Direct-acting oral anticoagulants (DOACs) have been introduced into clinical use for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), prevention of venous thrombosis after hip or knee surgery, and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).^1-7 Advantages of DOACs over warfarin are often stated as fixed dosing, minor drug and food interactions, wider therapeutic index, and no need for laboratory test monitoring.^1,8 Yet, recommended DOAC dosages vary by renal function and therapeutic indications. Dosing recommendations for prevention of stroke in patients with NVAF are based on estimated creatinine clearance (dabigatran, rivaroxaban, edoxaban), age (apixaban), weight (apixaban, edoxaban), serum creatinine level (apixaban, edoxaban), and presence of cirrhosis by Child-Pugh class^9,10 (apixaban, edoxaban).^4-6,11,12 Dosing recommendations based on coadministration of strong CYP34A and P-glycoprotein inhibitors or inducers vary by DOAC. In addition, dabigatran cannot be crushed and must be stored in its original packaging, and rivaroxaban should be taken with food when the dose is over 10 mg.

We studied DOAC prescribing in adults admitted to a large academic medical center by comparing initial prescribed dosing with FDA-approved prescribing information. We hypothesized that the complexity of DOAC dosing may not be recognized by prescribers.

Our study protocol was approved by the Committee on Human Research (Institutional Review Board) of the University of California San Francisco.

Data Collection

We used electronic medical records (EMRs) to identify adult inpatients who were prescribed a DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) at the University of California San Francisco Medical Center, a large academic hospital, between July 1, 2014 and June 30, 2015. Demographic and medical information related to therapeutic indications, contraindications, and indications for dose adjustments were collected and included diagnoses classified by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for venous thromboses; phlebitis or thrombophlebitis; PE or venous embolism; atrial arrhythmias; surgical procedures; cirrhosis and/or ascites or liver disease; coagulopathies; artificial heart valves or implanted devices; prior use of medications including parenteral anticoagulants; and laboratory data obtained before the first DOAC order (serum creatinine level, estimated glomerular filtration rate [eGFR] determined by Chronic Kidney Disease Epidemiology Collaboration,¹³ international normalized ratio, or, if available, activated partial thromboplastin time and bilirubin level). Creatinine clearance was calculated with the Cockcroft-Gault method¹⁴ using total body weight, per drug label recommendation. Child-Pugh class was calculated if cirrhosis was diagnosed.¹⁰ DOAC dose, frequency, dosing directions, and prescriber medical specialty were determined.

Accuracy of search results was confirmed by review of the first 200 patients’ records. Records were manually reviewed for encounters lacking ICD-9/10 codes and approved DOAC indications (30%) and encounters having multiple coded diagnostic indications (to identify the indication). ICD-9 codes for venous thrombosis were reviewed to differentiate acute from chronic events.

Data Analysis

The main outcome was concordance or discordance between the first DOAC prescribing order and the FDA-approved prescribing information at the time. Initial classification, performed by 2 independent reviewers (a pharmacist and a physician, or 2 pharmacists), was followed by adjudication and individual record review (by 2 independent reviewers) of all initial prescribing orders classified as discordant. A third reviewer adjudicated any disagreement. Records and notes were reviewed to identify stated or potential reasons for dosing variation and pre-admission prescriptions. Data are presented as means and standard deviations (SDs) and as raw numbers and percentages. Differences in patient characteristics by DOAC or therapeutic indication were determined by analysis of variance (ANOVA) with Bonferroni correction for post hoc comparisons. Dosing information was categorized as the same as recommended, lower than recommended, higher than recommended, or avoid drug use (drug–drug or drug–disease interaction), per FDA-approved prescribing information, and χ² tests were used to determine whether variation in dosing occurred by individual DOAC, therapeutic indication, or prescriber specialty. Relationships between dosing variation and age or renal function were tested by ANOVA with Bonferroni correction for post hoc comparisons.

Patients with AF were older with lower creatinine clearance compared to patients with other diagnoses. Mean (SD) patient age was 72.1 (12.7) years for AF, 53.1 (10.9) years for chronic PE, 55.5 (14) years for acute PE, 56.4 (15.9) years for chronic DVT, 57.9 (18.4) years for acute DVT, and 61.4 (11.6) years for DVT prevention after hip or knee surgery (P < 0.0001 for all comparisons). Mean (SD) estimated creatinine clearance was 76.8 (43.5) mL/min for AF, 92.4 (44.4) mL/min for DVT prevention after hip or knee surgery, 111 (53) mL/min for chronic DVT, 118 (55) mL/min for acute DVT, 126 (60) mL/min for chronic PE, and 127 (54) mL/min for acute PE (P < 0.0001 for all comparisons). Differences between patient groups by therapeutic indication were not detected for weight, body mass index, or serum creatinine level.

The most frequent deviation from prescribing recommendations was omission of directions to administer rivaroxaban with food—93% (248/268) of orders—but not for DVT prevention after hip or knee surgery, for which the 10-mg dose is appropriately administered without food. Doses were the same as recommended for 82% of apixaban orders, 84% of rivaroxaban orders, and 93% of initial dabigatran orders (P < 0.05 for differences; Table 3). Dosages not concordant with FDA recommendations were prescribed in 44 (18.1%) of 243 apixaban orders, 41 (14.3%) of 286 rivaroxaban orders, and 7 (7.2%) of 89 initial dabigatran orders. Lower than recommended doses were more common than higher than recommended doses (Table 3, Figure 1): 15.2% versus 2.1% of apixaban orders, 9.4% versus 3.5% of rivaroxaban orders, and 4.2% versus 1.0% of initial dabigatran orders (P < 0.05). Failure to avoid drug use (for potential drug–drug or drug–disease interactions) was uncommon (1%-2%). There were more deviations from recommended doses for patients with AF or DVT prevention after hip or knee surgery than for patients with acute or chronic PE or acute DVT (Table 3). No significant differences were detected between prescribed and recommended doses by prescriber specialty.

For apixaban, patients who were prescribed lower than recommended doses were older than those prescribed recommended doses: mean (SD), 78.1 (12.2) years versus 71 (13.6) years (P = 0.003). Seventy-six percent of those prescribed lower than recommended doses were older than 75. Prescriptions for apixaban at lower than recommended doses were continuations of prior outpatient prescriptions in 20 of 37 cases (almost half), and in 12 cases (one-fourth) antiplatelet drugs were coprescribed (aspirin in 10 cases, clopidogrel in 1, prasugrel in 1). For rivaroxaban, older age was associated with both lower than recommended dosing (P = 0.003) and higher than recommended dosing (P < 0.001). Variations from prescribing recommendations were continuations of outpatient rivaroxaban doses in about two-thirds (26 of 41; 63.4 %) with 13 receiving antiplatelet drugs. For dabigatran, 6 of 7 orders not in agreement with recommendations were continuations of outpatient dosing.

