us to develop a clear and direct course of action as we pursue the tremendous potential of LYN-005.”

To read more on previous studies of LYN-005, see 

Extended-Release Risperidone Capsule Making Waves

1. Lyndra Therapeutics announces positive outcome of end-of-phase 2 meeting with the FDA for Lyndra’s weekly risperidone (LYN-005) for the treatment of adults with schizophrenia and other indications. News release. July 19, 2021. 

https://www.businesswire.com/news/home/20210719005181/en/Lyndra-Therapeutics-Announces-Positive-Outcome-of-End-of-Phase-2-Meeting-with-the-FDA-for-Lyndra’s-Weekly-Risperidone-LYN-005-for-the-Treatment-of-Adults-with-Schizophrenia-and-Other-Indications

2. Kuntz L. Extended-release risperidone capsule making waves. 

https://www.psychiatrictimes.com/view/extended-release-risperidone-capsule-making-waves

Articles

An extended release, ultra-long acting antipsychotic takes another step forward in the approval process.

Positive End-Of-Phase 2 Meeting for Extended-Release Risperidone Capsule 

According to a recent report from the Centers for Disease Control and Prevention (CDC), overdose deaths in 2020 are up 30% compared to 2019, the largest increase in at least 50 years. In response to the deaths of more than 93,000 Americans from drug overdoses, the American Psychiatric Association (APA) renewed its call to action.

“This week’s CDC report is a devastating reminder that the opioid crisis continues and, as we suspected, reached tragically high levels during the pandemic,” said Vivian Pender, MD, APA President. “It’s critical that policymakers continue to take action to save lives, and that families and patients know that treatment works.”

The APA stated the following 3 items are important to focus on:

1) Improved access to mental health and substance use care via early identification in evidence-based models that integrate behavioral health treatment into primary care services.

2) The development and implementation of science-based policies and programs to provide effective substance use disorder treatment for all patients, created through a review and discussion with Congress, federal policymakers, and experts in the field of addiction treatment.

3) Policies and programs to support accredited medical schools and residency programs in training clinicians to manage substance use disorders.

“The federal government and the states have taken a number of actions to address the opioid crisis, and APA has been supportive of those actions,” said APA CEO and Medical Director Saul Levin, MD, MPA. “A critical step in addressing the problem is ensuring early identification of substance use disorders and that all physicians have the adequate training to recognize and treat opioid use and substance use disorders when they see it.”

(Are you seeing increased cases of opioid use disorder (OUD)? Do you have any pressing concerns or questions about OUD or success stories to share? Write to us at

. Your story may be included in an upcoming special discussion on OUD—Ed)

1. American Psychiatric Association. American Psychiatric Association renews call to action after dramatic increase in overdose deaths. July 16, 2021. Accessed July 19, 2021. 

https://www.psychiatry.org/newsroom/news-releases/american-psychiatric-association-renews-call-to-action-after-dramatic-increase-in-overdose-deaths

After the largest increase in overdose deaths in 50 years, the American Psychiatric Association sends out the call for improved substance use care. 

Fighting the Opioid Epidemic: The APA’s Call to Action

The first patient has been dosed in the second part of Seelos Therapeutics’ registrational study of their formulation of intranasal racemic ketamine (SLS-002) for acute suicidal ideation and behavior (ASIB) in patients with major depressive disorder (MDD).

“There is a significant unmet need within the MDD market for pharmacotherapies that can demonstrate rapid antidepressant effects, in particular for patients with severe MDD requiring hospitalization including those with ASIB. In part 1 of the study, SLS-002 showed significant improvement in depressive symptoms at 24 hours compared to placebo,” said Philippa Salter, Neurology Analyst at GlobalData.

If approved, SLS-002 would become the second product approved specifically for ASIB. The first product, Johnson & Johnson’s rapid-acting esketamine (Spravato), was approved for moderate-to-severe MDD patients with ASIB in 2020. Due to risk of sedation and disassociation, Spravato is only available through a restricted program.

“Although Spravato was a breakthrough treatment for ASIB, its high cost of therapy, and requirement for 2 hours of patient observation after administration will also limit its uptake,” Salter continued. “As a related compound, and with the same intranasal route of administration, it is possible that SLS-002 will face similar issues to Spravato. However, in a small, randomized trial intranasal ketamine caused minimal dissociative effects, which, if replicated in larger trials, would give SLS-002 an advantage over Spravato.”

