Current Psychiatry

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Excessive daytime sleepiness (EDS) is “the inability to maintain wakefulness and alertness during the major waking periods of the day, with sleep occurring unintentionally or at inappropriate times, almost daily for at least 3 months,” according to the American Academy of Sleep Medicine.¹ EDS is common, with a prevalence up to 25% to 30% in the general population.^1-4 The prevalence rate varies in different studies, primarily because of inconsistent definitions of EDS, and therefore differences in diagnosis and assessment.^1,2,4 In a study of 300 psychiatric outpatients, 34% had EDS.³ However, studies and evidence reviewing EDS in psychiatric patients are limited.

EDS vs fatigue

Many patients describe EDS as “fatigue”¹; however, a patient’s report of fatigue could be mistaken for EDS.⁴ Although there is overlap, it is important for physicians to distinguish between these 2 entities for accurate identification and treatment.^1,4

Risk of inadequate screening

A study of 117 patients with symptomatic coronary artery disease showed that EDS is associated with significantly greater incidence of cardiovascular adverse events at 16-month follow up.² This study had limitations such as small sample size; therefore, more studies are needed. Because of these risks, timely and accurate diagnosis not only improves the patient’s quality of life and reduces polypharmacy but also can be life-saving.

Common causes of EDS in psychiatric patients

Because of the high prevalence and severity of impairments caused by EDS, it is essential for psychiatrists to be informed about causes of EDS and thoroughly assess for the potential underlying etiology before concluding that the sleep problem is a manifestation of the psychiatric disorder and prescribing psychotropic medication for it.

Some common causes of EDS in psychiatric patients include:

Sleep-disordered breathing.⁸ Obstructive sleep apnea (OSA) is often underdiagnosed,^6,7 and considering how common it is,⁶ psychiatrists likely will see many patients with OSA in their practice.⁵ OSA has a higher prevalence among patients with psychiatric disorders such as depression^6,9 and schizophrenia. Additionally, there is evidence suggesting that patients with OSA are more likely to suffer from depression and EDS than healthy controls^6,9,10; some of the proposed mechanisms are sleep fragmentation and hypoxemia.^6,9-11 OSA is the most common form of sleep-disordered breathing and is a common cause of EDS.^1,2,12 Also, undiagnosed and untreated OSA in patients with depression could cause refractoriness to pharmacological treatment of depression.^6,9,10

When unrecognized and untreated, OSA can be life-threatening. Despite this, OSA is not regularly screened for in clinical psychiatric practice.^6,10 Therefore, it is imperative that psychiatrists be well-acquainted with measures to identify at-risk patients and refer to a sleep specialist when appropriate.

OSA is accompanied by irritability, cognitive difficulties, and poor sleep, creating an overlap with symptoms of depressive disorders.^6,10 Use of sedative hypnotic medications, such as benzodiazepines, which further reduces muscle tone in the airway and suppresses respiratory effort, can worsen OSA symptoms^5,6,10 and pose cerebrovascular, cardiovascular, and potentially life-threatening risks, and therefore is not indicated in this population.^9,13

Obesity is a risk factor for OSA.⁶ Patients with mood disorders or schizophrenia or other psychotic disorders are at higher risk of obesity because of psychotropic-induced weight gain, stress-induced mechanisms, and/or lower levels of self-care. When these patients have unrecognized or untreated OSA and are prescribed sedative medications at night or stimulant medications during the day, they could be at increased cardiac or respiratory risks without resolving their underlying condition. A diligent psychiatrist can dramatically reduce the risks by referring a patient for nocturnal polysomnography,¹ helping the patient implement lifestyle modifications (eg, exercise, weight loss, and healthy nutrition), prescribing judiciously, and monitoring closely for such risks. An accurate diagnosis of and treatment for OSA can improve sleep⁶ dramatically and help depressive symptoms through better sleep, more daytime energy and concentration, and adequate oxygenation of the brain while sleeping.

Psychiatrists can screen for OSA using the STOP-Bang (Snoring, Tired, Observed apnea, Pressure, Body mass index, Age, Neck circumference, Gender) Questionnaire, which is a quick, 8-item screening scale that helps to categorize OSA risk as mild, moderate, or severe.¹² Hypertension, snoring, and/or gasping for breath (“observed apnea”)—a history which often is provided by spouses or significant others—daytime dozing and/or tiredness, having a large neck circumference or volume, body mass index, male sex, and age are items on the STOP-Bang Questionnaire and also are features that should raise high clinical suspicion of OSA.¹² Referral for nocturnal polysomnography in at-risk patients should be the next step^1,5 in any sleep-related breathing disorder.

Treatment for OSA involves continuous positive airway pressure (CPAP) therapy, which has been shown to relieve OSA and decrease related EDS.^5,6 Other treatment modalities, such as oral appliances and surgery, may be used⁵ in some cases, but more studies are needed for conclusive results.