The specific equation used to estimate renal function also had the potential to lead to dosing errors. Among the 41 rivaroxaban patients categorized as receiving doses discordant with recommendations, 8 would have had an inappropriate DOAC dose if eGFR were used instead of eCrCL as recommended. No relationships were detected for other patient variables/measures and dosing deviations from recommendations.

We examined initial hospital orders for DOACs in adults admitted to a single academic medical center during 2014-2015. Dabigatran, apixaban and rivaroxaban were prescribed for prevention of stroke in patients with atrial fibrillation/flutter (AF) in three quarters of the encounters similar to national patterns. (15) Prescribing departures from FDA-approved recommendations ranged from failure to prescribe rivaroxaban with food to failure to recognize drug-drug interactions in 1% to 2%. Unexpectedly, lower than recommended dosing was more common than higher than recommended dosing of the three DOACs.

Rivaroxaban bioavailability is dose dependent with the presence of food required to enhance absorption for doses over 10 mg that are used for prevention of stroke in patients with non-valvular AF or treatment of DVT or PE.^5,16 Peak rivaroxaban concentrations are 75% higher and the total area under the concentration vs. time curve after dosing is 40% higher when rivaroxaban is administered with high fat high calorie meals compared to the fasting state.¹⁶ If rivaroxaban is not administered with food, drug concentrations and pharmacologic effects may be less than in clinical trials that specified co-administration with food.^17-19 A small survey of outpatients receiving rivaroxaban found that 23% reported taking it without food.²⁰ With electronic pharmacy systems in almost all hospitals and electronic prescriber order entry in most, automated addition of directions for rivaroxaban administration with food for doses over 10 mg to labels or dispensing instructions could easily correct this deviation from recommended practice.

Lower than recommended doses were prescribed in 9.4% of orders for rivaroxaban and 15.2% of orders for apixaban, with dose-deviations often appearing to be a continuation of outpatient doses. Patients 75 years or older were more likely to receive lower than recommended dosing of apixaban. Reductions in apixaban doses from 5 mg twice daily to 2.5 mg twice daily are recommended in patients with non-valvular AF with two of the following criteria: age ≥80 y, weight ≤60 kg, serum creatinine ≥1.5 mg/dL or co-administration of a strong PgP inhibitor to a patient without 2 of the 3 dose reduction criteria. Our study was not designed to determine reasons for under-dosing, but we speculate that clinicians may have considered patients aged 75-79 years to be similar to those 80 years of age or older, or, older and not as healthy as those enrolled in randomized trials.^21-25 The median age of our patients with AF receiving apixaban was 75y (interquartile range of 16) vs 70y ( interquartile range 63-76) in the pivotal trial comparing warfarin to apixaban.²¹ Renal function was also lower with 37% having eCrCL below 50 mL/min compared to 17% in ARISTOTLE. (21). Twenty-six percent of our apixaban-treated AF patients qualified for the lower 2.5 mg twice daily compared to only 5% of ARISTOTLE participants,²¹ further suggesting differences between patients in our sample compared to randomized trial participants.

Concerns regarding bleeding or falls in older patients, may also have contributed to lower than recommended doses. Recent analyses of patients at risk for falls confirmed that increased risk of falling was associated with more bone fractures, bleeding and all-cause death but not stroke or systemic emboli, and with less severe bleeding with the DOAC edoxaban compared to warfarin.²⁶ While a rationale for personalized or lower than recommended dosing of apixaban may exist in very old patients and those at risk of falls and bleeding, more data are needed to determine outcomes of lower than recommended doses of DOACs before such an approach can be endorsed. Monitoring of anticoagulant effect in patients who receive doses lower than those investigated in clinical trials could provide important information. The assays that measure DOAC effects are likely to be more available because of the use of reversal agents in the setting of bleeding with DOACs.²⁷

We had anticipated higher than recommended dosing for rivaroxaban as recommendations are based on creatinine clearance while laboratories routinely report estimated glomerular filtration rate (eGFR) that can provide higher estimates of renal clearance and estimated DOAC doses in older and smaller individuals.²⁸ Higher than recommended dosing was found in only 3.5% of our sample. In half, eGFR estimates were higher than creatinine clearance estimates. An international postmarketing registry of rivaroxaban use for the prevention of stroke in patients with NVAF, which included outpatients, found that 36% of those with creatinine clearances below 50 mL/min received a dose higher than recommended, and 15% received a dose lower than expected.²⁹ A more recent outpatient registry report on patients with NVAF, in which apixaban, dabigatran, or rivaroxaban was administered, found that overall 9.4% received a dose lower than recommended, and 3.4% were overdosed, with a similar percentage (34%) of rivaroxaban patients with creatinine clearance of 15 to 50 mL/min receiving higher than recommended dosing.³⁰ The lower rate of higher-than-recommended doses that we observed may have been related to the routine measurement of serum creatinine and attention to dosing adjustments for renal function in the inpatient setting compared to the outpatient setting. In addition, renal function data may not be available to outpatient pharmacies, limiting potential input on dosing recommendations. At least one cardiac society recommends monitoring of renal function in patients treated with DOACs, annually in patients with normal estimated creatinine clearance and more frequently (at intervals in months equal to the creatinine clearance divided by 10) in patients with abnormal creatinine clearance.¹¹ A hospital encounter provides an opportunity to assess or reassess renal status to optimize DOAC dosing.

Dabigatran was the first DOAC introduced into use in the United States with the same dose recommended for prevention of stroke in patients with AF or venous thromboembolic disease with reductions for creatinine clearance below 30 mL/min or creatinine clearance between 30 and 50 mL/min and concomitant use of the potent P-glycoprotein inhibitor dronedarone or systemic ketoconazole. The relative simplicity of dosing may have been responsible for the lowest rate of prescribing outside of recommendations observed in this study, but the low dabigatran use limits analyses of contributing factors.

Failure to avoid drug use in combination with use of strong P-glycoprotein inducers or inhibitors was infrequent but should be preventable. Current prescribing recommendations refer to “strong” P-glycoprotein inhibitors and list different specific agents that interact with each DOAC without a standardized definition or classification. Standardized classifications or reference sources would be helpful.