Several fast-acting antidepressants are looking to enter the market, including the following late-stage products: Sage Therapeutics/Biogen’s 

. While these products are not specifically in development for ASIB, if they demonstrate strong efficacy for MDD, a label expansion could be sought in the future.

1. GlobalData. Seelos Therapeutics’ SLS-002 could be a strong competitior to Spravato for treatment of suicidal behavior, says GlobalData. News release. July 13, 2021. Accessed July 16, 2021. 

https://www.globaldata.com/seelos-therapeutics-sls-002-strong-competitior-spravato-treatment-suicidal-behavior-says-globaldata/

If approved, SLS-002 would be only the second approved product for ASIB. 

New Treatment for Acute Suicidal Ideation and Behavior

A disruption in blood clotting and the first line immune system could contribute to the development psychosis, according to a recent scientific review published in 

“Early identification and treatment significantly improves clinical outcomes of psychotic disorders. Our theory may provide a further step to biomarkers of psychosis and allow the identification of therapeutic targets for early and more effective treatment,” said Melanie Föcking, PhD, joint first author on the paper and Lecturer in Psychiatric Neuroscience at RCSI Department of Psychiatry.

Investigators at RCSI University of Medicine and Health Sciences, Cardiff University, and the UCD Conway Institute led the research. Their findings resonate with other recent studies, which have identified blood proteins and blood clotting networks as instrumental in psychosis development. The researchers developed their new theory after analyzing these studies, proposing the imbalance of these systems leads to inflammation, which in turn contributes to the development of psychosis.

“While the idea of psychosis resulting from some form of inflammation and immune activation is not new, our data suggest a new understanding and change of focus towards a combined function of the innate immune complement system and coagulation pathways to the progression to psychotic disorder,” said joint first author Meike Heurich, PhD, lecturer at School of Pharmacy and Pharmaceutical Sciences at Cardiff University.

The new theory builds upon the “two-hit” hypothesis. In this hypothesis, early genetic and environmental factors disrupt the developing central nervous system, or the “first-hit,” and thus increases the individual’s vulnerability to subsequent, late environmental disruptions, or the “second-hit.”

“The works builds on our recent studies, which increasingly implicate dysregulation of the complement and coagulation pathways both in and preceding psychotic disorder,” said David Cotter, PhD, senior author of the paper and professor of Molecular Psychiatry at RCSI Department of Psychiatry.

1. Heurich M, Föcking M, Mongan D, et al. Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis. 

2. RCSI. New theory suggests blood immune and clotting components could contribute to psychosis. News release. July 16, 2021. 

https://www.eurekalert.org/pub_releases/2021-07/r-nts071621.php

New research may help better understand psychosis etiology as well as provide potential biomarkers for psychosis. 

Do Blood Clotting and Immune System Contribute to Psychosis? 

The first participant has officially enrolled in Orexo’s study of digital therapeutic modia, part of a clinician-supervised treatment program for the treatment of opioid use disorder (OUD).

“When it comes to treating OUD, research has proven time and time again that we need to take a whole-person approach by addressing both the physical withdrawal symptoms and the mental health issues associated with addiction,” said Nikolaj Sørensen, President and CEO of Orexo. “Yet, all too often, the resources needed to effectively do so just aren’t available. The enrollment of our first patient in the pivotal study of modia™ is a significant milestone toward closing that treatment gap and allowing more people easy access to a tool designed to support them in the battle against addiction.”

In this randomized, open-label, parallel-group study, modia will be evaluated in combination with sublingual buprenorphine/naloxone background therapy to see whether it is superior to sublingual buprenorphine/naloxone alone in reducing opioid use. An estimated 400 participants at 35 sites will be enrolled across the US and evaluated over 24 weeks, including a screening period where they will be stabilized on buprenorphine/naloxone. These participants will be volunteers aged 18 to 65 seeking treatment for moderate to severe OUD.

This news comes just in time to meet a rising need: The opioid epidemic has grown by 36% during the COVID-19 pandemic, with the number of fatal opioid overdoses reaching more than 67,500, from December 1, 2019, to November 30, 2020.

Additionally, modia aims at helping users develop a customized relapse prevention plan, structured using the responses collected throughout the program.