Several studies have shown improved depression, mood, and cognition after administering treatment such as CPAP^6,9,14 in patients with OSA and depression. Considering the significant risks of cardiovascular,⁸ cerebrovascular,⁸ and overall morbidity and mortality associated with untreated OSA,¹² it is important to routinely screen for sleep-disordered breathing in patients with depression⁹ or other psychiatric disorders and refer for specialized sleep evaluation and treatment, when indicated.

Medications. EDS can result from some prescription and over-the-counter medications.^1,2,5,7 Sedating antidepressants, antihistamines, antipsychotics, anticonvulsants,^1,8 and beta blockers² could cause sedation, which can persist during daytime, although a few studies did not find an association between antipsychotic use and EDS.³ Benzodiazepines and other sedative-hypnotics,^1,7 especially long-acting agents or higher dosages,⁵ can lead to EDS and decreased alertness. Non-psychotropics, such as opioid pain medications,^1,7 anti­tussives, and skeletal muscle relaxants, also can contribute to or cause daytime sedation.⁷ When using these agents, psychiatrists should monitor and routinely assess patients while aiming for the lowest effective dosage when feasible.

This strategy creates a framework for psychiatrists to routinely educate patients about these commonly encountered side effects, reduce polypharmacy when possible, and help patients effectively manage or prevent these adverse effects.

Depression.¹ Some studies found >45% patients with depression had EDS.^3,13,15 Besides an association between depression and EDS,^13,16 Chellappa and Araújo¹³ also found a significant association between EDS and suicidal ideation. The causes of EDS in patients with depression may be varied, ranging from restless legs syndrome, residual depressive symptoms,¹⁵ to OSA. Depression is often comorbid with OSA,⁶ with up to 20% of patients with depression suffering from OSA,¹⁰ creating higher risk for EDS. Depressive disorders are routinely assessed during an evaluation of OSA at sleep centers, but OSA often is not screened in psychiatric practice.¹⁰

There is a strong need for regular screening for OSA in patients with depression, particularly because most studies show a link between the 2 conditions.¹⁰ Both depression and OSA have some common risk factors, such as obesity, hypertension, and metabolic syndrome.¹⁰ Patients with these conditions are at greater risk for OSA, and therefore a psychiatrist should proactively screen and refer such patients for nocturnal polysomnography when they suspect OSA. Patients with OSA and depression often present to the psychiatrist with depressive symptoms that appear to be resistant to pharmacological treatment,¹⁰ therefore underscoring the importance of screening and ruling out OSA in patients with depression.

Circadian rhythm disorders, restless legs syndrome, alcohol and other substance use, and use of prescription sedative-hypnotics are more common in patients with depression; therefore, this population is at high risk for EDS.

Circadian rhythm disorders and insufficient sleep syndrome. Insufficient sleep syndrome^1,2,8 frequently causes EDS and occurs more commonly in busy people who try to get by with less sleep.⁸ Over time, the effect of sleep loss is cumulative and can be accompanied by mood symptoms, such as irritability, fatigue, and problems with concentration.⁸ Shift workers^1,8 commonly experience insufficient sleep as well as circadian rhythm disorders and EDS. Modafinil is FDA-approved for EDS in shift work sleep disorder.

Geriatric patients may experience advanced sleep phase syndrome involving early awakenings.⁸ Adolescents, on the other hand, often suffer from delayed sleep phase syndrome, which is a type of circadian rhythm disorder, related to increasing academic and social pressures, natural pubertal shift to later sleep onset, pervading technology use, and often nebulous bedtime routines. This can be a cause of sleep persisting into daytime.⁸ Taking a careful history and a sleep diary may be useful because this disorder might be confused for insomnia. Treatment involves gradual shifting of the time of sleep onset through bright light exposure and other modalities.⁸

Adolescents might not be forthcoming about the severity of their sleep problems; therefore, psychiatrists should screen proactively through clinical interviews of patients and parents and consider this possibility when encountering an adolescent with recent-onset attention or cognitive difficulties.

Treatment for circadian rhythm disorders usually includes planned or prescribed sleep scheduling, timed light exposure,⁸ and occasional use of melatonin or other sedative agents.¹⁷

Hypersomnia of central origin, which includes narcolepsy, idiopathic hypersomnia, and recurrent hypersomnia, can present with EDS.^1,18,19 Narcolepsy is a rare, debilitating sleep disorder that manifests as EDS or sleep attacks, with or without cataplexy, and sleep paralysis.^5,8,18,19 The Multiple Sleep Latency Test and polysomnography are used for diagnosis.^1,5 Shortened REM latency is a classic finding often noted on polysomnography. Treatment involves pharmacologic and behavioral strategies and education.^5,8 Modafinil is FDA-approved for EDS associated with narcolepsy. Stimulant medications have been used for narcolepsy in the past; further studies are needed to establish benefit–risk ratio of use in this population.¹⁸

Kleine-Levin syndrome is a form of recurrent hypersomnia, a less common sleep disorder, characterized by episodes of excessive sleepiness accompanied by hyperphagia and hypersexuality.^5,18,19

Other medical conditions,¹ such as the rare familial fatal insomnia, neurological conditions¹ such as encephalitis,⁸ epilepsy,⁸ Alzheimer’s disease or other types of dementia,⁸ Parkinson’s disease,¹ or multiple sclerosis,^1,18 can cause excessive daytime fatigue by causing secondary insomnia or hypersomnia.

