Academy of Consultation-Liaison Psychiatry

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

Although vitamin deficiencies and their associated adverse effects are usually considered a public health problem in the developing world, they remain an important clinical consideration for select populations across the globe. In fact, there is concern that we may be confronted with increased negative consequences of poor nutrition due to decreased testing and screening and less education in our medical institutions about the importance of good nutrition to optimal health.

Casimir Funk, PhD, discovered that key nutrients, which he termed 

, are essential to maintaining good health and that deficiencies in these key nutrients led to pathognomonic disease states. This realization was a result of observing birds that were fed a diet of polished rice and developed a diffuse polyneuritis (beriberi). The same birds were then fed a diet of brown rice, and their “nervous symptoms rapidly disappeared.”

 This experiment helped establish the importance of vital amines, later shortened to “vitamin.”

Vitamins can be broadly delineated into water-soluble and fat-soluble categories. Water-soluble 

 are typically absorbed very quickly via the gastrointestinal tract and widely distributed in various tissues throughout the body. However, because these vitamins are water soluble, they are not efficiently stored in tissues. Therefore, this class of vitamins requires regular consumption (either through diet or supplementation) to avoid deficiency. Conversely, fat-soluble vitamins are more easily stored, typically in adipose tissue; therefore, they require less frequent intake.

 Examples of water-soluble and fat-soluble vitamins can be found in 

Table 1. Water-soluble vs Fat-soluble Vitamins

Table 2. Select Food Sources of Folate and Folic Acid

Table 3. Select Common Medications Associated With Folate Deficiency

, also known as folate or folic acid, is crucial for DNA synthesis and repair, as well as the metabolism of amino acids involved in methylation reactions.

, folate deficiency can lead to neural tube defects in the fetus.

 In adults, folate deficiency can result in multiple neuropsychiatric symptoms. These symptoms may include cognitive impairment, insomnia, psychosis, depression, peripheral sensory deficits, and weakness. These manifestations are very similar to those of vitamin B

 deficiency. In patients with depression, folate deficiency can contribute to severity and can impede depression treatment.

Folate, which is absorbed in the small intestine, is obtained via diet or supplementation. Select food sources of folate or folic acid can be found in 

 Most serum folate is found in its active form, methyltetrahydrofolate (methyl THF). Methyl THF undergoes a B

-dependent enzymatic reaction, donating its methyl group to form tetrahydrofolate, which, in turn, is later involved in DNA formation. Any disruption in this process can lead to a deficiency in folate and its associated manifestations.

Folate deficiency can manifest from several different causes. High anabolic states, such as pregnancy, can result in increased utilization and depletion of folate stores. Similarly, chronic alcohol abuse causes poor absorption, impaired metabolism, and increased destruction of folate. Even moderate amounts of alcohol (for instance, 8 oz of red wine or 2.7 oz of vodka per day for a 2-week period) have been shown to reduce folate levels in otherwise healthy men.

 Certain medications have been shown to contribute to folate deficiency. A summary of common medications as well as their mechanism of folate deficiency can be found in 

Patients who appear to be at highest risk for deficiency include individuals with 

; individuals who take the noted medications (

); patients who require increased intake of folate (eg, pregnancy, hemodialysis, chronic anemias); and those patients with poor absorption because of intestinal dysfunction from surgery or inflammatory bowel syndromes. Women of childbearing age are also considered to be at risk. According to the 

National Health and Nutrition Examination Survey

, nearly 20% of women aged 14 to 30 years have inadequate serum levels of folate. The survey also found that almost 25% of non-Hispanic Black women have insufficient intake of folate compared with 13% of non-Hispanic White women.

Screening and testing should occur in individuals who are at high risk, have evidence of a macrocytosis or hyper-segmented neutrophils, and have unexplained neuropsychiatric conditions (eg, weakness, ataxia, paresthesia, 

Folic acid supplementation is recommended for all individuals who are at high risk. Evidence suggests that pregnant women should take at least 600 μg of folic acid daily to prevent neural tube defects.

 Folic acid is also typically given to patients on methotrexate to reduce adverse effects, although the dose given varies among rheumatologists.

 Patients with chronic hemolytic states and renal dialysis are recommended to take 5 mg daily to weekly, depending on requirement.