“A great deal of work went into designing and building modia to deliver a unique digital therapeutic for patients struggling with OUD,” Mike Sumner, Chief Medical Officer of Orexo, said to the press. “We fully anticipate that the outcomes of the study will prove that modia can be a valuable addition to existing treatment plans for patients with OUD when paired with medications like buprenorphine/naloxone.”

1. Orexo. Orexo announces first patient enrolled in pivotal study evaluating the efficacy of modia™ in combination with sublingual buprenorphine/ naloxone for the treatment of OUD. News release. July 1, 2021. Accessed July 15, 2021. 

https://orexo.com/posts/2021-07-01-orexo-announces-first-patient-enrolled-in-pivotal-study-evaluating-the-efficacy-of-modia-in-combination-with-sublingual-buprenorphine-naloxone-for-the-treatment-of-oud

2. Centers for Disease Control and Prevention. Provisional drug overdose death counts. June 16, 2021. Accessed July 15, 2021. 

https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm#dashboard

Novel digital therapy modia will be evaluated in combination with sublingual buprenorphine/naloxone background therapy to see whether it is superior in reducing opioid use.

First Participant Joins Opioid Use Disorder Treatment Study 

Rhode Island Governor Daniel McKee recently signed a bill that authorizes a 2-year pilot program 

 In these centers, people can consume pre-obtained substances under the supervision of trained staff.

There are approximately 120 similar programs operating worldwide, but Rhode Island is the first US state to pass a law authorizing the implementation of harm reduction centers for supervised drug consumption.

In response to the news, Managing Director of Policy for the Drug Policy Alliance, Lindsey LaSalle, said: “Today’s victory in Rhode Island gives us hope that there are policymakers that are willing to actually lead and do what needs to be done to save lives in the face of one of the worst public health crises of our time. With at least 92,000 of our friends and family members lost to overdose in 2020 alone, we simply cannot wait any longer. We have to use every public health resource at our disposal—especially the ones we know work. And we have to do it now. There are mountains of evidence, from years and years of experience in other countries, to show that 

, increase the likelihood of a person entering treatment, and provide people access to other vitally important health resources.”

Harm reduction centers provide a hygienic and safe space for people who use drugs. Center staff members do not directly assist in the consumption of any drugs brought in by clients. Instead, staff will: provide sterile equipment and supplies, answer questions on safe consumption practices, administer first aid if needed, monitor for overdose, offer general medical advice, and offer referrals to drug treatment, medical treatment, and other social support programs.

Harm reduction centers also reduce health and public order issues by targeting high-risk, socially marginalized drug users who would otherwise inject in public spaces. These services are not intended to replace existing prevention, harm reduction, and treatment interventions, but instead complement them.

“Our general assembly and Governor's office has been very supportive of helping people with substance use disorders, people who use drugs, and people in recovery and really actively engaging with those populations to move this law along. We hope this will set a precedent for other states to follow suit, with Rhode Island being the leader,” said Haley McKee, co-chair of the 

Substance Use Policy Education & Recovery PAC

1. State of Rhode Island General Assembly. Harm reduction center pilot program to combat overdose deaths becomes law. News release. July 7, 2021. Accessed July 8, 2021. 

http://www.rilin.state.ri.us/pressrelease/_layouts/RIL.PressRelease.ListStructure/Forms/DisplayForm.aspx?List=c8baae31-3c10-431c-8dcd-9dbbe21ce3e9&ID=371925

2. Drug Policy Alliance. Drug Policy Alliance statement on Rhode Island becoming first in the nation to authorize harm reduction centers to prevent overdose deaths. News release. July 7, 2021. Accessed July 8, 2021. 

https://drugpolicy.org/press-release/2021/07/drug-policy-alliance-statement-rhode-island-becoming-first-nation-authorize

To combat drug overdoses, the Rhode Island governor signed a bill allowing people to consume pre-obtained drugs under safe, professional supervision of trained staff. 

Rhode Island: The First State to Allow Harm Reduction Centers for Safe Drug Consumption 

Weeks of criticism for the approval of Biogen’s aducanumab for the treatment of anyone with Alzheimer disease (AD) has led to the US Food and Drug Administration (FDA) deciding to 

 to only patients with milder forms of AD.