Treating the underlying disorder is an important first step in these cases. In addition, coordinating with neurologists or other specialists involved in caring for patients with these conditions is important. Regularly reviewing and simplifying the often complex medication regimen, when possible, can go a long way in mitigating EDS in this population.

Other disorders affecting sleep. Restless legs syndrome and periodic limb movement disorder are other causes of EDS.³ Treatment involves lifestyle modifications, iron supplementation in certain patients, and use of dopaminergic agents such as ropinirole, pramipexole, and other medications, depending on severity of the condition, comorbidities, and other factors.²⁰

Alcohol or substance use. Substance use or withdrawal can be associated with sleep disorders, such as hypersomnia,¹⁹ insomnia,¹⁹ and related EDS.⁵ For example, alcohol use disorder affects REM sleep, and can cause EDS. Secondary central apnea can be the result of long-standing opioid use¹⁹ and can present like EDS.

Insomnia. Primary insomnia rarely causes EDS.⁵ Insomnia due to a medical or psychiatric condition may be an indirect cause of EDS by causing sleep deprivation.

Steps for timely and accurate diagnosis

Utilize the following steps for facilitating timely diagnosis and treatment of EDS:

Thorough history. Patients often describe “tiredness” instead of sleepiness.⁸ Therefore, the astute psychiatrist should explore further when patients are presenting with this concern, especially by asking more specific questions such as the tendency to doze off during daytime.⁸

Family members can be vital sources for obtaining a complete history,⁵ especially because patients might deny,⁸ minimize, or not be fully aware¹ of the extent of their symptoms. Asking family members about patient’s snoring, irregular breathing, or gasping at night can be particularly valuable.⁵ Obtaining a family history of sleep disorders can be particularly important, especially in conditions such as OSA and narcolepsy.

Asking about any history of safety issues,⁸ including sleepiness during driving, cooking, or other activities, is also important.

Use of scales and other screening measures. Psychiatrists can use initial screening measures in the office setting. Epworth Sleepiness Scale^15,21 is a validated,² short, self-administered measure to assess the level of daytime sleepiness; however, it has some limitations such as not being able to measure changes in sleepiness from hour to hour or day to day. Because of its limitations, the Epworth Sleepiness Scale should not be used by itself as a diagnostic tool.³ It has been commonly used for detecting OSA² and narcolepsy. The Stanford Sleepiness Scale is a self-rating scale that measures the subjective degree of sleepiness and alertness; it has limitations as well, such as having little correlation with chronic sleep loss.⁸ Other tools such as visual analogue scales also could be helpful.⁸ For more specialized testing, such as Multiple Sleep Latency Test or polysomnography, referral to a sleep specialist is ideal.⁸

Education. The assessment is an opportunity for the psychiatrist to educate patients about sleep hygiene, the importance of regular bedtimes, and getting adequate sleep to avoid accumulating a sleep deficit.

Urgent referral of at-risk populations. Prompt or urgent referral of at-risk populations, such as geriatric patients or those with a history of dozing off during driving, is invaluable in preventing morbidity and mortality from untreated sleep disorders.

Patients with severe daytime sleepiness should be advised to not drive or operate heavy machinery until this condition is adequately controlled.¹⁸

Bottom Line

Excessive daytime sleepiness (EDS) is “the inability to maintain wakefulness and alertness during the major waking periods of the day, with sleep occurring unintentionally or at inappropriate times, almost daily for at least 3 months,” according to the American Academy of Sleep Medicine.¹ EDS is common, with a prevalence up to 25% to 30% in the general population.^1-4 The prevalence rate varies in different studies, primarily because of inconsistent definitions of EDS, and therefore differences in diagnosis and assessment.^1,2,4 In a study of 300 psychiatric outpatients, 34% had EDS.³ However, studies and evidence reviewing EDS in psychiatric patients are limited.

EDS vs fatigue

Many patients describe EDS as “fatigue”¹; however, a patient’s report of fatigue could be mistaken for EDS.⁴ Although there is overlap, it is important for physicians to distinguish between these 2 entities for accurate identification and treatment.^1,4

Risk of inadequate screening

A study of 117 patients with symptomatic coronary artery disease showed that EDS is associated with significantly greater incidence of cardiovascular adverse events at 16-month follow up.² This study had limitations such as small sample size; therefore, more studies are needed. Because of these risks, timely and accurate diagnosis not only improves the patient’s quality of life and reduces polypharmacy but also can be life-saving.

Common causes of EDS in psychiatric patients

Because of the high prevalence and severity of impairments caused by EDS, it is essential for psychiatrists to be informed about causes of EDS and thoroughly assess for the potential underlying etiology before concluding that the sleep problem is a manifestation of the psychiatric disorder and prescribing psychotropic medication for it.