In 2018, a systematic review of survey data examined global folate status in women of childbearing age. Despite methodological limitations such as nonuniform measurement techniques and/or cutoff values, Rogers et al

 determined that the prevalence of folate deficiency was more than 20% in lower income countries and less than 5% in higher income countries. In January 1998, the United States implemented a mandate to fortify grain products with folate in an effort to 

 the incidence of fetal neural tube defects.

 Since then, folate deficiency has become very rare in the United States, with a prevalence of less than 1%.

Patients exhibiting macrocytic anemia on initial complete blood count and peripheral blood smear should be evaluated for both folate and vitamin B

 deficiency because these 2 conditions often present simultaneously. The diagnosis of folate deficiency is usually made when serum levels are less than 2.0 mcg/L.

 Measurement of serum homocysteine and methylmalonic acid (MMA) can also aid in differentiating between folate and B

 deficiencies. In folate deficiency, only serum homocysteine levels are elevated. In B

 deficiency, both homocysteine and MMA levels are elevated because B

 is involved in both homocysteine and MMA metabolism. Folate, on the other hand, has a role in only the homocysteine pathway

). Clinically elevated homocysteine can result in increased risk of thrombosis and its complications, such as myocardial infarction.

Oral replacement of folate is the recommended treatment. If the patient is unable to take oral medications, intravenous repletion is acceptable. The typical dose is dependent on the deficiency severity but ranges from 1 mg to 5 mg daily.

 Folate-deficient megaloblastic anemia due to dietary insufficiency or medications should be treated with 5 mg of folic acid daily for 4 months. Patients with malabsorptive states should be treated with up to 15 mg daily for 4 months.

s an associate clinical professor in the Department of Psychiatry at The University of North Texas Health Science Center at Fort Worth in Texas. 

 is a research coordinator in the Department of Behavioral Health Research at John Peter Smith Health Network in Fort Worth, Texas.

The authors report no conflicts of interest.

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2. Piro A, Tagarelli G, Lagonia P, Tagarelli A, Quattrone A. Casimir Funk: his discovery of the vitamins and their deficiency disorders. Ann Nutr Metab. 2010;57(2):85-88.

3. Reinhard T. The Vitamin Sourcebook. NTC/Contemporary Publishing Group; 1998.

4. Chan YM, Bailey R, O’Connor DL. Folate. Adv Nutr. 2013;4(1):123-125.

5. Scott JM, Weir DG, Molloy A, McPartlin J, Daly L, Kirke P. Folic acid metabolism and mechanisms of neural tube defects. Ciba Found Symp. ١٩٩٤;١٨١:١٨٠-187; discussion 187-191.

6. Papakostas GI, Petersen T, Lebowitz BD, et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol. 2005;8(4):523-528.

7. US Department of Agriculture (USDA), Agricultural Research Service, Nutrient Data Laboratory. USDA National Nutrient Database for Standard Reference, Legacy. Updated April 2018. Accessed January 19, 2021. 

8. Greenberg JA, Bell SJ, Guan Y, Yu YH. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4(2):52-59.

9. Gibson A, Woodside JV, Young IS, et al. Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study. QJM. 2008;101(11):881-887.

10. Hesdorffer CS, Longo DL. Drug‐induced megaloblastic anemia. N Engl J Med. 2015;373(17):1649-1658.

11. Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among US women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med. 2010;38(5):534-542.

12. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academies Press; 1998.

13. Taylor PC, Balsa Criado A, Mongey AB, Avouac J, et al. How to get the most from methotrexate (MTX) treatment for your rheumatoid arthritis patient?-MTX in the treat-to-target strategy. J Clin Med. 2019;8(4):515.

14. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513.

15. Rogers LM, Cordero AM, Pfeiffer CM, et al. Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues. Ann N Y Acad Sci. 2018;1431(1):35-57.

16. FDA. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register. August 5, 1996. 

https://www.federalregister.gov/documents/1996/08/05/96-19803/food-standards-amendment-of-standards-of-identity-for-enriched-grain-products-to-require-addition-of

17. Khan KM, Jialal I. Folic Acid Deficiency. StatPearls Publishing; 2020.

18. Vuckovic BA, Cabarkapa VS, Ilic TA, Salatic IR, et al. Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients. Croat Med J. 2013;54(5):480-488.

19. Lever EG, Elwes RD, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry. 1986;49(10):1203-1207.❒

Articles

A myriad of neuropsychiatric symptoms result from folate deficiency, including cognitive impairment, insomnia, psychosis, depression, peripheral sensory deficits, and weakness. Treatment and prevention strategies are discussed. 