The FDA stated that there is “no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”

Aducanumab—Biogen’s anti-amyloid, disease-modifying agent—is the 

first new treatment approved for Alzheimer disease since 2003

 It was approximately a month ago, June 2021, when the drug received 

After “ongoing conversations with prescribing physicians, FDA and patient advocates,” Biogen requested the update. Research head 

Alfred Sandrock Jr, MD, PhD, told the press this

: “[W]e submitted this label update with the goal to further clarify the patient population that was studied across the 3 [aducanumab] clinical trials that supported approval. We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option.”

Following the original FDA approval, criticism and questions arose concerning the 

 Medicare, which covers most AD patients in the US, might not be able to cover the cost of aducanumab. However, Biogen maintains that aducanumab’s launch would only target the 1 to 2 million mild disease patients, rather than the entire AD market.

Furthermore, this new label could help narrow reimbursement decisions and get aducanumab to the appropriate patients faster, according to Jefferies analysts.

“It helps get people going on the right direction to refined and appropriately focused reimbursement, which helps get everyone comfortable that 

,” Jefferies analyst Michael Yee said to the press.

Biogen reported satisfaction with this update.

1. Higgins-Dunn N. Biogen, FDA walk back controversial Aduhelm label after weeks of fierce criticism. Fierce Pharma. July 8, 2021. Accessed July 8, 2021. 

https://www.fiercepharma.com/pharma/facing-pushback-biogen-and-fda-agree-to-narrow-aduhelm-s-broad-label?mkt_tok=Mjk0LU1RRi0wNTYAAAF-JWkHTIeL0uFqfSeMOe7ihwmdeyy8jOopH3QueVDjp1-zlnj6tmhh5ijO--P6DNp1Uwf1fnemcemk5285MEDwewcfLhm9kqk9JrshzwCUCjKlKo0pHL4&mrkid=112621670

2. US Food and Drug Administration. FDA grants accelerated approval for Alzheimer’s drug. June 7, 2021. Accessed July 8, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

3. Kuntz L. First new treatment approved for Alzheimer disease in nearly 2 decades. June 7, 2021. Accessed July 8, 2021. 

https://www.psychiatrictimes.com/view/first-new-treatment-approved-for-alzheimer-disease-in-nearly-2-decades

4. Biogen. FDA approves updated ADUHELM™ prescribing information to emphasize population studied in clinical trials. News release. July 8, 2021. Accessed July 8, 2021. 

https://investors.biogen.com/news-releases/news-release-details/fda-approves-updated-aduhelmtm-prescribing-information-emphasize

5. Higgins-Dunn N. A $57B drug? Medicare faces a massive bill for Biogen's Aduhelm—even if it limits coverage. Fierce Pharma. June 24, 2021. Accessed July 8, 2021. 

https://www.fiercepharma.com/pharma/11-500-copays-and-diagnostic-hoops-biogen-s-alzheimer-s-56k-drug-aduhelm-set-to-balloon

6. Reuters staff. U.S. FDA narrows use of Biogen Alzheimer's drug; shares rise. News release. July 8, 2021. Accessed July 8, 2021. 

https://www.reuters.com/article/us-biogen-alzheimers-fda/us-fda-narrows-use-of-biogen-alzheimers-drug-shares-rise-idUSKCN2EE18V

Following criticism for its wide-labeled June approval, the FDA has decided to narrow the patient recommendation for aducanumab.  

Narrower Label for Alzheimer Disease Treatment, Aducanumab 

The US Food and Drug Administration (FDA) has granted 

 for donanemab, Eli Lilly and Company's investigational antibody therapy for Alzheimer disease (AD).

, a monoclonal antibody, was designed to target a particular form of post-translationally modified Aß, N-terminal pyroglutamate, and completely clear amyloid plaques.

The Breakthrough Therapy designation, created to expedite the development of drugs meant to treat serious conditions when preliminary evidence suggests the drug may demonstrate substantial improvements over already available therapies that have full FDA approval, is based on clinical evidence from Eli Lilly and Company’s phase 2 trial, TRAILBLAZER-ALZ for donanemab.

TRAILBLAZER-ALZ studied the efficacy and safety of donanemab in patients with early, symptomatic AD. The safety, tolerability, and efficacy of donanemab are also being evaluated in the ongoing randomized, placebo-controlled, double-blind, multi-center phase 3 study TRAILBLAZER-ALZ 2.