Some common causes of EDS in psychiatric patients include:

Sleep-disordered breathing.⁸ Obstructive sleep apnea (OSA) is often underdiagnosed,^6,7 and considering how common it is,⁶ psychiatrists likely will see many patients with OSA in their practice.⁵ OSA has a higher prevalence among patients with psychiatric disorders such as depression^6,9 and schizophrenia. Additionally, there is evidence suggesting that patients with OSA are more likely to suffer from depression and EDS than healthy controls^6,9,10; some of the proposed mechanisms are sleep fragmentation and hypoxemia.^6,9-11 OSA is the most common form of sleep-disordered breathing and is a common cause of EDS.^1,2,12 Also, undiagnosed and untreated OSA in patients with depression could cause refractoriness to pharmacological treatment of depression.^6,9,10

When unrecognized and untreated, OSA can be life-threatening. Despite this, OSA is not regularly screened for in clinical psychiatric practice.^6,10 Therefore, it is imperative that psychiatrists be well-acquainted with measures to identify at-risk patients and refer to a sleep specialist when appropriate.

OSA is accompanied by irritability, cognitive difficulties, and poor sleep, creating an overlap with symptoms of depressive disorders.^6,10 Use of sedative hypnotic medications, such as benzodiazepines, which further reduces muscle tone in the airway and suppresses respiratory effort, can worsen OSA symptoms^5,6,10 and pose cerebrovascular, cardiovascular, and potentially life-threatening risks, and therefore is not indicated in this population.^9,13

Obesity is a risk factor for OSA.⁶ Patients with mood disorders or schizophrenia or other psychotic disorders are at higher risk of obesity because of psychotropic-induced weight gain, stress-induced mechanisms, and/or lower levels of self-care. When these patients have unrecognized or untreated OSA and are prescribed sedative medications at night or stimulant medications during the day, they could be at increased cardiac or respiratory risks without resolving their underlying condition. A diligent psychiatrist can dramatically reduce the risks by referring a patient for nocturnal polysomnography,¹ helping the patient implement lifestyle modifications (eg, exercise, weight loss, and healthy nutrition), prescribing judiciously, and monitoring closely for such risks. An accurate diagnosis of and treatment for OSA can improve sleep⁶ dramatically and help depressive symptoms through better sleep, more daytime energy and concentration, and adequate oxygenation of the brain while sleeping.

Psychiatrists can screen for OSA using the STOP-Bang (Snoring, Tired, Observed apnea, Pressure, Body mass index, Age, Neck circumference, Gender) Questionnaire, which is a quick, 8-item screening scale that helps to categorize OSA risk as mild, moderate, or severe.¹² Hypertension, snoring, and/or gasping for breath (“observed apnea”)—a history which often is provided by spouses or significant others—daytime dozing and/or tiredness, having a large neck circumference or volume, body mass index, male sex, and age are items on the STOP-Bang Questionnaire and also are features that should raise high clinical suspicion of OSA.¹² Referral for nocturnal polysomnography in at-risk patients should be the next step^1,5 in any sleep-related breathing disorder.

Treatment for OSA involves continuous positive airway pressure (CPAP) therapy, which has been shown to relieve OSA and decrease related EDS.^5,6 Other treatment modalities, such as oral appliances and surgery, may be used⁵ in some cases, but more studies are needed for conclusive results.

Several studies have shown improved depression, mood, and cognition after administering treatment such as CPAP^6,9,14 in patients with OSA and depression. Considering the significant risks of cardiovascular,⁸ cerebrovascular,⁸ and overall morbidity and mortality associated with untreated OSA,¹² it is important to routinely screen for sleep-disordered breathing in patients with depression⁹ or other psychiatric disorders and refer for specialized sleep evaluation and treatment, when indicated.

Medications. EDS can result from some prescription and over-the-counter medications.^1,2,5,7 Sedating antidepressants, antihistamines, antipsychotics, anticonvulsants,^1,8 and beta blockers² could cause sedation, which can persist during daytime, although a few studies did not find an association between antipsychotic use and EDS.³ Benzodiazepines and other sedative-hypnotics,^1,7 especially long-acting agents or higher dosages,⁵ can lead to EDS and decreased alertness. Non-psychotropics, such as opioid pain medications,^1,7 anti­tussives, and skeletal muscle relaxants, also can contribute to or cause daytime sedation.⁷ When using these agents, psychiatrists should monitor and routinely assess patients while aiming for the lowest effective dosage when feasible.

This strategy creates a framework for psychiatrists to routinely educate patients about these commonly encountered side effects, reduce polypharmacy when possible, and help patients effectively manage or prevent these adverse effects.

Depression.¹ Some studies found >45% patients with depression had EDS.^3,13,15 Besides an association between depression and EDS,^13,16 Chellappa and Araújo¹³ also found a significant association between EDS and suicidal ideation. The causes of EDS in patients with depression may be varied, ranging from restless legs syndrome, residual depressive symptoms,¹⁵ to OSA. Depression is often comorbid with OSA,⁶ with up to 20% of patients with depression suffering from OSA,¹⁰ creating higher risk for EDS. Depressive disorders are routinely assessed during an evaluation of OSA at sleep centers, but OSA often is not screened in psychiatric practice.¹⁰

There is a strong need for regular screening for OSA in patients with depression, particularly because most studies show a link between the 2 conditions.¹⁰ Both depression and OSA have some common risk factors, such as obesity, hypertension, and metabolic syndrome.¹⁰ Patients with these conditions are at greater risk for OSA, and therefore a psychiatrist should proactively screen and refer such patients for nocturnal polysomnography when they suspect OSA. Patients with OSA and depression often present to the psychiatrist with depressive symptoms that appear to be resistant to pharmacological treatment,¹⁰ therefore underscoring the importance of screening and ruling out OSA in patients with depression.