Our primary goal in this study was to compare initial prescribed dosing of DOACs with FDA-approved prescribing directions. However, therapeutic indication data warrant discussion. In our sample, 7.5% of patients with AF had bioprosthetic valves or recent mitral valve repair or replacement. Using the NVAF definition found in the 2014 AHA/ACC/HRS (American Heart Association, American College of Cardiology, Heart Rhythm Society) AF guidelines¹—“absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair”—these patients would not appear to be candidates for DOACs. However, arguments have been made that a bioprosthetic heart valve or native valve after valve repair does not have a risk profile for thromboembolism that differs from other forms of NVAF and would be equally responsive to DOAC therapy.³¹ Data are sparse, but retrospective subanalyses of limited numbers of patients with valvular disease (including bioprosthesis and mitral repair patients but excluding mechanical valve patients) enrolled in the pivotal DOAC studies support this conclusion.³² For the first months after biological valve replacement (including catheter-based valve replacement), recent European guidelines recommend vitamin K antagonists but also state, “NOACs probably deliver the same protection.”⁸ DOACs were also used for management of venous thromboembolic disease (both acute and chronic) in patients with active cancer. Our data predate the most recent American College of Chest Physician guidelines on treatment of venous thromboembolism in patients with cancer, which provide grade 2B recommendations for use of low-molecular-weight heparin (LMWH) over vitamin K antagonists and grade 2C recommendations for use of LMWH over dabigatran, rivaroxaban, apixaban, or edoxaban.³³

Our study had several limitations. First, data were from a single US academic medical center, though similar rates of prescribing deviation from recommendations have been reported for rivaroxaban and dabigatran in NVAF patients in other countries.^29,34 Second, therapeutic indications may have been misclassified because of errors, incomplete EMR data, or multiple indications. Third, we analyzed the first DOAC order and not dispensing information or subsequent corrections. Therefore, deviations from recommendations should not be interpreted as errors that reached patients. We evaluated dosing based on the measures used at the time of hospital admission, noting that, in a significant fraction of deviations from recommended doses, they represented continuations of outpatient doses when renal function or weight may have differed, and it is unknown whether patients were counseled to take rivaroxaban with food in the outpatient setting. Fourth, the number of patients with acute DVT was small, so firm conclusions cannot be drawn for this specific population. Fifth, our estimates of off-label dosing may have been underestimates, as data on cancer and cancer activity or cardiac valvular disease may not have been complete.

Healthcare professionals are prescribing DOACs in ways that differ from recommendations. These differences may reflect the older ages and reduced renal function of clinical populations relative to randomized clinical trial groups, but they could also potentially alter clinical efficacy. Our findings support the need to evaluate the appropriateness and dosing of DOACs at each encounter and to determine the outcomes of patients treated with lower than recommended doses of DOACs and the outcomes of DOAC-treated patients with bioprostheses or active malignancies.

Acknowledgment

The authors thank Tobias Schmelzinger for electronic data extraction and compilation and University of California San Francisco students Eduardo De La Torre Cruz (School of Pharmacy) and Carlos Mikell (School of Medicine) for assistance with data review.

Disclosure

Dr. Schwartz reports receiving personal fees from Bristol-Myers Squibb and Amgen and grants from Bristol-Myers Squibb and Pfizer, outside the submitted work. The other authors have nothing to report.

Direct-acting oral anticoagulants (DOACs) have been introduced into clinical use for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), prevention of venous thrombosis after hip or knee surgery, and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).^1-7 Advantages of DOACs over warfarin are often stated as fixed dosing, minor drug and food interactions, wider therapeutic index, and no need for laboratory test monitoring.^1,8 Yet, recommended DOAC dosages vary by renal function and therapeutic indications. Dosing recommendations for prevention of stroke in patients with NVAF are based on estimated creatinine clearance (dabigatran, rivaroxaban, edoxaban), age (apixaban), weight (apixaban, edoxaban), serum creatinine level (apixaban, edoxaban), and presence of cirrhosis by Child-Pugh class^9,10 (apixaban, edoxaban).^4-6,11,12 Dosing recommendations based on coadministration of strong CYP34A and P-glycoprotein inhibitors or inducers vary by DOAC. In addition, dabigatran cannot be crushed and must be stored in its original packaging, and rivaroxaban should be taken with food when the dose is over 10 mg.

We studied DOAC prescribing in adults admitted to a large academic medical center by comparing initial prescribed dosing with FDA-approved prescribing information. We hypothesized that the complexity of DOAC dosing may not be recognized by prescribers.

Our study protocol was approved by the Committee on Human Research (Institutional Review Board) of the University of California San Francisco.

Data Collection

We used electronic medical records (EMRs) to identify adult inpatients who were prescribed a DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) at the University of California San Francisco Medical Center, a large academic hospital, between July 1, 2014 and June 30, 2015. Demographic and medical information related to therapeutic indications, contraindications, and indications for dose adjustments were collected and included diagnoses classified by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for venous thromboses; phlebitis or thrombophlebitis; PE or venous embolism; atrial arrhythmias; surgical procedures; cirrhosis and/or ascites or liver disease; coagulopathies; artificial heart valves or implanted devices; prior use of medications including parenteral anticoagulants; and laboratory data obtained before the first DOAC order (serum creatinine level, estimated glomerular filtration rate [eGFR] determined by Chronic Kidney Disease Epidemiology Collaboration,¹³ international normalized ratio, or, if available, activated partial thromboplastin time and bilirubin level). Creatinine clearance was calculated with the Cockcroft-Gault method¹⁴ using total body weight, per drug label recommendation. Child-Pugh class was calculated if cirrhosis was diagnosed.¹⁰ DOAC dose, frequency, dosing directions, and prescriber medical specialty were determined.

Accuracy of search results was confirmed by review of the first 200 patients’ records. Records were manually reviewed for encounters lacking ICD-9/10 codes and approved DOAC indications (30%) and encounters having multiple coded diagnostic indications (to identify the indication). ICD-9 codes for venous thrombosis were reviewed to differentiate acute from chronic events.