“At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo,” wrote the study’s authors.

Lilly intends to submit a biologics license application for donanemab under the accelerated approval pathway later in 2021.

1. Eli Lilly and Company. Lilly's donanemab receives U.S. FDA's Breakthrough Therapy designation for treatment of Alzheimer's disease. News release. June 24, 2021. Accessed June 25, 2021. 

https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-receives-us-fdas-breakthrough-therapy

2. Kuntz L. New data for Alzheimer agent presented at international conference. 

. March 23, 2021. Accessed June 25, 2021. 

https://www.psychiatrictimes.com/view/new-data-for-alzheimer-agent-presented-at-international-conference

Donanemab for the treatment of Alzheimer disease has received Breakthrough Therapy designation from the FDA. 

Another New Alzheimer Drug on the Horizon

Scottish Parliament is considering legislation on medical aid in dying (MAID) for the first time since 2015. Liam McArthur, MSP for Orkney, plans to lodge proposals in Parliament for a new Members Bill—the Assisted Dying Scotland Bill—that would legalize MAID as a choice for terminally ill, mentally competent adult patients.

“This represents a watershed moment for dying Scots. Momentum on changing the law to allow our dying citizens the right to a peaceful assisted death has been building and it is clear that the current blanket ban is unjust and unsustainable. Given the majority of Scots support the proposals and want the Parliament to take swift action, this is clearly the right bill at the right time. So many families across Scotland have spoken out about the injustice of the current law and the suffering it permits. It is right that their voices have been heard,” said Ally Thomson, Director of Dignity in Dying Scotland.

 “There is rigorous research and robust evidence from across the world to show that legalizing assisted dying is the compassionate and safe thing to do. I am delighted to welcome the introduction of the Bill and urge MSPs to listen to the people of Scotland, examine the evidence before them and back this Bill.”

In England and Wales, assisted dying is prohibited under the Suicide Act (1961). In Northern Ireland, it is prohibited under the Criminal Justice Act (1966), which states that anyone who assists a suicide could be imprisoned for up to 14 years. While there is no specific crime of assisting a suicide in Scotland, those who help a person to die could be prosecuted for homicide.

Recent polling, conducted by Populus 2019 and The Diffley Partnership 2021, shows that 86% of Scots would like the Scottish Parliament to examine the issue of MAID. Furthermore, 75% want this done within 2 years.

Chief Executive of Humanist Society Scotland, Fraser Sutherland, calls this bill the compassionate choice, saying: “We are delighted to back Liam’s proposal to bring a compassionate choice to dying people. Humanists, both in Scotland and globally, have long been at the forefront of the campaign for assisted dying laws. People at the end of their life need to be listened to and have their choices respected. The current practice of ignoring the demand for assisted dying at home but allowing people well and rich enough to travel to a private clinic abroad is simply immoral and without a shred of compassion. Given the overwhelming weight of public opinion is on the side of change, we think it is the right time for the Scottish Parliament to consider this issue. Scotland is able to learn from many countries around the world who have passed safe, dignified and properly regulated assisted dying laws.”

A Consultation on the contents of the bill is planned to take place in fall of 2021.

This follows in the footsteps of Canada’s newest legislation, although Canada’s bill allows for MAID in patients with psychiatric disorders. To read more about this, see 

First, Do No Harm: New Canadian Law Allows for Assisted Suicide for Patients with Psychiatric Disorders.

1. Dignity in Dying in Scotland. Dignity in Dying in Scotland welcome introduction of new assisted dying bill in Scottish Parliament. News release. June 21, 2021. Accessed June 23, 2021. 

https://www.dignityindyingscotland.org.uk/news/dignity-in-dying-scotland-welcome-introduction-of-new-assisted-dying-scotland-bill-in-scottish-parliament/

2. World Federation Right to Die Societies. Assisted dying bill introduced in UK. News release. May 26, 2021. Accessed June 23, 2021. 

https://wfrtds.org/assisted-dying-bill-introduced-in-uk/

For the first time since 2015, Scottish Parliament is considering legislation on medical aid in dying. 

Scotland Introduces Bill in Favor of Assisted Dying 

Is It a Psychiatric Disorder or a TBI Medical Mimic?