Circadian rhythm disorders, restless legs syndrome, alcohol and other substance use, and use of prescription sedative-hypnotics are more common in patients with depression; therefore, this population is at high risk for EDS.

Circadian rhythm disorders and insufficient sleep syndrome. Insufficient sleep syndrome^1,2,8 frequently causes EDS and occurs more commonly in busy people who try to get by with less sleep.⁸ Over time, the effect of sleep loss is cumulative and can be accompanied by mood symptoms, such as irritability, fatigue, and problems with concentration.⁸ Shift workers^1,8 commonly experience insufficient sleep as well as circadian rhythm disorders and EDS. Modafinil is FDA-approved for EDS in shift work sleep disorder.

Geriatric patients may experience advanced sleep phase syndrome involving early awakenings.⁸ Adolescents, on the other hand, often suffer from delayed sleep phase syndrome, which is a type of circadian rhythm disorder, related to increasing academic and social pressures, natural pubertal shift to later sleep onset, pervading technology use, and often nebulous bedtime routines. This can be a cause of sleep persisting into daytime.⁸ Taking a careful history and a sleep diary may be useful because this disorder might be confused for insomnia. Treatment involves gradual shifting of the time of sleep onset through bright light exposure and other modalities.⁸

Adolescents might not be forthcoming about the severity of their sleep problems; therefore, psychiatrists should screen proactively through clinical interviews of patients and parents and consider this possibility when encountering an adolescent with recent-onset attention or cognitive difficulties.

Treatment for circadian rhythm disorders usually includes planned or prescribed sleep scheduling, timed light exposure,⁸ and occasional use of melatonin or other sedative agents.¹⁷

Hypersomnia of central origin, which includes narcolepsy, idiopathic hypersomnia, and recurrent hypersomnia, can present with EDS.^1,18,19 Narcolepsy is a rare, debilitating sleep disorder that manifests as EDS or sleep attacks, with or without cataplexy, and sleep paralysis.^5,8,18,19 The Multiple Sleep Latency Test and polysomnography are used for diagnosis.^1,5 Shortened REM latency is a classic finding often noted on polysomnography. Treatment involves pharmacologic and behavioral strategies and education.^5,8 Modafinil is FDA-approved for EDS associated with narcolepsy. Stimulant medications have been used for narcolepsy in the past; further studies are needed to establish benefit–risk ratio of use in this population.¹⁸

Kleine-Levin syndrome is a form of recurrent hypersomnia, a less common sleep disorder, characterized by episodes of excessive sleepiness accompanied by hyperphagia and hypersexuality.^5,18,19

Other medical conditions,¹ such as the rare familial fatal insomnia, neurological conditions¹ such as encephalitis,⁸ epilepsy,⁸ Alzheimer’s disease or other types of dementia,⁸ Parkinson’s disease,¹ or multiple sclerosis,^1,18 can cause excessive daytime fatigue by causing secondary insomnia or hypersomnia.

Treating the underlying disorder is an important first step in these cases. In addition, coordinating with neurologists or other specialists involved in caring for patients with these conditions is important. Regularly reviewing and simplifying the often complex medication regimen, when possible, can go a long way in mitigating EDS in this population.

Other disorders affecting sleep. Restless legs syndrome and periodic limb movement disorder are other causes of EDS.³ Treatment involves lifestyle modifications, iron supplementation in certain patients, and use of dopaminergic agents such as ropinirole, pramipexole, and other medications, depending on severity of the condition, comorbidities, and other factors.²⁰

Alcohol or substance use. Substance use or withdrawal can be associated with sleep disorders, such as hypersomnia,¹⁹ insomnia,¹⁹ and related EDS.⁵ For example, alcohol use disorder affects REM sleep, and can cause EDS. Secondary central apnea can be the result of long-standing opioid use¹⁹ and can present like EDS.

Insomnia. Primary insomnia rarely causes EDS.⁵ Insomnia due to a medical or psychiatric condition may be an indirect cause of EDS by causing sleep deprivation.

Steps for timely and accurate diagnosis

Utilize the following steps for facilitating timely diagnosis and treatment of EDS:

Thorough history. Patients often describe “tiredness” instead of sleepiness.⁸ Therefore, the astute psychiatrist should explore further when patients are presenting with this concern, especially by asking more specific questions such as the tendency to doze off during daytime.⁸

Family members can be vital sources for obtaining a complete history,⁵ especially because patients might deny,⁸ minimize, or not be fully aware¹ of the extent of their symptoms. Asking family members about patient’s snoring, irregular breathing, or gasping at night can be particularly valuable.⁵ Obtaining a family history of sleep disorders can be particularly important, especially in conditions such as OSA and narcolepsy.