Vital Amines: The Who, What, When, Where, Why, and How of Folate Deficiency

The immune system has an essential underlying role in both physiological and pathological conditions. The immune response is the result of the complex interaction of inflammatory cells and circulating humoral factors, which trigger immune surveillance, immune defenses, and the healing processes that are crucial for survival.

In recent years, immunotherapies have become increasingly effective options for cancer treatment, but they can also lead to abnormal immune reactions and adverse effects ranging from minor to severe toxicities against crucial organ systems, including the brain. Cancer immunotherapy was first attempted with nonspecific immune stimulation using Bacillus Calmette-GuÃ©rin (BCG) or vaccination against other infectious agents with limited success. Treatment with immune modulating cytokines such as interleukin and interferon proved effective, and identification of tumor specific antigens led to attempts at active immunization of the patient with better results. The newer methods of adoptive cell transfer and blockade of immune checkpoints show additional promise.

Traditional cytotoxic chemotherapy is the most commonly used and generally most effective class of antineoplastic agents. It acts by targeting rapidly dividing malignant cells. The adverse effects of chemotherapy are related to antimetabolic effects on normal cells while simultaneously targeting the malignant cells. Immunotherapy can often bypass these toxicity problems and may be more effective in selected patients, but it can also result in its own toxicity, including adverse neuropsychiatric consequences.

The immune system normally detects cancer by recognizing antigens expressed by cancer cells but not by normal cells. These tumor-associated antigens may be tumor-specific antigens uniquely expressed on cancer cells, or they may be neoantigen (ie, new antigens that result from mutations in cancer cells). When tumor specific antigens and neoantigens are detected, they are regarded as foreign by the patient’s immune surveillance mechanisms, and elicit anti-tumor immune responses.

The prognosis is usually considered to be better when an inflammatory reaction is present in tumor tissues, which indicates the presence of immunity to the tumor. When the patient’s immune system attack on the tumor cells has eliminated the most highly immunogenic cancer cell clones, less immunogenic malignant cells remain, which can multiply relatively undisturbed. By the time of diagnosis, most cancers no longer have evidence of an inflammatory response, indicating a poorer prognosis.

This article is a brief introduction to the immunotherapy of malignancy for psychiatrists who may encounter patients who have received these newer immune-mediated therapies for cancer as well as for the consultation-liaison psychiatrists who are more likely to encounter patients who have been exposed to an array of immunotherapy options and their potential adverse consequences. It is important for psychiatrists to be aware of the potential neuropsychiatric toxicities and complications to be able to distinguish them from primary psychiatric disorders and to be able to address them when they occur.

Identification of human tumor-associated antigens has led to antigen specific immunotherapy using these antigens as targets for monoclonal antibodies and cancer vaccines. Specific monoclonal antibodies have been developed against a variety of molecular targets expressed on different cancer cells. These anti-tumor antibodies represent autoimmunity and can also react against normal cells or can present like paraneoplastic neurologic disorders.

Antigens used in cancer vaccines usually include peptides and whole proteins with adjuvants to improve immunogenicity. For example, glypican-3 (GPC-3) is a carcinoembryonic antigen overexpressed in human hepatocellular carcinoma. Vaccination with GPC3-derived peptide has shown clinical benefits and a peptide specific immune response that is predictive of overall survival.

Tumor associated antigens have also been encoded in recombinant viruses in an attempt to generate a more robust immune response to the tumor antigens. As it became easier to identify tumor specific and neoantigens from individual cancer patients, it was hoped that vaccines that target them could be developed for personalized anti-cancer immunization therapy. Unfortunately, cancer vaccine trials frequently report immunologic responses without any clinical benefit.

Cytotoxic chemotherapy is typically immunosuppressive because immune cells rapidly divide and are vulnerable to chemotherapy’s cytotoxic effects. There is often a period of shrinkage or limited growth of the tumor after chemotherapy is started, followed by possible resistance to the chemotherapeutic drug, stimulating tumor growth and metastases. Tumor cell death can reactivate antitumor immunity and restore immunosurveillance, which suggests the anticancer activity of chemotherapy by both cytotoxicity and immune mechanisms.