Data Analysis

The main outcome was concordance or discordance between the first DOAC prescribing order and the FDA-approved prescribing information at the time. Initial classification, performed by 2 independent reviewers (a pharmacist and a physician, or 2 pharmacists), was followed by adjudication and individual record review (by 2 independent reviewers) of all initial prescribing orders classified as discordant. A third reviewer adjudicated any disagreement. Records and notes were reviewed to identify stated or potential reasons for dosing variation and pre-admission prescriptions. Data are presented as means and standard deviations (SDs) and as raw numbers and percentages. Differences in patient characteristics by DOAC or therapeutic indication were determined by analysis of variance (ANOVA) with Bonferroni correction for post hoc comparisons. Dosing information was categorized as the same as recommended, lower than recommended, higher than recommended, or avoid drug use (drug–drug or drug–disease interaction), per FDA-approved prescribing information, and χ² tests were used to determine whether variation in dosing occurred by individual DOAC, therapeutic indication, or prescriber specialty. Relationships between dosing variation and age or renal function were tested by ANOVA with Bonferroni correction for post hoc comparisons.

Patients with AF were older with lower creatinine clearance compared to patients with other diagnoses. Mean (SD) patient age was 72.1 (12.7) years for AF, 53.1 (10.9) years for chronic PE, 55.5 (14) years for acute PE, 56.4 (15.9) years for chronic DVT, 57.9 (18.4) years for acute DVT, and 61.4 (11.6) years for DVT prevention after hip or knee surgery (P < 0.0001 for all comparisons). Mean (SD) estimated creatinine clearance was 76.8 (43.5) mL/min for AF, 92.4 (44.4) mL/min for DVT prevention after hip or knee surgery, 111 (53) mL/min for chronic DVT, 118 (55) mL/min for acute DVT, 126 (60) mL/min for chronic PE, and 127 (54) mL/min for acute PE (P < 0.0001 for all comparisons). Differences between patient groups by therapeutic indication were not detected for weight, body mass index, or serum creatinine level.

The most frequent deviation from prescribing recommendations was omission of directions to administer rivaroxaban with food—93% (248/268) of orders—but not for DVT prevention after hip or knee surgery, for which the 10-mg dose is appropriately administered without food. Doses were the same as recommended for 82% of apixaban orders, 84% of rivaroxaban orders, and 93% of initial dabigatran orders (P < 0.05 for differences; Table 3). Dosages not concordant with FDA recommendations were prescribed in 44 (18.1%) of 243 apixaban orders, 41 (14.3%) of 286 rivaroxaban orders, and 7 (7.2%) of 89 initial dabigatran orders. Lower than recommended doses were more common than higher than recommended doses (Table 3, Figure 1): 15.2% versus 2.1% of apixaban orders, 9.4% versus 3.5% of rivaroxaban orders, and 4.2% versus 1.0% of initial dabigatran orders (P < 0.05). Failure to avoid drug use (for potential drug–drug or drug–disease interactions) was uncommon (1%-2%). There were more deviations from recommended doses for patients with AF or DVT prevention after hip or knee surgery than for patients with acute or chronic PE or acute DVT (Table 3). No significant differences were detected between prescribed and recommended doses by prescriber specialty.

For apixaban, patients who were prescribed lower than recommended doses were older than those prescribed recommended doses: mean (SD), 78.1 (12.2) years versus 71 (13.6) years (P = 0.003). Seventy-six percent of those prescribed lower than recommended doses were older than 75. Prescriptions for apixaban at lower than recommended doses were continuations of prior outpatient prescriptions in 20 of 37 cases (almost half), and in 12 cases (one-fourth) antiplatelet drugs were coprescribed (aspirin in 10 cases, clopidogrel in 1, prasugrel in 1). For rivaroxaban, older age was associated with both lower than recommended dosing (P = 0.003) and higher than recommended dosing (P < 0.001). Variations from prescribing recommendations were continuations of outpatient rivaroxaban doses in about two-thirds (26 of 41; 63.4 %) with 13 receiving antiplatelet drugs. For dabigatran, 6 of 7 orders not in agreement with recommendations were continuations of outpatient dosing.

The specific equation used to estimate renal function also had the potential to lead to dosing errors. Among the 41 rivaroxaban patients categorized as receiving doses discordant with recommendations, 8 would have had an inappropriate DOAC dose if eGFR were used instead of eCrCL as recommended. No relationships were detected for other patient variables/measures and dosing deviations from recommendations.

We examined initial hospital orders for DOACs in adults admitted to a single academic medical center during 2014-2015. Dabigatran, apixaban and rivaroxaban were prescribed for prevention of stroke in patients with atrial fibrillation/flutter (AF) in three quarters of the encounters similar to national patterns. (15) Prescribing departures from FDA-approved recommendations ranged from failure to prescribe rivaroxaban with food to failure to recognize drug-drug interactions in 1% to 2%. Unexpectedly, lower than recommended dosing was more common than higher than recommended dosing of the three DOACs.

Rivaroxaban bioavailability is dose dependent with the presence of food required to enhance absorption for doses over 10 mg that are used for prevention of stroke in patients with non-valvular AF or treatment of DVT or PE.^5,16 Peak rivaroxaban concentrations are 75% higher and the total area under the concentration vs. time curve after dosing is 40% higher when rivaroxaban is administered with high fat high calorie meals compared to the fasting state.¹⁶ If rivaroxaban is not administered with food, drug concentrations and pharmacologic effects may be less than in clinical trials that specified co-administration with food.^17-19 A small survey of outpatients receiving rivaroxaban found that 23% reported taking it without food.²⁰ With electronic pharmacy systems in almost all hospitals and electronic prescriber order entry in most, automated addition of directions for rivaroxaban administration with food for doses over 10 mg to labels or dispensing instructions could easily correct this deviation from recommended practice.

Lower than recommended doses were prescribed in 9.4% of orders for rivaroxaban and 15.2% of orders for apixaban, with dose-deviations often appearing to be a continuation of outpatient doses. Patients 75 years or older were more likely to receive lower than recommended dosing of apixaban. Reductions in apixaban doses from 5 mg twice daily to 2.5 mg twice daily are recommended in patients with non-valvular AF with two of the following criteria: age ≥80 y, weight ≤60 kg, serum creatinine ≥1.5 mg/dL or co-administration of a strong PgP inhibitor to a patient without 2 of the 3 dose reduction criteria. Our study was not designed to determine reasons for under-dosing, but we speculate that clinicians may have considered patients aged 75-79 years to be similar to those 80 years of age or older, or, older and not as healthy as those enrolled in randomized trials.^21-25 The median age of our patients with AF receiving apixaban was 75y (interquartile range of 16) vs 70y ( interquartile range 63-76) in the pivotal trial comparing warfarin to apixaban.²¹ Renal function was also lower with 37% having eCrCL below 50 mL/min compared to 17% in ARISTOTLE. (21). Twenty-six percent of our apixaban-treated AF patients qualified for the lower 2.5 mg twice daily compared to only 5% of ARISTOTLE participants,²¹ further suggesting differences between patients in our sample compared to randomized trial participants.