Asking about any history of safety issues,⁸ including sleepiness during driving, cooking, or other activities, is also important.

Use of scales and other screening measures. Psychiatrists can use initial screening measures in the office setting. Epworth Sleepiness Scale^15,21 is a validated,² short, self-administered measure to assess the level of daytime sleepiness; however, it has some limitations such as not being able to measure changes in sleepiness from hour to hour or day to day. Because of its limitations, the Epworth Sleepiness Scale should not be used by itself as a diagnostic tool.³ It has been commonly used for detecting OSA² and narcolepsy. The Stanford Sleepiness Scale is a self-rating scale that measures the subjective degree of sleepiness and alertness; it has limitations as well, such as having little correlation with chronic sleep loss.⁸ Other tools such as visual analogue scales also could be helpful.⁸ For more specialized testing, such as Multiple Sleep Latency Test or polysomnography, referral to a sleep specialist is ideal.⁸

Education. The assessment is an opportunity for the psychiatrist to educate patients about sleep hygiene, the importance of regular bedtimes, and getting adequate sleep to avoid accumulating a sleep deficit.

Urgent referral of at-risk populations. Prompt or urgent referral of at-risk populations, such as geriatric patients or those with a history of dozing off during driving, is invaluable in preventing morbidity and mortality from untreated sleep disorders.

Patients with severe daytime sleepiness should be advised to not drive or operate heavy machinery until this condition is adequately controlled.¹⁸

Bottom Line

Excessive daytime sleepiness (EDS) is “the inability to maintain wakefulness and alertness during the major waking periods of the day, with sleep occurring unintentionally or at inappropriate times, almost daily for at least 3 months,” according to the American Academy of Sleep Medicine.¹ EDS is common, with a prevalence up to 25% to 30% in the general population.^1-4 The prevalence rate varies in different studies, primarily because of inconsistent definitions of EDS, and therefore differences in diagnosis and assessment.^1,2,4 In a study of 300 psychiatric outpatients, 34% had EDS.³ However, studies and evidence reviewing EDS in psychiatric patients are limited.

EDS vs fatigue

Many patients describe EDS as “fatigue”¹; however, a patient’s report of fatigue could be mistaken for EDS.⁴ Although there is overlap, it is important for physicians to distinguish between these 2 entities for accurate identification and treatment.^1,4

Risk of inadequate screening

A study of 117 patients with symptomatic coronary artery disease showed that EDS is associated with significantly greater incidence of cardiovascular adverse events at 16-month follow up.² This study had limitations such as small sample size; therefore, more studies are needed. Because of these risks, timely and accurate diagnosis not only improves the patient’s quality of life and reduces polypharmacy but also can be life-saving.

Common causes of EDS in psychiatric patients

Because of the high prevalence and severity of impairments caused by EDS, it is essential for psychiatrists to be informed about causes of EDS and thoroughly assess for the potential underlying etiology before concluding that the sleep problem is a manifestation of the psychiatric disorder and prescribing psychotropic medication for it.

Some common causes of EDS in psychiatric patients include:

Sleep-disordered breathing.⁸ Obstructive sleep apnea (OSA) is often underdiagnosed,^6,7 and considering how common it is,⁶ psychiatrists likely will see many patients with OSA in their practice.⁵ OSA has a higher prevalence among patients with psychiatric disorders such as depression^6,9 and schizophrenia. Additionally, there is evidence suggesting that patients with OSA are more likely to suffer from depression and EDS than healthy controls^6,9,10; some of the proposed mechanisms are sleep fragmentation and hypoxemia.^6,9-11 OSA is the most common form of sleep-disordered breathing and is a common cause of EDS.^1,2,12 Also, undiagnosed and untreated OSA in patients with depression could cause refractoriness to pharmacological treatment of depression.^6,9,10

When unrecognized and untreated, OSA can be life-threatening. Despite this, OSA is not regularly screened for in clinical psychiatric practice.^6,10 Therefore, it is imperative that psychiatrists be well-acquainted with measures to identify at-risk patients and refer to a sleep specialist when appropriate.

OSA is accompanied by irritability, cognitive difficulties, and poor sleep, creating an overlap with symptoms of depressive disorders.^6,10 Use of sedative hypnotic medications, such as benzodiazepines, which further reduces muscle tone in the airway and suppresses respiratory effort, can worsen OSA symptoms^5,6,10 and pose cerebrovascular, cardiovascular, and potentially life-threatening risks, and therefore is not indicated in this population.^9,13

Obesity is a risk factor for OSA.⁶ Patients with mood disorders or schizophrenia or other psychotic disorders are at higher risk of obesity because of psychotropic-induced weight gain, stress-induced mechanisms, and/or lower levels of self-care. When these patients have unrecognized or untreated OSA and are prescribed sedative medications at night or stimulant medications during the day, they could be at increased cardiac or respiratory risks without resolving their underlying condition. A diligent psychiatrist can dramatically reduce the risks by referring a patient for nocturnal polysomnography,¹ helping the patient implement lifestyle modifications (eg, exercise, weight loss, and healthy nutrition), prescribing judiciously, and monitoring closely for such risks. An accurate diagnosis of and treatment for OSA can improve sleep⁶ dramatically and help depressive symptoms through better sleep, more daytime energy and concentration, and adequate oxygenation of the brain while sleeping.