Many of the functions of the immune system are mediated through the production of small proteins called cytokines. These proteins include interleukins, interferons, and tumor necrosis factor. Cytokines modulate the highly complex, interrelated inflammatory response depending on clinical, physiological, and immune factors. Chemokines are locally acting cytokines that enhance the migration of inflammatory cells, and lymphokines are mediators that are produced transiently during an immune response.

Cytokines have major effects on cerebral function and affect sleep patterns, mood, behavior, cognition, and memory. Cytokines can inhibit acetylcholinergic pathways, resulting in delirium. Interleukins 1 and 2 (IL-1, IL-2), interferon (IFN), and tumor necrosis factor (TNF) can trigger excitatory CNS effects including agitation, delirium, delusions, hallucinations, and seizures.

 Patients receiving IL-2 or IFN-Î± for cancer treatment have experienced hypotension, multiorgan failure, and severe neurotoxicity with cognitive, behavioral, and mood symptoms.

IFN-Î± has been used for over 30 years to treat myeloproliferative disorders. It can induce cell differentiation and cell death, and it can inhibit cell proliferation and angiogenesis required for tumor growth.

 IFN-Î± therapy for cancer has been associated with autoimmune disorders of vitiligo and diabetes and can aggravate preexisting autoimmune disease.

 Although IFN-Î±2 can be an effective anticancer agent, its use has been limited by its toxicities.

IL-2 is a cytokine that plays a major role in the growth and proliferation of immune cells. Trials of high dose IL-2 to treat a variety of disorders, including malignancy, began in 1985 and IL-2 has proved to be an important immunotherapy cytokine for the treatment of cancer.

 IL-2 induces activation of lymphocytes and their differentiation into lymphokine-activated killer cells, which can recognize and eliminate tumor cells. By inducing systemic inflammation, IL-2 can exacerbate autoimmunity or trigger it de novo. Nebulized and aerosolized IL-2 has enabled localized delivery directly to the lungs resulting in less systemic effects, higher local immune cell activation, and greater antitumor effect in patients with primary lung cancer and pulmonary metastases.

The use of IL-2 has been limited by systemic toxicities, including the capillary leak syndrome (CLS). It can occur following administration of cancer drugs, bone marrow transplant, and IL-2.

 In patients with CLS, fluid from the circulatory system leaks into the interstitial space and results in edema, hypotension, hypoalbuminemia, hemoconcentration, dyspnea, circulatory shock, cardiopulmonary collapse, and multiple organ failure. Prophylactic pretreatment with intravenous immunoglobulin and supportive therapy with careful fluid management are of clinical benefit when CLS occurs.

Adoptive cell therapy is based on infusions of autologous T cells to mediate an antitumor response. Chimeric Antigen Receptors (CARs) are synthetic receptors for T-cell antigens that redirect the specificity and reprogram the function of the T cells onto which they are genetically introduced. Chimeric antigen receptor T cells (CAR-T) are the patient’s own T cells modified using viral vectors to express these CARs.

CAR-T cells were first made in 1993 and represent a form of adoptive cell therapy. To make CAR-T cells, lymphocytes are harvested from a tumor biopsy or a resected tumor. These lymphocytes are then grown in vitro with IL-2 and reinfused into the patient after the patient’s T-regulatory cells are eliminated. The infused CAR-T cells retain their cytotoxic activity and recognizing tumor antigens, eliminate the malignant cells.

Currently, CAR-T cells are usually CD19 specific, and they target and lyse CD19 positive cells in both normal and malignant B cell lineages. CD19 is a cell surface antigen unique to B-cells, thus specifically targeting CD19 is effective for B-cell leukemias and lymphomas even in patients with a high tumor burden. Moreover, treatment with CAR-T cells has yielded high remission rates in patients with other refractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.

Adverse events following infusion of CAR-T cells are reversible in most instances, although they often require specific medical intervention and transfer to intensive care for support and management. The most common adverse effect is cytokine release syndrome (CRS). It typically begins within the first week after T-cell infusion and follows the in vivo proliferation of the infused CAR-T cells.

CRS occurs in 13% to 43% of patients and is characterized by high fever, cardiac dysfunction, hypotension, dyspnea, respiratory compromise, hypoxia, and multiorgan failure. The severity of CRS may range from mild to severe life-threatening multiorgan failure. Corticosteroids are considered the main treatment for CRS, but they are toxic to infused CAR-T cells, which limits the outcome of CAR-T treatment as well as the efficacy of corticosteroid treatment itself.