Concerns regarding bleeding or falls in older patients, may also have contributed to lower than recommended doses. Recent analyses of patients at risk for falls confirmed that increased risk of falling was associated with more bone fractures, bleeding and all-cause death but not stroke or systemic emboli, and with less severe bleeding with the DOAC edoxaban compared to warfarin.²⁶ While a rationale for personalized or lower than recommended dosing of apixaban may exist in very old patients and those at risk of falls and bleeding, more data are needed to determine outcomes of lower than recommended doses of DOACs before such an approach can be endorsed. Monitoring of anticoagulant effect in patients who receive doses lower than those investigated in clinical trials could provide important information. The assays that measure DOAC effects are likely to be more available because of the use of reversal agents in the setting of bleeding with DOACs.²⁷

We had anticipated higher than recommended dosing for rivaroxaban as recommendations are based on creatinine clearance while laboratories routinely report estimated glomerular filtration rate (eGFR) that can provide higher estimates of renal clearance and estimated DOAC doses in older and smaller individuals.²⁸ Higher than recommended dosing was found in only 3.5% of our sample. In half, eGFR estimates were higher than creatinine clearance estimates. An international postmarketing registry of rivaroxaban use for the prevention of stroke in patients with NVAF, which included outpatients, found that 36% of those with creatinine clearances below 50 mL/min received a dose higher than recommended, and 15% received a dose lower than expected.²⁹ A more recent outpatient registry report on patients with NVAF, in which apixaban, dabigatran, or rivaroxaban was administered, found that overall 9.4% received a dose lower than recommended, and 3.4% were overdosed, with a similar percentage (34%) of rivaroxaban patients with creatinine clearance of 15 to 50 mL/min receiving higher than recommended dosing.³⁰ The lower rate of higher-than-recommended doses that we observed may have been related to the routine measurement of serum creatinine and attention to dosing adjustments for renal function in the inpatient setting compared to the outpatient setting. In addition, renal function data may not be available to outpatient pharmacies, limiting potential input on dosing recommendations. At least one cardiac society recommends monitoring of renal function in patients treated with DOACs, annually in patients with normal estimated creatinine clearance and more frequently (at intervals in months equal to the creatinine clearance divided by 10) in patients with abnormal creatinine clearance.¹¹ A hospital encounter provides an opportunity to assess or reassess renal status to optimize DOAC dosing.

Dabigatran was the first DOAC introduced into use in the United States with the same dose recommended for prevention of stroke in patients with AF or venous thromboembolic disease with reductions for creatinine clearance below 30 mL/min or creatinine clearance between 30 and 50 mL/min and concomitant use of the potent P-glycoprotein inhibitor dronedarone or systemic ketoconazole. The relative simplicity of dosing may have been responsible for the lowest rate of prescribing outside of recommendations observed in this study, but the low dabigatran use limits analyses of contributing factors.

Failure to avoid drug use in combination with use of strong P-glycoprotein inducers or inhibitors was infrequent but should be preventable. Current prescribing recommendations refer to “strong” P-glycoprotein inhibitors and list different specific agents that interact with each DOAC without a standardized definition or classification. Standardized classifications or reference sources would be helpful.

Our primary goal in this study was to compare initial prescribed dosing of DOACs with FDA-approved prescribing directions. However, therapeutic indication data warrant discussion. In our sample, 7.5% of patients with AF had bioprosthetic valves or recent mitral valve repair or replacement. Using the NVAF definition found in the 2014 AHA/ACC/HRS (American Heart Association, American College of Cardiology, Heart Rhythm Society) AF guidelines¹—“absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair”—these patients would not appear to be candidates for DOACs. However, arguments have been made that a bioprosthetic heart valve or native valve after valve repair does not have a risk profile for thromboembolism that differs from other forms of NVAF and would be equally responsive to DOAC therapy.³¹ Data are sparse, but retrospective subanalyses of limited numbers of patients with valvular disease (including bioprosthesis and mitral repair patients but excluding mechanical valve patients) enrolled in the pivotal DOAC studies support this conclusion.³² For the first months after biological valve replacement (including catheter-based valve replacement), recent European guidelines recommend vitamin K antagonists but also state, “NOACs probably deliver the same protection.”⁸ DOACs were also used for management of venous thromboembolic disease (both acute and chronic) in patients with active cancer. Our data predate the most recent American College of Chest Physician guidelines on treatment of venous thromboembolism in patients with cancer, which provide grade 2B recommendations for use of low-molecular-weight heparin (LMWH) over vitamin K antagonists and grade 2C recommendations for use of LMWH over dabigatran, rivaroxaban, apixaban, or edoxaban.³³

Our study had several limitations. First, data were from a single US academic medical center, though similar rates of prescribing deviation from recommendations have been reported for rivaroxaban and dabigatran in NVAF patients in other countries.^29,34 Second, therapeutic indications may have been misclassified because of errors, incomplete EMR data, or multiple indications. Third, we analyzed the first DOAC order and not dispensing information or subsequent corrections. Therefore, deviations from recommendations should not be interpreted as errors that reached patients. We evaluated dosing based on the measures used at the time of hospital admission, noting that, in a significant fraction of deviations from recommended doses, they represented continuations of outpatient doses when renal function or weight may have differed, and it is unknown whether patients were counseled to take rivaroxaban with food in the outpatient setting. Fourth, the number of patients with acute DVT was small, so firm conclusions cannot be drawn for this specific population. Fifth, our estimates of off-label dosing may have been underestimates, as data on cancer and cancer activity or cardiac valvular disease may not have been complete.

Healthcare professionals are prescribing DOACs in ways that differ from recommendations. These differences may reflect the older ages and reduced renal function of clinical populations relative to randomized clinical trial groups, but they could also potentially alter clinical efficacy. Our findings support the need to evaluate the appropriateness and dosing of DOACs at each encounter and to determine the outcomes of patients treated with lower than recommended doses of DOACs and the outcomes of DOAC-treated patients with bioprostheses or active malignancies.

Acknowledgment

The authors thank Tobias Schmelzinger for electronic data extraction and compilation and University of California San Francisco students Eduardo De La Torre Cruz (School of Pharmacy) and Carlos Mikell (School of Medicine) for assistance with data review.

Disclosure

Dr. Schwartz reports receiving personal fees from Bristol-Myers Squibb and Amgen and grants from Bristol-Myers Squibb and Pfizer, outside the submitted work. The other authors have nothing to report.