Psychiatrists can screen for OSA using the STOP-Bang (Snoring, Tired, Observed apnea, Pressure, Body mass index, Age, Neck circumference, Gender) Questionnaire, which is a quick, 8-item screening scale that helps to categorize OSA risk as mild, moderate, or severe.¹² Hypertension, snoring, and/or gasping for breath (“observed apnea”)—a history which often is provided by spouses or significant others—daytime dozing and/or tiredness, having a large neck circumference or volume, body mass index, male sex, and age are items on the STOP-Bang Questionnaire and also are features that should raise high clinical suspicion of OSA.¹² Referral for nocturnal polysomnography in at-risk patients should be the next step^1,5 in any sleep-related breathing disorder.

Treatment for OSA involves continuous positive airway pressure (CPAP) therapy, which has been shown to relieve OSA and decrease related EDS.^5,6 Other treatment modalities, such as oral appliances and surgery, may be used⁵ in some cases, but more studies are needed for conclusive results.

Several studies have shown improved depression, mood, and cognition after administering treatment such as CPAP^6,9,14 in patients with OSA and depression. Considering the significant risks of cardiovascular,⁸ cerebrovascular,⁸ and overall morbidity and mortality associated with untreated OSA,¹² it is important to routinely screen for sleep-disordered breathing in patients with depression⁹ or other psychiatric disorders and refer for specialized sleep evaluation and treatment, when indicated.

Medications. EDS can result from some prescription and over-the-counter medications.^1,2,5,7 Sedating antidepressants, antihistamines, antipsychotics, anticonvulsants,^1,8 and beta blockers² could cause sedation, which can persist during daytime, although a few studies did not find an association between antipsychotic use and EDS.³ Benzodiazepines and other sedative-hypnotics,^1,7 especially long-acting agents or higher dosages,⁵ can lead to EDS and decreased alertness. Non-psychotropics, such as opioid pain medications,^1,7 anti­tussives, and skeletal muscle relaxants, also can contribute to or cause daytime sedation.⁷ When using these agents, psychiatrists should monitor and routinely assess patients while aiming for the lowest effective dosage when feasible.

This strategy creates a framework for psychiatrists to routinely educate patients about these commonly encountered side effects, reduce polypharmacy when possible, and help patients effectively manage or prevent these adverse effects.

Depression.¹ Some studies found >45% patients with depression had EDS.^3,13,15 Besides an association between depression and EDS,^13,16 Chellappa and Araújo¹³ also found a significant association between EDS and suicidal ideation. The causes of EDS in patients with depression may be varied, ranging from restless legs syndrome, residual depressive symptoms,¹⁵ to OSA. Depression is often comorbid with OSA,⁶ with up to 20% of patients with depression suffering from OSA,¹⁰ creating higher risk for EDS. Depressive disorders are routinely assessed during an evaluation of OSA at sleep centers, but OSA often is not screened in psychiatric practice.¹⁰

There is a strong need for regular screening for OSA in patients with depression, particularly because most studies show a link between the 2 conditions.¹⁰ Both depression and OSA have some common risk factors, such as obesity, hypertension, and metabolic syndrome.¹⁰ Patients with these conditions are at greater risk for OSA, and therefore a psychiatrist should proactively screen and refer such patients for nocturnal polysomnography when they suspect OSA. Patients with OSA and depression often present to the psychiatrist with depressive symptoms that appear to be resistant to pharmacological treatment,¹⁰ therefore underscoring the importance of screening and ruling out OSA in patients with depression.

Circadian rhythm disorders, restless legs syndrome, alcohol and other substance use, and use of prescription sedative-hypnotics are more common in patients with depression; therefore, this population is at high risk for EDS.

Circadian rhythm disorders and insufficient sleep syndrome. Insufficient sleep syndrome^1,2,8 frequently causes EDS and occurs more commonly in busy people who try to get by with less sleep.⁸ Over time, the effect of sleep loss is cumulative and can be accompanied by mood symptoms, such as irritability, fatigue, and problems with concentration.⁸ Shift workers^1,8 commonly experience insufficient sleep as well as circadian rhythm disorders and EDS. Modafinil is FDA-approved for EDS in shift work sleep disorder.

Geriatric patients may experience advanced sleep phase syndrome involving early awakenings.⁸ Adolescents, on the other hand, often suffer from delayed sleep phase syndrome, which is a type of circadian rhythm disorder, related to increasing academic and social pressures, natural pubertal shift to later sleep onset, pervading technology use, and often nebulous bedtime routines. This can be a cause of sleep persisting into daytime.⁸ Taking a careful history and a sleep diary may be useful because this disorder might be confused for insomnia. Treatment involves gradual shifting of the time of sleep onset through bright light exposure and other modalities.⁸

Adolescents might not be forthcoming about the severity of their sleep problems; therefore, psychiatrists should screen proactively through clinical interviews of patients and parents and consider this possibility when encountering an adolescent with recent-onset attention or cognitive difficulties.