Rarely, severe CRS can evolve into fulminant hemophagocytic lymphohistiocytosis. It is related to tumor burden and cell lysis and is associated with elevated levels of inflammatory markers such as ferritin, C-reactive protein, lactate dehydrogenase, IFN-Î³, soluble IL-2 receptor, and IL-6.

Neurologic toxicity is the second most common toxicity associated with CAR-T therapy. It is distinct from CRS and has been termed “CAR-T-cell-related encephalopathy syndrome (CRES).” It appears to result from endothelial dysfunction and increased blood brain barrier permeability, and is associated with headache, seizures, confusion, agitation, delirium, hallucinations, aphasia, and myoclonus, and may require hospitalization in an intensive care unit. The management of CRES neurotoxicity has been non-specific, generally emphasizing supportive care. Antipsychotics are effective for agitation, delirium, and psychotic symptoms associated with CRES.

New engineering modalities may further enhance the efficacy and safety of CAR-T cells. Modifications in the way CARs are made to allow destruction of CAR-T cells when serious toxicity occurs have been suggested, but they have increased the risk of graft-versus-host disease.

 Recent FDA approval of CD19 CAR-T cells for acute lymphoblastic leukemia and non-Hodgkin lymphoma will likely lead to expanded use of these therapies to physicians without prior experience in managing toxicities, increasing risks of adverse consequences and problems in management.

Melanoma antigen gene (MAGE) proteins are a large group of proteins expressed in reproductive tissue and a wide variety of cancers. These proteins are associated with aggressive cancers, a worse clinical prognosis, increased tumor growth, and increased metastases.

 Adoptive cell therapy using autologous anti-MAGE-A3 engineered T cells has been attempted. The patients experienced clinical regression of their cancers, but Parkinson-like symptoms and mental status changes were noted, and a few patients lapsed into coma and subsequently died. MRI showed perivascular leukomalacia, and autopsy showed necrotizing leukoencephalopathy with extensive white matter defects, widespread neuronal cell destruction and lymphocyte infiltration in the brain parenchyma.

Immune checkpoints are normal inhibitory signals in the immune system that maintain self-tolerance and modulate immune response. Cancer cells can bypass immune checkpoints and immune surveillance, which interferes with the patient’s normal immunologic ability to recognize and destroy cancer cells. Checkpoint inhibitors are monoclonal antibodies that block specific immune checkpoint molecules that antagonize immune inhibitory pathways and promote immune activation by removing or blocking the inhibitory signals. Immune checkpoint inhibition has been effective and safe in patients with solid tumors and some hematologic malignancies, resulting in both long-lasting tumor responses and adverse effects.

The most prominent checkpoint blocking target is cytotoxic T-lymphocyte-associated protein-4 (CTLA-4).

 CTLA-4 is a potent inhibitor of T-cell activation that helps maintain self-tolerance. Anti-CTLA-4 antibodies result in activation of T-cells and initiate an anti-tumor response. While the therapeutic blockade of CTLA-4 enhances anti-tumor immunity, it may also inadvertently increase the likelihood of paraneoplastic neurologic disorders due to antibodies against tumor associated antigens that cross react with neurologic cells.

Most adverse effects of CTLA-4 blockade usually resolve after several weeks. Mild liver and gastrointestinal effects respond to steroids, and mild dermatitis is usually managed by antihistamines, but more severe intestinal perforation and toxic epidermal necrolysis have been described.

 Endocrinopathies associated with CTLA-4 blockade occur with either hormone excess or deficiency, and one or more endocrine glands can be affected sequentially or simultaneously. They are mostly irreversible and require long-term hormone therapy.

Programmed cell death protein 1 (PD-1) is an immune checkpoint regulator that helps prevent auto-immunity and uncontrolled inflammation in chronic infections.

 Inhibition of PD-1 has been used to treat melanoma, lung cancer, and renal cell carcinoma. Adverse effects include fatigue, pruritis, rash, diarrhea, colitis, and pneumonitis.

Checkpoint inhibitors are associated with a unique group of autoimmune toxicities called “immune-related adverse events.” These include neutropenia, thrombocytopenia, red cell aplasia, hemophilia A, orbital inflammation, uveitis, keratitis, lupus nephritis as well as a range of potentially severe neurologic toxicities the affect the central and peripheral nervous system including myositis, myasthenia gravis, Guillain-Barre, and encephalitis with altered mental status. These conditions are usually responsive to corticosteroids, plasmaphoresis, and IV immunoglobulin.