Direct-acting oral anticoagulants (DOACs) have been introduced into clinical use for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), prevention of venous thrombosis after hip or knee surgery, and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).^1-7 Advantages of DOACs over warfarin are often stated as fixed dosing, minor drug and food interactions, wider therapeutic index, and no need for laboratory test monitoring.^1,8 Yet, recommended DOAC dosages vary by renal function and therapeutic indications. Dosing recommendations for prevention of stroke in patients with NVAF are based on estimated creatinine clearance (dabigatran, rivaroxaban, edoxaban), age (apixaban), weight (apixaban, edoxaban), serum creatinine level (apixaban, edoxaban), and presence of cirrhosis by Child-Pugh class^9,10 (apixaban, edoxaban).^4-6,11,12 Dosing recommendations based on coadministration of strong CYP34A and P-glycoprotein inhibitors or inducers vary by DOAC. In addition, dabigatran cannot be crushed and must be stored in its original packaging, and rivaroxaban should be taken with food when the dose is over 10 mg.

We studied DOAC prescribing in adults admitted to a large academic medical center by comparing initial prescribed dosing with FDA-approved prescribing information. We hypothesized that the complexity of DOAC dosing may not be recognized by prescribers.

Our study protocol was approved by the Committee on Human Research (Institutional Review Board) of the University of California San Francisco.

Data Collection

We used electronic medical records (EMRs) to identify adult inpatients who were prescribed a DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) at the University of California San Francisco Medical Center, a large academic hospital, between July 1, 2014 and June 30, 2015. Demographic and medical information related to therapeutic indications, contraindications, and indications for dose adjustments were collected and included diagnoses classified by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) for venous thromboses; phlebitis or thrombophlebitis; PE or venous embolism; atrial arrhythmias; surgical procedures; cirrhosis and/or ascites or liver disease; coagulopathies; artificial heart valves or implanted devices; prior use of medications including parenteral anticoagulants; and laboratory data obtained before the first DOAC order (serum creatinine level, estimated glomerular filtration rate [eGFR] determined by Chronic Kidney Disease Epidemiology Collaboration,¹³ international normalized ratio, or, if available, activated partial thromboplastin time and bilirubin level). Creatinine clearance was calculated with the Cockcroft-Gault method¹⁴ using total body weight, per drug label recommendation. Child-Pugh class was calculated if cirrhosis was diagnosed.¹⁰ DOAC dose, frequency, dosing directions, and prescriber medical specialty were determined.

Accuracy of search results was confirmed by review of the first 200 patients’ records. Records were manually reviewed for encounters lacking ICD-9/10 codes and approved DOAC indications (30%) and encounters having multiple coded diagnostic indications (to identify the indication). ICD-9 codes for venous thrombosis were reviewed to differentiate acute from chronic events.

Data Analysis

The main outcome was concordance or discordance between the first DOAC prescribing order and the FDA-approved prescribing information at the time. Initial classification, performed by 2 independent reviewers (a pharmacist and a physician, or 2 pharmacists), was followed by adjudication and individual record review (by 2 independent reviewers) of all initial prescribing orders classified as discordant. A third reviewer adjudicated any disagreement. Records and notes were reviewed to identify stated or potential reasons for dosing variation and pre-admission prescriptions. Data are presented as means and standard deviations (SDs) and as raw numbers and percentages. Differences in patient characteristics by DOAC or therapeutic indication were determined by analysis of variance (ANOVA) with Bonferroni correction for post hoc comparisons. Dosing information was categorized as the same as recommended, lower than recommended, higher than recommended, or avoid drug use (drug–drug or drug–disease interaction), per FDA-approved prescribing information, and χ² tests were used to determine whether variation in dosing occurred by individual DOAC, therapeutic indication, or prescriber specialty. Relationships between dosing variation and age or renal function were tested by ANOVA with Bonferroni correction for post hoc comparisons.

Patients with AF were older with lower creatinine clearance compared to patients with other diagnoses. Mean (SD) patient age was 72.1 (12.7) years for AF, 53.1 (10.9) years for chronic PE, 55.5 (14) years for acute PE, 56.4 (15.9) years for chronic DVT, 57.9 (18.4) years for acute DVT, and 61.4 (11.6) years for DVT prevention after hip or knee surgery (P < 0.0001 for all comparisons). Mean (SD) estimated creatinine clearance was 76.8 (43.5) mL/min for AF, 92.4 (44.4) mL/min for DVT prevention after hip or knee surgery, 111 (53) mL/min for chronic DVT, 118 (55) mL/min for acute DVT, 126 (60) mL/min for chronic PE, and 127 (54) mL/min for acute PE (P < 0.0001 for all comparisons). Differences between patient groups by therapeutic indication were not detected for weight, body mass index, or serum creatinine level.

The most frequent deviation from prescribing recommendations was omission of directions to administer rivaroxaban with food—93% (248/268) of orders—but not for DVT prevention after hip or knee surgery, for which the 10-mg dose is appropriately administered without food. Doses were the same as recommended for 82% of apixaban orders, 84% of rivaroxaban orders, and 93% of initial dabigatran orders (P < 0.05 for differences; Table 3). Dosages not concordant with FDA recommendations were prescribed in 44 (18.1%) of 243 apixaban orders, 41 (14.3%) of 286 rivaroxaban orders, and 7 (7.2%) of 89 initial dabigatran orders. Lower than recommended doses were more common than higher than recommended doses (Table 3, Figure 1): 15.2% versus 2.1% of apixaban orders, 9.4% versus 3.5% of rivaroxaban orders, and 4.2% versus 1.0% of initial dabigatran orders (P < 0.05). Failure to avoid drug use (for potential drug–drug or drug–disease interactions) was uncommon (1%-2%). There were more deviations from recommended doses for patients with AF or DVT prevention after hip or knee surgery than for patients with acute or chronic PE or acute DVT (Table 3). No significant differences were detected between prescribed and recommended doses by prescriber specialty.

For apixaban, patients who were prescribed lower than recommended doses were older than those prescribed recommended doses: mean (SD), 78.1 (12.2) years versus 71 (13.6) years (P = 0.003). Seventy-six percent of those prescribed lower than recommended doses were older than 75. Prescriptions for apixaban at lower than recommended doses were continuations of prior outpatient prescriptions in 20 of 37 cases (almost half), and in 12 cases (one-fourth) antiplatelet drugs were coprescribed (aspirin in 10 cases, clopidogrel in 1, prasugrel in 1). For rivaroxaban, older age was associated with both lower than recommended dosing (P = 0.003) and higher than recommended dosing (P < 0.001). Variations from prescribing recommendations were continuations of outpatient rivaroxaban doses in about two-thirds (26 of 41; 63.4 %) with 13 receiving antiplatelet drugs. For dabigatran, 6 of 7 orders not in agreement with recommendations were continuations of outpatient dosing.

