Academy of Consultation-Liaison Psychiatry

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

This article is the second of a 3-part series that aims to highlight and review the prevalence, risk factors, clinical manifestations, diagnostic recommendations, proposed mechanisms of disease, and current treatment recommendations of folate, B

As reviewed in the previous article, key nutrients—or what Casimir Funk, PhD, termed vital amines—are essential to maintaining good health. Deficiencies in these key nutrients lead to certain pathognomonic disease states, as Funk initially observed when he fed birds a diet of only polished rice and they developed a diffuse polyneuritis (beriberi). Afterwards, the same birds were fed a diet of brown rice, and their “nervous symptoms rapidly disappeared.”

 What did this experiment establish? The importance of vital amines, or as we know them, 

Vitamins can be broadly delineated into 2 categories: water-soluble and fat-soluble. Water-soluble vitamins are absorbed rapidly via the gastrointestinal tract and distributed widely in various body tissues; however, as these vitamins are water-soluble, they are not efficiently stored in tissues. Therefore, these vitamins require regular consumption (either through diet or supplementation) to avoid deficiency states. Fat-soluble vitamins, on the other hand, are more easily stored, typically in adipose tissue, and require less frequent intake.

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

 (cobalamin) is a water-soluble vitamin that is found in certain foods and is required for DNA synthesis and the formation of several hematologic elements, such as red blood cells (RBCs), white blood cells, and platelets.

 Individuals who have low levels of vitamin B

, due to either increased demand or poor absorption, are labeled vitamin B

 deficiency can lead to the formation of abnormal hematopoietic precursor cells such as megaloblastic RBCs, as seen in 

 deficiency is not only problematic for hematopoiesis; it also has severe neuropsychiatric consequences, including cognitive impairment, depression, 

, peripheral sensory deficits, and weakness. Lhermitte sign (

 can be tested by flexing the neck and assessing for shock-like sensations radiating to the feet. The mechanism is better understood for neuropathies (primarily dorsolateral myelopathy) associated with this deficiency as opposed to neuropsychiatric conditions. Most theories suggest that elevated methylmalonic acid (MMA) levels found in vitamin B

 deficiency may lead to demyelination of the peripheral nervous system and central nervous system.

 MMA accumulates in cells due to lack of vitamin B

 as a cofactor in the conversion of MMA to succinyl Co-A in cell metabolism.

There are several potential causes of vitamin B

 deficiency. Autoimmune pernicious anemia is the most common cause of vitamin B

 deficiency. Intrinsic factor (IF) and gastric parietal cells are attacked by gastric autoantibodies. IF is a glycoprotein that binds cobalamin and aids in the absorption of vitamin B

 in the terminal ileum. The depletion or lack of IF in pernicious anemia causes cobalamin deficiency.

 Other causes such as poor absorption related to pancreatic insufficiency, gastrectomy, intestinal surgeries, and inflammatory bowel disorders can also contribute to poor vitamin B

 absorption. Intestinal infections competing for vitamin B

 absorption such as small intestinal bacterial overgrowth or a parasitic infection should also be considered. 

 affecting absorption and transport of vitamin B

, such as transcobalamin deficiency, are currently being studied. Several medications can also lead to vitamin B

 deficiency via impaired absorption, metabolism, and utilization; these are listed in 

 Pure nutritional deficiency is usually only seen in strict vegans and is extremely rare.

Who Is at Highest Risk for This Disorder?

Some people are at more of an increased risk of vitamin B

 deficiency than others. Older adults are at increased risk of vitamin B

 deficiency due to gastric malabsorption secondary to gastric atrophy, chronic H. pylori infection, increased probability of gastric surgery history, and chronic use of medications like metformin and proton pump inhibitors.

 In patients with alcoholic liver disease, cobalamin levels may remain falsely elevated or normal despite low concentrations of liver tissue cobalamin and its active metabolites. This leads to a functional cobalamin deficiency. Proposed mechanisms of action include impaired uptake of serum cobalamin by the damaged liver, impaired storage of cobalamin in the liver that causes it to leak out, and reduced hepatic ability to synthesize transcobalamin. Vitamin B

 treatment has proven beneficial to some alcohol-dependent patients with megaloblastic anemia.

 Older adults, individuals taking the medications listed in 

 those with alcohol use disorders, pure vegans, and individuals with poor access to adequate nutrition (either through economic limitations or malabsorptive limitations) are at highest risk.

In 2008, the World Health Organization recommended vitamin B

 fortification standards in order to prevent deficiency in high-risk populations. Since then, some nations have implemented these strategies and are working to improve dosing standards. The United States has yet to implement mandatory vitamin B

 fortification, but certain foods, such as cereals, can be found to be fortified voluntarily.

When Should Screening and Prevention Be Done?