There has been significant improvement in the outcome of many malignancies from increased understanding and application of the anti-tumor immune system and subsequent development of new immunotherapy approaches, which have required balancing anti-tumor immunity and immune toxicity.

 The authors acknowledge the Academy of Consultation-Liaison Psychiatry for helping to bring this article to fruition. The Academy is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions.

Dr Charoensook is Senior Fellow, Child-Adolescent Psychiatry, Los Angeles County-University of Southern California Medical Center and Dr Turkel is Attending Psychiatrist, Children’s Hospital Los Angeles, Emerita Associate Professor of Psychiatry and the Behavioral Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA.

The authors report no conflicts of interest concerning the subject matter of this article.

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There has been significant improvement in the outcome of many malignancies, which have required balancing anti-tumor immunity and immune toxicity.

Introduction to Immunotherapy of Malignancies for Psychiatrists

Emergency department (ED) visits for psychiatric complaints are increasingly common. The 1% to 3% of ED patients who screen positive for suicidal ideation comprise a population at heightened risk of completing suicide.

While emergency psychiatric presentations are often associated with serious mental illness, patients of all acuity levels present in this setting. The most common psychiatric presentations in the ED are for anxiety, depression, or stress reactions.

Providing treatment to these patients in the ED introduces complexity of care that emergency psychiatrists are attempting to address with a mix of service delivery models. This article discusses the peculiarities of emergency psychiatric practice and reviews innovations in models of care delivery designed to overcome the challenges of this subspecialty.

The growth of psychiatric care in ED settings is driven by several factors. Foremost is a trend towards treating sicker patients in less restrictive care environments. Increasingly, patients with significant psychiatric disease are being treated in outpatient and integrated care environments. At the same time, long-term inpatient and residential treatment has become scarcer.

 Thus, EDs become the backstop for highly acute patients who present with suicidality, violent thoughts, intoxication, and/or acute psychosis. Other factors driving this trend towards less restrictive treatments include financial incentives and the ready accessibility of emergency care compared with the limited availability of community mental health facilities. Also driving the trend toward acute care in the ED is the American epidemic of psychiatric illnesses, particularly substance use disorders, that are associated with increased use of emergency services.

Delivering psychiatric care in the ED is not easy. Most emergency medicine providers feel comfortable managing common psychiatric presentations, however, their expertise does not always extend to managing sicker patients or those requiring more nuanced psychiatric assessments-for example, patients with personality disorders and chronic suicidal ideation, or patients with schizophrenia whose ability to care for themselves is called into question.

Patients with psychiatric illness frequently have undertreated medical illness that requires attention and care coordination. Delirium is commonly missed among ED patients, and longer ED stays are associated with an increasing risk of incident delirium.

 Frequent changes of staff, lack of specialty consultants, constant sensory stimulation, and ill-suited infrastructure all render EDs a challenging environment in which to deliver care for patients in psychiatric crisis. 

 summarizes these and other clinical challenges unique to the field of emergency psychiatry.

This confluence of psychiatric illness, medical comorbidity, and systemic challenges adversely affects ED patients’ psychiatric care. The duration of stay is 42% longer for patients with psychiatric complaints compared with patients with medical illness.

 Disposition for patients is a particular challenge. Many general hospitals have closed their inpatient psychiatric units, and free-standing behavioral hospitals are less frequently equipped to manage medical comorbidity, treat complicated withdrawal syndromes, or safely treat agitated patients. Nationally, 73% of patients presenting for suicidal ideation to the ED are hospitalized-a rate triple that for medical complaints.

 Helping patients access treatment is thus a challenge driven by both high demand for service and also inherent limitations of existing inpatient facilities to meet patients’ needs. How, then, can we help patients in crisis receive great psychiatric care?

Emergency psychiatry: a subspecialty to the rescue

The subspecialty of emergency psychiatry has attracted growing interest among a range of clinicians who are drawn to its diverse patient population, highly multidisciplinary work environment, and fast pace. There is no Accreditation Council for Graduate Medical Education (ACGME)-accredited subspecialty pathway for emergency psychiatry; rather, psychiatrists often bring their interests in consultation-liaison, addiction, or forensic psychiatry to their ED work. Other clinicians enjoy providing psychotherapy to patients in crisis and appreciate the challenge of quickly building rapport and framing treatment for these patients in the ED.