The specific equation used to estimate renal function also had the potential to lead to dosing errors. Among the 41 rivaroxaban patients categorized as receiving doses discordant with recommendations, 8 would have had an inappropriate DOAC dose if eGFR were used instead of eCrCL as recommended. No relationships were detected for other patient variables/measures and dosing deviations from recommendations.

We examined initial hospital orders for DOACs in adults admitted to a single academic medical center during 2014-2015. Dabigatran, apixaban and rivaroxaban were prescribed for prevention of stroke in patients with atrial fibrillation/flutter (AF) in three quarters of the encounters similar to national patterns. (15) Prescribing departures from FDA-approved recommendations ranged from failure to prescribe rivaroxaban with food to failure to recognize drug-drug interactions in 1% to 2%. Unexpectedly, lower than recommended dosing was more common than higher than recommended dosing of the three DOACs.

Rivaroxaban bioavailability is dose dependent with the presence of food required to enhance absorption for doses over 10 mg that are used for prevention of stroke in patients with non-valvular AF or treatment of DVT or PE.^5,16 Peak rivaroxaban concentrations are 75% higher and the total area under the concentration vs. time curve after dosing is 40% higher when rivaroxaban is administered with high fat high calorie meals compared to the fasting state.¹⁶ If rivaroxaban is not administered with food, drug concentrations and pharmacologic effects may be less than in clinical trials that specified co-administration with food.^17-19 A small survey of outpatients receiving rivaroxaban found that 23% reported taking it without food.²⁰ With electronic pharmacy systems in almost all hospitals and electronic prescriber order entry in most, automated addition of directions for rivaroxaban administration with food for doses over 10 mg to labels or dispensing instructions could easily correct this deviation from recommended practice.

Lower than recommended doses were prescribed in 9.4% of orders for rivaroxaban and 15.2% of orders for apixaban, with dose-deviations often appearing to be a continuation of outpatient doses. Patients 75 years or older were more likely to receive lower than recommended dosing of apixaban. Reductions in apixaban doses from 5 mg twice daily to 2.5 mg twice daily are recommended in patients with non-valvular AF with two of the following criteria: age ≥80 y, weight ≤60 kg, serum creatinine ≥1.5 mg/dL or co-administration of a strong PgP inhibitor to a patient without 2 of the 3 dose reduction criteria. Our study was not designed to determine reasons for under-dosing, but we speculate that clinicians may have considered patients aged 75-79 years to be similar to those 80 years of age or older, or, older and not as healthy as those enrolled in randomized trials.^21-25 The median age of our patients with AF receiving apixaban was 75y (interquartile range of 16) vs 70y ( interquartile range 63-76) in the pivotal trial comparing warfarin to apixaban.²¹ Renal function was also lower with 37% having eCrCL below 50 mL/min compared to 17% in ARISTOTLE. (21). Twenty-six percent of our apixaban-treated AF patients qualified for the lower 2.5 mg twice daily compared to only 5% of ARISTOTLE participants,²¹ further suggesting differences between patients in our sample compared to randomized trial participants.

Concerns regarding bleeding or falls in older patients, may also have contributed to lower than recommended doses. Recent analyses of patients at risk for falls confirmed that increased risk of falling was associated with more bone fractures, bleeding and all-cause death but not stroke or systemic emboli, and with less severe bleeding with the DOAC edoxaban compared to warfarin.²⁶ While a rationale for personalized or lower than recommended dosing of apixaban may exist in very old patients and those at risk of falls and bleeding, more data are needed to determine outcomes of lower than recommended doses of DOACs before such an approach can be endorsed. Monitoring of anticoagulant effect in patients who receive doses lower than those investigated in clinical trials could provide important information. The assays that measure DOAC effects are likely to be more available because of the use of reversal agents in the setting of bleeding with DOACs.²⁷

We had anticipated higher than recommended dosing for rivaroxaban as recommendations are based on creatinine clearance while laboratories routinely report estimated glomerular filtration rate (eGFR) that can provide higher estimates of renal clearance and estimated DOAC doses in older and smaller individuals.²⁸ Higher than recommended dosing was found in only 3.5% of our sample. In half, eGFR estimates were higher than creatinine clearance estimates. An international postmarketing registry of rivaroxaban use for the prevention of stroke in patients with NVAF, which included outpatients, found that 36% of those with creatinine clearances below 50 mL/min received a dose higher than recommended, and 15% received a dose lower than expected.²⁹ A more recent outpatient registry report on patients with NVAF, in which apixaban, dabigatran, or rivaroxaban was administered, found that overall 9.4% received a dose lower than recommended, and 3.4% were overdosed, with a similar percentage (34%) of rivaroxaban patients with creatinine clearance of 15 to 50 mL/min receiving higher than recommended dosing.³⁰ The lower rate of higher-than-recommended doses that we observed may have been related to the routine measurement of serum creatinine and attention to dosing adjustments for renal function in the inpatient setting compared to the outpatient setting. In addition, renal function data may not be available to outpatient pharmacies, limiting potential input on dosing recommendations. At least one cardiac society recommends monitoring of renal function in patients treated with DOACs, annually in patients with normal estimated creatinine clearance and more frequently (at intervals in months equal to the creatinine clearance divided by 10) in patients with abnormal creatinine clearance.¹¹ A hospital encounter provides an opportunity to assess or reassess renal status to optimize DOAC dosing.

Dabigatran was the first DOAC introduced into use in the United States with the same dose recommended for prevention of stroke in patients with AF or venous thromboembolic disease with reductions for creatinine clearance below 30 mL/min or creatinine clearance between 30 and 50 mL/min and concomitant use of the potent P-glycoprotein inhibitor dronedarone or systemic ketoconazole. The relative simplicity of dosing may have been responsible for the lowest rate of prescribing outside of recommendations observed in this study, but the low dabigatran use limits analyses of contributing factors.

Failure to avoid drug use in combination with use of strong P-glycoprotein inducers or inhibitors was infrequent but should be preventable. Current prescribing recommendations refer to “strong” P-glycoprotein inhibitors and list different specific agents that interact with each DOAC without a standardized definition or classification. Standardized classifications or reference sources would be helpful.