Screening and testing should occur in the following groups: those at high risk; individuals who have evidence of a macrocytosis or hyper-segmented neutrophils on peripheral blood smear; those with unexplained neurological conditions (eg, cognitive decline, weakness, ataxia, paresthesia); and those with unexplained psychosis and mood disturbances. Serum cobalamin levels are not always reliable in detecting vitamin B

 deficiency. If an asymptomatic high-risk patient presents with low to normal serum vitamin B

 levels, obtain serum homocysteine and MMA levels as a confirmatory test.

 If pernicious anemia is suspected, confirm the diagnosis by obtaining anti-IF antibody levels and serum gastrin/pepsinogen levels.

Those aged 50 years or older and strict vegetarians may benefit from vitamin B

 supplements or food fortified with vitamin B

, as the crystalline formulation is better absorbed than natural dietary cobalamin. Following gastric bypass surgery, patients should supplement with vitamin B

In the United States, older adults have the highest prevalence of vitamin B

 deficiency. In the United States and the United Kingdom, the prevalence of vitamin B

 deficiency was found to be 6% in adults 60 years of age or younger. In adults 60 years of age or older, the prevalence increases to 20%.

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

 deficiency, as these 2 conditions often present simultaneously. This can be done by assessing serum folate and B

 deficiency is usually made when serum levels are less than 111 pmol/L (150 pg/mL).

 Measurement of serum homocysteine and MMA can also aid in differentiating between folate and vitamin B

 deficiency, both homocysteine and MMA levels can be elevated.

 is the standard treatment. The cause of the deficiency will dictate how one administers the medication and how much to dose. Those with poor absorption, altered anatomy, and/or neurological/neuropsychiatric manifestations would likely benefit more from parenteral than from oral administration. Typical dosing for adults is 1000 mcg parenterally several times per week until the deficiency is corrected, then once per month.

 are both effective treatments for vitamin B

 is a key nutrient that is essential for our hematologic and neuropsychiatric functioning. With the prevalence of vitamin B

 deficiency reaching 20% in certain populations, it is crucial to recognize patients who are at risk and/or require treatment. Vitamin B

 replacement is relatively inexpensive and can be lifesaving when administered via the appropriate route and at the appropriate dosage.

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

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

is a resident physician in the Department of Psychiatry at John Peter Smith Hospital. 

 is a pre-med Neuroscience student at the University of Texas at Austin. Drs DeMoss, Elbasheer, Kunnel, and Mahi Raju report no conflicts of interest concerning the subject matter of this article.

1. Piro A, Tagarelli G, Lagonia P, et al. 

Casimir Funk: his discovery of the vitamins and their deficiency disorders.

3. National Center for Biotechnology Information. PubChem Compound Summary for CID 46853873, Cobalamin. Accessed August 26, 2021. 

https://pubchem.ncbi.nlm.nih.gov/compound/Cobalamin

5. Leishear K, Boudreau RM, Studenski SA, et al. 

 and sensory and motor peripheral nerve function in older adults.

6. Rodriguez NM, Shackelford K. Pernicious anemia. In: 

7. Busti AJ. Medications known to decrease vitamin B

 levels. Evidence-Based Medicine Consult. October 2015. Accessed August 26, 2021. 

https://www.ebmconsult.com/articles/vitamin-b12-medication-interactions-lower-levels

Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies

9. US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference. Accessed August 26, 2021. 

https://www.ars.usda.gov/ARSUserFiles/80400535/DATA/sr21/sr21_doc.pdf

10. Andrès E, Loukili NH, Noel E, et al. 

 (cobalamin) deficiency in elderly patients. 

11. Fragasso A, Mannarella C, Ciancio A, Sacco A. 

 deficiency in alcoholics: an intriguing finding in a retrospective study of megaloblastic anemic patients

Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline

Articles

Key nutrients are essential to maintaining health. Here's an overview of B12. 

Exploring Vital Amines: The Who, What, When, Where, Why, and How of B12 Deficiency

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.

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%.

 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.

1. Adams KM, Kohlmeier M, Zeisel SH. Nutrition education in US medical schools: latest update of a national survey. Acad Med. 2010;85(9):1537-1542.

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.❒

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.

Tada Y, Yoshikawa T, Shimomura M, et al. Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican-3-derived peptide. 

 Dunlop RJ, Campbell CW. Cytokines and advanced cancer. 

 Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. 

 Miwa S, Shirai T, Yamamoto N, et al. Current and emerging targets in immunotherapy for osteosarcoma. 

https://www.hindawi.com/journals/jo/2019/7035045/

 Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. 

 Dhupkar P, Gordon N. Interleukin-2: old and new approaches to enhance immune-therapeutic efficacy. 

 Koury J, Lucero M, Cato C, et al. Immunotherapies: exploiting the immune system for cancer treatment. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872614/

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

Academy of Consultation-Liaison Psychiatry

Articles

Exploring Vital Amines: The Who, What, When, Where, Why, and How of B12 Deficiency

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

Introduction to Immunotherapy of Malignancies for Psychiatrists

Necessity Is the Mother of Invention: Emergency Psychiatry’s Era of Innovation