Treatment for circadian rhythm disorders usually includes planned or prescribed sleep scheduling, timed light exposure,⁸ and occasional use of melatonin or other sedative agents.¹⁷

Hypersomnia of central origin, which includes narcolepsy, idiopathic hypersomnia, and recurrent hypersomnia, can present with EDS.^1,18,19 Narcolepsy is a rare, debilitating sleep disorder that manifests as EDS or sleep attacks, with or without cataplexy, and sleep paralysis.^5,8,18,19 The Multiple Sleep Latency Test and polysomnography are used for diagnosis.^1,5 Shortened REM latency is a classic finding often noted on polysomnography. Treatment involves pharmacologic and behavioral strategies and education.^5,8 Modafinil is FDA-approved for EDS associated with narcolepsy. Stimulant medications have been used for narcolepsy in the past; further studies are needed to establish benefit–risk ratio of use in this population.¹⁸

Kleine-Levin syndrome is a form of recurrent hypersomnia, a less common sleep disorder, characterized by episodes of excessive sleepiness accompanied by hyperphagia and hypersexuality.^5,18,19

Other medical conditions,¹ such as the rare familial fatal insomnia, neurological conditions¹ such as encephalitis,⁸ epilepsy,⁸ Alzheimer’s disease or other types of dementia,⁸ Parkinson’s disease,¹ or multiple sclerosis,^1,18 can cause excessive daytime fatigue by causing secondary insomnia or hypersomnia.

Treating the underlying disorder is an important first step in these cases. In addition, coordinating with neurologists or other specialists involved in caring for patients with these conditions is important. Regularly reviewing and simplifying the often complex medication regimen, when possible, can go a long way in mitigating EDS in this population.

Other disorders affecting sleep. Restless legs syndrome and periodic limb movement disorder are other causes of EDS.³ Treatment involves lifestyle modifications, iron supplementation in certain patients, and use of dopaminergic agents such as ropinirole, pramipexole, and other medications, depending on severity of the condition, comorbidities, and other factors.²⁰

Alcohol or substance use. Substance use or withdrawal can be associated with sleep disorders, such as hypersomnia,¹⁹ insomnia,¹⁹ and related EDS.⁵ For example, alcohol use disorder affects REM sleep, and can cause EDS. Secondary central apnea can be the result of long-standing opioid use¹⁹ and can present like EDS.

Insomnia. Primary insomnia rarely causes EDS.⁵ Insomnia due to a medical or psychiatric condition may be an indirect cause of EDS by causing sleep deprivation.

Steps for timely and accurate diagnosis

Utilize the following steps for facilitating timely diagnosis and treatment of EDS:

Thorough history. Patients often describe “tiredness” instead of sleepiness.⁸ Therefore, the astute psychiatrist should explore further when patients are presenting with this concern, especially by asking more specific questions such as the tendency to doze off during daytime.⁸

Family members can be vital sources for obtaining a complete history,⁵ especially because patients might deny,⁸ minimize, or not be fully aware¹ of the extent of their symptoms. Asking family members about patient’s snoring, irregular breathing, or gasping at night can be particularly valuable.⁵ Obtaining a family history of sleep disorders can be particularly important, especially in conditions such as OSA and narcolepsy.

Asking about any history of safety issues,⁸ including sleepiness during driving, cooking, or other activities, is also important.

Use of scales and other screening measures. Psychiatrists can use initial screening measures in the office setting. Epworth Sleepiness Scale^15,21 is a validated,² short, self-administered measure to assess the level of daytime sleepiness; however, it has some limitations such as not being able to measure changes in sleepiness from hour to hour or day to day. Because of its limitations, the Epworth Sleepiness Scale should not be used by itself as a diagnostic tool.³ It has been commonly used for detecting OSA² and narcolepsy. The Stanford Sleepiness Scale is a self-rating scale that measures the subjective degree of sleepiness and alertness; it has limitations as well, such as having little correlation with chronic sleep loss.⁸ Other tools such as visual analogue scales also could be helpful.⁸ For more specialized testing, such as Multiple Sleep Latency Test or polysomnography, referral to a sleep specialist is ideal.⁸

Education. The assessment is an opportunity for the psychiatrist to educate patients about sleep hygiene, the importance of regular bedtimes, and getting adequate sleep to avoid accumulating a sleep deficit.

Urgent referral of at-risk populations. Prompt or urgent referral of at-risk populations, such as geriatric patients or those with a history of dozing off during driving, is invaluable in preventing morbidity and mortality from untreated sleep disorders.

Patients with severe daytime sleepiness should be advised to not drive or operate heavy machinery until this condition is adequately controlled.¹⁸

Bottom Line

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

[polldaddy:9777325]

The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

[polldaddy:9777325]

The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

[polldaddy:9777325]

The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.