Too often, the medical issues associated with traumatic brain injury (TBI) are mistaken for psychiatric disorders, and patients are mistakenly referred to psychiatrists for treatment, Gregory J. O’Shanick, MDDLFAPA, told attendees.

O’Shanick, medical director of the Center for Neurorehabilitation Services in Richmond, Virginia, reminded psychiatrists to leverage their medical knowledge when assessing patients to help distinguish TBI-related medical mimics and true psychiatric diagnoses.

As the prevalence of TBI has increased, so too has 

research linking psychiatric disorders and TBI

 Jennie Ponsford, PhD, and colleagues explored this phenomenon and found that only about 23% and 21% of individuals had a pre-TBI history of a mood disorder or an anxiety disorder, respectively.

 They found an increase in psychiatric symptomology within the first year after TBI; mood and anxiety symptoms were most common (prevalence, 17.2%-62.0% and 10.3%-34.2%, respectively). Interestingly, O’Shanick noted depression is 4 to 6 times more common in patients with TBI than in the general population, and it is the most common cause of depression in men.

It is possible, he explained, that some of these mood disturbances and anxiety symptoms may be better explained as a medical consequence of TBI—or a signal of homeostatic disruption. In such cases, providing psychopharmacological treatment might improve symptoms but will not address the underlying cause.

To illustrate this issue, O’Shanick discussed examples of phobias misattributed to psychiatric diagnoses. For instance, if an individual has unrecognized balance and visual issues as a result of TBI, they may feel a sense of anxiety when in crowds. Instead of recognizing that the uneasiness is due to stability issues, the person may inappropriately link the feeling to an anxiety disorder.

“As physicians, we need to figure that out,” O’Shanick emphasized.

Fortunately, a few simple questions and exercises can help determine the root cause of the psychiatric symptoms. For example, to determine if agoraphobia symptoms may actually be vestibular in nature, ask your patient if they need to touch the wall to prevent falling when closing their eyes in the shower. Or, if the patients feels anxious in a crowded area like a store or mall, ask if pushing a cart or stroller, or holding on to another person, makes them feel better. If they answer yes, a few simple follow-up tests (eg, the Balance Error Scoring System and Fukuda Stepping Test) can confirm the presence of the medical mimic. Referrals for vestibular physical therapy and a neuro-ENT consultation may prove useful for such patients.

Similarly, to determine if there is social phobia or vergence, ask your patient if they are having trouble seeing or reading books at a normal distance. Then, check their near point of convergence and conduct a cover test. Consider a referral to a neuro-optometrist.

In other cases, a central auditory processing disorder may be confused with attention-deficit/hyperactivity disorder. Ask your patient if they have better sustained attention for visual vs verbal interactions, or if they have trouble understanding what people say if they cannot see their faces or mouths. Weber and Rinne tests can also prove useful, and a referral to an audiologist is indicated.

Posttraumatic neuroendocrine (PTNE) disorders may be relatively common in patients with TBI,

 and mood symptoms are associated with PTNE, O’Shanick explained. Psychiatrists should inquire about changes in menses, sex drive, cold intolerance, and skin and hair dryness to elucidate if PTNE is a potential cause of the mood symptoms. Lab studies should be considered, including free thyroxine, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, immunoglobulin-1, estradiol/testosterone, and AM/PM cortisol. In considering TBI in these cases, O’Shanick reminded attendees that they should not overlook intimate partner violence and child abuse.

Finally, O’Shanick illuminated the inherent biases in the Minnesota Multiphasic Personality Inventory-2 that could lead to incorrect diagnoses. For instance, stomach trouble and headaches score positively on the hypochondriasis scale, but both of these symptos may be related to TBI and TBI treatments. Similarly, positive scores on the hysteria scale result from the patient noting they are unable to work, feel sad, and have trouble sleeping, all of which are associated with TBI.

Ultimately, the psychiatrist is in the ideal position to leverage their medical and behavioral knowledge to support these patients.

“Hopefully, [these insights] will allow you to think a little bit differently when patients come into your office,” O’Shanick concluded. “Maybe ask some increased questions when it comes to injury-related issues, concussion-related issues… to see if there are some other types of medical issues behind some of the anxieties that your patients have. At the end, you may just find that you’re practicing … much more successfully and ultimately helping your patients.”

1. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths. CDC. 2014. Accessed May 2, 2021. 

https://www.cdc.gov/traumaticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf

2. Ponsford J, Alway Y, Gould KR. Epidemiology and natural history of psychiatric disorders after TBI. 

3. Beyer C, Zaytsev J, Donegan D, et al. The effects of traumatic brain injury on pituitary function: a systematic review and meta-analysis. 

Ketamine: Not a Simple Treatment, but a Worthy One

"This is not a simple treatment or a treatment to take lightly,” Richard C. Shelton, MD, said during the Q+A portion of the presentation “Ketamine for Depression: Is the Hype Holding Up? Mechanisms and Evidence.” “On the other hand, we’ve seen remarkable results.”

Shelton, director of research of the Huntsville Regional Medical Campus of the University of Alabama, Birmingham (UAB), School of Medicine; the Charles B. Ireland Professor in UAB’s Department of Psychiatry and Behavioral Neurobiology; and director of the UAB Depression and Suicide Center, began with a discussion of ketamine’s functions in the brain. He discussed how it restores the regulatory processes for patients with depression and other mood disorders, using the results of a 

“Stressful experiences cause a reduction or retraction of spines and synapses. The brain is less able to control or regulate the emotional state,” Shelton explained.

With ketamine administration, there is an almost immediate increase in formation of critical spine and synaptic proteins.

“When you add ketamine to the system, you produce a rapid return and restoration of those spines and synapses. We see an effect within 24 hours,” Shelton continued. “Ketamine has the ability to restore the regulatory control to the brain and helps, theoretically, to normalize mood.”

Shelton shared data from 8 studies that investigated ketamine; they found ketamine produced a rapid, robust effect for patients with severe treatment-resistant depression.

 Data from additional studies demonstrated how ketamine functioned for patients with suicidal ideation.

“The good news: Ketamine really seemed to work in these patients with highly treatment-resistant depression,” Shelton said.

Shelton also addressed key concerns regarding ketamine, especially how it may be a challenge to prescribe. First, the US Food and Drug Administration requires a “somewhat cumbersome” risk evaluation and mitigation strategy program, which requires registration by the clinic, provider, and patient. There are prior authorization hurdles as well as reimbursement issues, he added. Nonetheless, Shelton finds ketamine is more than worth the attendant logistical struggles.

“When I treated my first patient with IV ketamine in 2012, it was just amazing to see the effect occur within 24 hours,” Shelton said.

1. Li N, Liu R-J, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.

2. Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. 

3. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. 

4. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. 

5. Daly EJ, Singh JB. Adjunctive intranasal esketamine in treatment-resistant depression—reply. 

6. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). 

7. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. 

8. Daly EJ, Trivedi M, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. 

9. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). 

10. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. 

11. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. 

12. Fu D-J, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). 

13. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). 

Experts Express Concern Over Excited Delirium Syndrome Diagnosis

There is universal confusion around excited delirium syndrome (ExDS): What is it and how should it be treated? In short, we do not know all the answers, and no comprehensive treatment guidelines or formal criteria exist, according to a panel presentation. Representing the fields of emergency medicine, psychiatry, psychology, and emergency medical service (EMS), the expert panel consisted of Leslie Zun, MD, MBA; Thom Dunn, PhD; Julie Owen, MD, MBA; and Sarah E. Slocum, MD.

Recent events have brought to light the importance of clarifying the differential diagnosis, signs and symptoms, and universal treatment protocols of ExDS, which to date remain unclear.

In the last year, the world witnessed George Floyd dying at the hands of a police officer. In 2019, Elijah McClain, aged 23 years, a massage therapist, was placed in a chokehold by law enforcement and sedated by EMS with 500 mg of ketamine, a tactic that is legal in Colorado to control ExDS. By the time he arrived at the hospital, he was brain dead; he died 3 days later.

How McClain died is a matter of dispute, but 1 thing is clear: These and many, many more incidents in the public eye have shone a spotlight on the use of force by police and in emergency settings.

Dunn, a psychologist who is involved in emergency medical services, shared an ultimately tragic example of ExDS in a hospital setting in which an adult male Black patient demonstrated signs of the condition. The presence of police seemed to intensify the patient’s agitation. He began to sweat profusely, stripped naked, shouted incomprehensibly, and flailed his arms. After multiple attempts to restrain him, police tased him. Emergency staff then administered ketamine, and he subsequently died.