There are no data on the number of psychiatrists working in EDs. In many locations, the need for psychiatric consultation is filled by advanced practitioners and licensed social workers working alongside emergency medicine providers. Professional organizations that support emergency psychiatry-such as the Academy of Consultation-Liaison Psychiatry’s Emergency Psychiatry Special Interest Group and the American Association of Emergency Psychiatry-include robust participation by non-psychiatric clinicians.

Interest in the field often begins during psychiatry residency. The ACGME requires residents in psychiatry to experience emergency psychiatry “in an organized, supervised psychiatric emergency service” that “must include crisis evaluation and management, and triage of psychiatric patients.”

 The ACGME’s emergency medicine requirements do not require specific experience managing behavioral presentations.

The challenges of growing volume and acuity among psychiatric patients in the ED have prompted emergency psychiatrists to work alongside colleagues in medicine and ED leadership to imagine systems to improve the care of behavioral emergencies in their communities. These models typically arise to meet demands of emergency medicine clinicians and hospital systems and are designed to accommodate constraints of staff, facilities, and budget.

Just as communities and hospital systems vary, so too must models for delivering emergency psychiatric care. 

 summarizes some of the novel efforts that have been developed to meet the demand for high-quality, affordable psychiatric care that addresses the challenges of managing behavioral emergencies in the ED. These models comprise an overarching philosophy that EDs must provide active treatment of psychiatric emergencies-not merely triage patients to the next step in care.

Pre-hospital care. Management of behavioral emergencies begins in the community-well before patients’ arrival to the ED. Emergency psychiatrists have partnered with police departments and other first responders to provide training in the recognition and initial management of psychiatric emergencies. Typical skills include increasing awareness of the prevalence of psychiatric illness in the community and teaching verbal de-escalation to help patients in crisis. Crisis Intervention Training (CIT) is a national model for police departments to use for working with mentally ill patients in the community; some cities now train all officers in CIT. For ambulance crews, researchers have investigated the utility of novel medications for treating agitation quickly and safely prior to arrival in the ED.

These efforts build on the precedents set by community-based psychiatrists in promulgating patient-centered, easily accessible interventions such as mobile crisis teams and telephone crisis hotlines. Education among pre-hospital providers also encourages use of diversion facilities (eg, crisis centers) over EDs or jails.

Telepsychiatry. The need to deliver 24/7 care to rural and low volume EDs may be met in part through telepsychiatry services. ED diagnoses made via telepsychiatry are correlated with those provided by an in-person psychiatrist while enhancing outpatient follow-up, reducing hospital admissions, and decreasing costs.

 Large health systems and academic medical centers may utilize telepsychiatry to extend specialty consultation expertise to outlying EDs, urgent care centers, and partnership hospitals.

Telepsychiatry is well-suited for patients presenting in crisis who are able to participate and benefit from a therapeutic interview; patients with comorbid presentations may also benefit from evaluation by a telepsychiatry specialist. However, this medium is more limited for providing verbal de-escalation or management of disruptive behaviors and acute agitation.

Integrated care. Integrated behavioral health has transformed the delivery of mental health care in primary care settings. Several institutions including the Stanford Medical Center in California and the Denver Health Medical Center in Colorado have piloted integrated care models in ED and urgent care settings. Initial data are highly promising.

The Stanford experience has demonstrated a 90% decrease in duration of stay for psychiatric patients in the ED and improved discharge rates by 47%.

 In the ED, integrated care expands the availability of psychiatric services beyond the traditional consultation for suicidal ideation. For example, these models facilitate the treatment of patients with somatic symptom disorders, chronic pain, and high ED utilization. The presence of an integrated care provider also enhances the skill set of medicine providers who benefit from “at the elbow” consultation expertise provided by an integrated mental health provider.

Sustainable regional collaborations. Not all health care facilities have the patient volume to justify a dedicated psychiatric emergency service, 24/7 psychiatrist coverage, and dedicated staff on their own; yet when collaborating with other institutions, it becomes feasible to build and sustain such a service. The Unity Center for Behavioral Health in Portland, Oregon offers emergency and inpatient psychiatric service and is supported by 4 different health care systems in that city.

By pooling resources to fund a regional psychiatric emergency service, health systems ease patients’ access to psychiatric care while reducing duration of stay and psychiatric boarding in their EDs.