Our primary goal in this study was to compare initial prescribed dosing of DOACs with FDA-approved prescribing directions. However, therapeutic indication data warrant discussion. In our sample, 7.5% of patients with AF had bioprosthetic valves or recent mitral valve repair or replacement. Using the NVAF definition found in the 2014 AHA/ACC/HRS (American Heart Association, American College of Cardiology, Heart Rhythm Society) AF guidelines¹—“absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair”—these patients would not appear to be candidates for DOACs. However, arguments have been made that a bioprosthetic heart valve or native valve after valve repair does not have a risk profile for thromboembolism that differs from other forms of NVAF and would be equally responsive to DOAC therapy.³¹ Data are sparse, but retrospective subanalyses of limited numbers of patients with valvular disease (including bioprosthesis and mitral repair patients but excluding mechanical valve patients) enrolled in the pivotal DOAC studies support this conclusion.³² For the first months after biological valve replacement (including catheter-based valve replacement), recent European guidelines recommend vitamin K antagonists but also state, “NOACs probably deliver the same protection.”⁸ DOACs were also used for management of venous thromboembolic disease (both acute and chronic) in patients with active cancer. Our data predate the most recent American College of Chest Physician guidelines on treatment of venous thromboembolism in patients with cancer, which provide grade 2B recommendations for use of low-molecular-weight heparin (LMWH) over vitamin K antagonists and grade 2C recommendations for use of LMWH over dabigatran, rivaroxaban, apixaban, or edoxaban.³³

Our study had several limitations. First, data were from a single US academic medical center, though similar rates of prescribing deviation from recommendations have been reported for rivaroxaban and dabigatran in NVAF patients in other countries.^29,34 Second, therapeutic indications may have been misclassified because of errors, incomplete EMR data, or multiple indications. Third, we analyzed the first DOAC order and not dispensing information or subsequent corrections. Therefore, deviations from recommendations should not be interpreted as errors that reached patients. We evaluated dosing based on the measures used at the time of hospital admission, noting that, in a significant fraction of deviations from recommended doses, they represented continuations of outpatient doses when renal function or weight may have differed, and it is unknown whether patients were counseled to take rivaroxaban with food in the outpatient setting. Fourth, the number of patients with acute DVT was small, so firm conclusions cannot be drawn for this specific population. Fifth, our estimates of off-label dosing may have been underestimates, as data on cancer and cancer activity or cardiac valvular disease may not have been complete.

Healthcare professionals are prescribing DOACs in ways that differ from recommendations. These differences may reflect the older ages and reduced renal function of clinical populations relative to randomized clinical trial groups, but they could also potentially alter clinical efficacy. Our findings support the need to evaluate the appropriateness and dosing of DOACs at each encounter and to determine the outcomes of patients treated with lower than recommended doses of DOACs and the outcomes of DOAC-treated patients with bioprostheses or active malignancies.

Acknowledgment

The authors thank Tobias Schmelzinger for electronic data extraction and compilation and University of California San Francisco students Eduardo De La Torre Cruz (School of Pharmacy) and Carlos Mikell (School of Medicine) for assistance with data review.

Disclosure

Dr. Schwartz reports receiving personal fees from Bristol-Myers Squibb and Amgen and grants from Bristol-Myers Squibb and Pfizer, outside the submitted work. The other authors have nothing to report.

Click here to access the July 2017 Digital Edition.

Table of Contents

• Nonpathologic Postdeployment Transition Symptoms in Combat National Guard Members and Reservists
• Sarcopenia and the New ICD-10-CM Code: Screening, Staging, and Diagnosis Considerations
• Cerebral Venous Thrombosis
• Peer Support for Whistleblowers
• Symptoms Mimicking Those of Hypokalemic Periodic Paralysis Induced by Soluble Barium Poisoning
• Implementation of a Patient Medication Disposal Program at a VA Medical Center
• The VA Is in Critical Condition, but What Is the Prognosis?
• Leonard Wood: Advocate of Military Preparedness

Click here to access the July 2017 Digital Edition.

Table of Contents

• Nonpathologic Postdeployment Transition Symptoms in Combat National Guard Members and Reservists
• Sarcopenia and the New ICD-10-CM Code: Screening, Staging, and Diagnosis Considerations
• Cerebral Venous Thrombosis
• Peer Support for Whistleblowers
• Symptoms Mimicking Those of Hypokalemic Periodic Paralysis Induced by Soluble Barium Poisoning
• Implementation of a Patient Medication Disposal Program at a VA Medical Center
• The VA Is in Critical Condition, but What Is the Prognosis?
• Leonard Wood: Advocate of Military Preparedness

Click here to access the July 2017 Digital Edition.

Table of Contents

• Nonpathologic Postdeployment Transition Symptoms in Combat National Guard Members and Reservists
• Sarcopenia and the New ICD-10-CM Code: Screening, Staging, and Diagnosis Considerations
• Cerebral Venous Thrombosis
• Peer Support for Whistleblowers
• Symptoms Mimicking Those of Hypokalemic Periodic Paralysis Induced by Soluble Barium Poisoning
• Implementation of a Patient Medication Disposal Program at a VA Medical Center
• The VA Is in Critical Condition, but What Is the Prognosis?
• Leonard Wood: Advocate of Military Preparedness

Click here to access Federal Health Care Data Trends 2017

Table of Contents

• Introduction
• Hematology/Oncology
• Hepatitis C
• Infectious Diseases
• Diabetes Mellitus
• Cardiovascular Disease
• Respiratory Diseases
• Sleep Disorders
• Chronic Pain
• Suicide
• Traumatic Brain Injury
• Women’s Health
• Neurology
• Rheumatology
• References

Click here to access Federal Health Care Data Trends 2017

Table of Contents

• Introduction
• Hematology/Oncology
• Hepatitis C
• Infectious Diseases
• Diabetes Mellitus
• Cardiovascular Disease
• Respiratory Diseases
• Sleep Disorders
• Chronic Pain
• Suicide
• Traumatic Brain Injury
• Women’s Health
• Neurology
• Rheumatology
• References

Click here to access Federal Health Care Data Trends 2017

Table of Contents

• Introduction
• Hematology/Oncology
• Hepatitis C
• Infectious Diseases
• Diabetes Mellitus
• Cardiovascular Disease
• Respiratory Diseases
• Sleep Disorders
• Chronic Pain
• Suicide
• Traumatic Brain Injury
• Women’s Health
• Neurology
• Rheumatology
• References

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.

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