In 2020, the American Psychiatric Association released a 

DSM-5 recognizes Delirium, hyperactive type, but the symptoms of this condition differ in many ways from the symptoms typically attributed to excited delirium (eg, superhuman strength, impervious to pain, etc). Recent data suggest that persons being detained by the police and described as having ‘excited delirium have frequently received medication from emergency medical technicians (EMTs) intended to rapidly sedate them…In some reported cases, it is questionable whether the person identified as having an ‘excited delirium’ actually had any medical condition warranting its use.

The discussion concluded with Slocum’s call for action: “We really need to address this condition as a group and figure out what’s going to be best for that patient.”

1. American Psychiatric Association. Position statement on concerns about use of the term “excited delirium” and appropriate medical management in out-of-hospital contexts. December 2020. Accessed May 22, 2021. 

https://www.psychiatry.org/File%20Library/About-APA/Organization-Documents-Policies/Policies/Position-Use-of-Term-Excited-Delirium.pdf

"Ethical dilemmas arise when multiple ethical responsibilities stand in tension with each other,” Charles Dike, MBChB, MPH, told the attendees.

During the discussion, one issue stood out: the possible conflict between psychiatrists’ duties to their individual patients and their duties to promote the good of the public as a whole.

This conflict has become particularly pressing this past year due to the global pandemic, and the panelists considered the problem from several angles as they answered previously submitted questions.

One question concerned confidentiality: What should be done when a patient reports that their parents are sending the patient’s sibling to school, despite the child’s positive SARS-COV-2 virus results?

Daniel J. Anzia, MD, a member of the expert panel, explained, “The participation in public health endeavors is a long-standing, recognized potential exception to the obligation of psychiatrists, and all physicians, to maintain confidentiality.” Past department chair for psychiatry at Advocate Lutheran General Hospital in Park Ridge, Illinois, Anzia said that ideally, the patient—who was no longer a minor—would make the report to the school, and then inform the family that public health officials might be contacting them. But, he added, if the patient refused, “it is permissible for the psychiatrist to make such a report.”

Another questioner asked what psychiatrists should do if patients insisted on being seen in person, even at the height of the pandemic. Panel member Patricia (Tia) Powell, MD, director of the Montefiore Einstein Center for Bioethics in the Bronx, New York, told attendees that they are not required to put themselves at physical risk. “Among our many obligations as psychiatrists is to provide a safe space in which we can offer therapy for our patients. That includes keeping the patient and psychiatrist safe from each other in terms of communicating the virus,” she explained.

In addition, Powell noted that many psychiatrists have extended their knowledge and use of telehealth, discharging their obligation to offer care in person by working with patients to make telehealth possible. If the patient refuses telehealth, protective gear, and vaccination, she said, “it could be legitimate for a psychiatrist to say, ‘At this time, I’m not able to continue working with you.’”

Similarly, are psychiatrists obligated to get an available COVID-19 vaccine? Although “a psychiatrist has a right to refuse the vaccine, the psychiatrist should consider their wider obligations of such a decision, including an unspoken statement—to the psychiatrist’s colleagues and patients—that the psychiatrist does not trust the vaccine,” said Dike, associate professor of psychiatry at Yale School of Medicine and associate program director of its Law and Psychiatry Fellowship. “This could discourage vulnerable patients from taking what could be a life-saving intervention.”

What are the obligations of a psychiatrist to a new patient who has yet to be seen? The panel was presented with a situation in which a new patient reports suicidal thoughts on a previsit questionnaire, and then does not come to the appointment or answer calls. Should the psychiatrist send someone to check on the patient?

Panelist Rebecca Brendel, MD, JD, detected a potential conflict between the psychiatrist’s duty to the individual patient and the public at large. “We’d hate to say we’re not going to screen patients for suicidality because it’s too hard to figure out what to do with the information,” explained Brendel, assistant professor of psychiatry at Harvard Medical School and director of its Master in Bioethics program. However, she noted the need for a follow-up mechanism that does not overstep the bounds of a nascent doctor-patient relationship by violating the prospective patient’s rights to privacy and confidentiality.

The 2021 American Psychiatric Association Virtual Annual Meeting brought together leaders in psychiatry to discuss hot topics including diversity, COVID-19, mood disorders, and more.