 Bringing together clinicians passionate about emergency psychiatry enable programs to cultivate trauma-informed approaches to emergency psychiatry including the use of multidisciplinary assessment models and peer support services.

Enhanced training in emergency medicine. Just as most mental health care is provided in primary care settings, emergency medicine practitioners will continue to see the bulk of patients with psychiatric illness. The American College of Emergency Physicians is collaborating with specialty societies in emergency psychiatry to enhance the training of emergency medicine physicians in behavioral emergencies. This training includes assessing suicide risk, identifying delirium, managing agitation, and coordinating care for boarding psychiatric patients. These teaching efforts extend to the range of advanced practitioners working in the ED.

New interventions for behavioral emergencies

These service models enhance access and quality of care in emergency psychiatry across diverse health systems. They also recognize the need to improve services at different points of the patient’s ED visit, from initial contact in the community to facilitating discharge. The 

 illustrates how innovations are improving care at each step of the psychiatric patient’s ED visit. These platforms also provide a means to disseminate innovations in emergency psychiatric treatment.

Trauma-informed care. Trauma-informed care (TIC) is a treatment approach that recognizes harmful consequences of trauma on the well-being of individuals.

 In psychiatric care, TIC improves patient satisfaction and encourages collaborative, healing partnerships among patients and providers. Rarely can a busy medical ED provide this environment, but dedicated emergency psychiatry programs routinely integrate TIC into treatment planning. This includes the use of patient-centered de-escalation techniques such as the availability of non-pharmacologic relaxation tools like stress balls and scented lotions; peer counseling; and dedicated training to familiarize staff with TIC principles.

Peer support. Peer counselors comprise a growing category of health care workers who use their lived experience with illness to facilitate treatment. Behavioral health peer coun-selors are increasingly utilized in emergency service settings to engage patients ambivalent about mental health treatment, uncertain as to positive behavioral change, or in need of linkage to care. In EDs, peer counselors often interact with patients with substance use disorders or chronic mental illness; some programs include follow up with patients after ED discharge. The evidence base supporting peer services remains small but is growing as these services become increasingly available. Nationally, the application of peer counseling will develop heterogeneously alongside similarly varied models for emergency psychiatric care.

Psychological and medication treatments. New discoveries will influence the provision of emergency psychiatric treatment. As in all psychiatric fields, these discoveries will reflect the breadth of psychiatric practice. There is increasing emphasis on the use of verbal de-escalation for the management of agitation, and online training programs make evidence-based techniques freely available for all health care staff.

 Using standardized rating scales for evaluating agitation helps ED staff feel safer and better prepared in managing agitation.

 Finally, new medication approaches are fast-changing the face of emergency psychiatric care, from the use of intramuscular ketamine for acute agitation to the pro-active use of medication-assisted treatments of substance use disorders.

Emergency psychiatrists are rising to the challenge

Providing immediately accessible, high quality emergency psychiatric care continues to be a challenge for many communities. Obstacles to providing care include economic constraints, inconsistent training in emergency psychiatry among clinicians, the lack of a scientific evidence base for the field, and the prevalence of treatment-resistant illness. Nonetheless, a growing number of emergency psychiatrists are motivated to enhance the care of psychiatric patients through new models of service delivery and innovations in clinical care. Vital to the continued growth of this subspecialty and the improved treatment of our patients are recognition of this subspecialty among the psychiatric community and continued interest among new generations of psychiatrists.

Dr Simpson would like to thank members of the Academy of Consultation-Liaison Psychiatry’s (ACLP) Emergency Psychiatry Special Interest Group for their superb work in emergency psychiatry-and their assistance with this work. He also thanks Dr Christina Wichman DO, FACLP and ACLP’s leadership for their continued, robust support for emergency psychiatry.

The Academy is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions.

Dr Simpson is Medical Director, Psychiatric Emergency Services, Denver Health Medical Center.

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18. Riddell J, Tran A, Bengiamin R, et al. Ketamine as a first-line treatment for severely agitated emergency department patients. 

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

20. Bernstein SL, D’Onofrio G, Rosner J, et al. Successful tobacco dependence treatment in low-income emergency department patients: a randomized trial. 

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This article discusses the peculiarities of emergency psychiatric practice and reviews innovations in models of care delivery designed to overcome the challenges of this subspecialty.

Academy of Consultation-Liaison Psychiatry

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