Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve? 

This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:

1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.

2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself. 

3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.

4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable. 

5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.

6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.

7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.

8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.

9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.

It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.     

SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.

Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve? 

This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:

1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.

2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself. 

3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.

4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable. 

5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.

6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.

7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.

8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.

9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.

It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.     

SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.

Q: Help! How do you proceed if, after you’ve continually increased a patient’s insulin dose, his/her blood glucose levels do not improve? 

This is a common scenario in diabetes management. Here are nine things to consider when a patient’s situation just doesn’t make sense clinically:

1. Noncompliance with the prescribed dose. This is the most common scenario. Ask the patient, “How many injections do you miss in a typical week?” Assure that he or she is actually taking the currently prescribed amount of insulin before you further increase the dose.

2. Inaccurate insulin dosing. This problem can be due to impaired vision, poor technique, dexterity issues, or dementia. Ask the patient to demonstrate for you how he/she draws up and takes the insulin at home. You might just be surprised at what you see, even in patients who have been giving themselves insulin for years. Consider prescribing an insulin pen or having a family member or significant other dose the insulin if the patient is no longer reliable to accurately dose it for him- or herself. 

3. “Bad insulin.” What this actually means is loss of potency. This can be caused by improper storage, exposure to heat or cold, or use of an insulin delivery device (ie, vial or pen) past the 28- to 45-day period recommended, depending on the type of insulin. Replace the vial or pen and re-assess for improvement in diabetes control.

4. Lipohypertrophy of injection sites due to overuse. Palpate and visually inspect injection sites to look for firm or hypertrophied tissue. Advise the patient to avoid these areas for future injection, as absorption from these sites can be poor and unpredictable. 

5. Dietary issues. The patient may be increasing his/her food intake along with the increased insulin doses. One clue that should raise suspicion for this occurrence is rapidly increasing body weight. Consider referring the patient to a dietitian for nutrition counseling.

6. New medication. Sometimes a new treatment is added to a patient’s regimen by another provider, and the medication might have an adverse effect on blood glucose control. Common examples include steroids (typically a cortisone injection) or methylprednisolone dose-packs taken during an asthma flare.

7. Occult infection. Urinary tract infections, pneumonia, and the like can impact blood glucose control. Consider ordering a urinalysis and complete blood count if infection seems a likely cause.

8. Major life stressors. Inquire as to what is happening in the patient’s life that might impact his/her body’s response to insulin. They might be in the middle of a divorce or other family crisis or experiencing severe stress at work.

9. Technique and equipment issues. Inaccurate glucose monitoring technique or use of expired strips can lead to “false high” readings. Also, patients with a continuous glucose monitor may record false high results when they are taking acetaminophen. If this is the case, increasing the insulin dose will often result in hypoglycemia.

It may be helpful to keep this clinical checklist handy and add to it any other issues that you come across when the clinical picture doesn’t make sense. You may also want to consider referral to a diabetes educator; patients will often confide what is really going on to an educator in a longer visit, rather than in the typically shorter visits with their health care provider.     

SUGGESTED READING
Sadler C, Einhorn D. Tailoring insulin regimens for type 2 diabetes mellitus. JAAPA. 1998;11(4):55-71.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

One twin has cerebral palsy; $103 million verdict

AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.

PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.

VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.

Perforated uterus and severed iliac artery after D&C

A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.

PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.

PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.

VERDICT A $350,000 Wisconsin settlement was reached.

Failure to monitor a high-risk patient

A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.

The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.

PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.

DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.

VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.

Uterine cancer went undiagnosed

A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.

ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.

PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.

VERDICT A $820,000 Massachusetts settlement was reached.

Severe stenosis closes vaginal opening after TVT-O surgery

WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.

The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.

Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.

PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.

PHYSICIAN’S DEFENSE The case was settled before the trial concluded.

VERDICT A $390,000 Virginia settlement was reached.

Lumpectomy, though no mass palpated

A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).

The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.

On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.

The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.

PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.

PHYSICIAN’S DEFENSE Proper care was provided.

VERDICT A $950,000 Illinois verdict was returned.

Genetic testing fails to identify cystic fibrosis in one twin

AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.

PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.

DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.

VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.

A $13 million verdict was returned, including $7 million to the parents for emotional distress.

One twin has cerebral palsy; $103 million verdict

AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.

PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.

VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.

Perforated uterus and severed iliac artery after D&C

A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.

PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.

PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.

VERDICT A $350,000 Wisconsin settlement was reached.

Failure to monitor a high-risk patient

A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.

The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.

PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.

DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.

VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.

Uterine cancer went undiagnosed

A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.

ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.

PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.

VERDICT A $820,000 Massachusetts settlement was reached.

Severe stenosis closes vaginal opening after TVT-O surgery

WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.

The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.

Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.

PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.

PHYSICIAN’S DEFENSE The case was settled before the trial concluded.

VERDICT A $390,000 Virginia settlement was reached.

Lumpectomy, though no mass palpated

A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).

The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.

On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.

The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.

PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.

PHYSICIAN’S DEFENSE Proper care was provided.

VERDICT A $950,000 Illinois verdict was returned.

Genetic testing fails to identify cystic fibrosis in one twin

AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.

PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.

DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.

VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.

A $13 million verdict was returned, including $7 million to the parents for emotional distress.

One twin has cerebral palsy; $103 million verdict

AFTER PREMATURE RUPTURE OF MEMBRANES at 25 weeks’ gestation, a woman went to the emergency department (ED) and was later released. Eight days later, she returned to the ED with abdominal pain; a soporific drug was administered. After several hours, it was determined that she was in labor. Twins were delivered vaginally. One child has cerebral palsy and requires assistance in daily activities, although her cognitive function is intact.

PARENTS’ CLAIM The mother should not have been released after premature rupture of her membranes. The nurses and ObGyns failed to timely recognize that the mother was in labor, and failed to prevent premature delivery. Proper recognition of contractions would have allowed for administration of a tocolytic to delay delivery. That drug had been effectively administered during the first two trimesters of the pregnancy. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE There was no negligence. The hospital argued that fetal heart-rate monitors did not suggest contractions.

VERDICT A $103 million New York verdict was returned against the hospital; a defense verdict was returned for the physicians.

Perforated uterus and severed iliac artery after D&C

A GYNECOLOGIC SURGEON performed a dilation and curettage (D&C) on a 47-year-old woman. During surgery, the patient suffered a perforated uterus and a severed iliac artery, resulting in a myocardial infarction.

PATIENT’S CLAIM The surgeon failed to dilate the cervix appropriately to assess the cervical and endometrial cavity length, and then failed to use proper instrumentation in the uterus. He did not assess uterine shape before the D&C. The patient suffered cognitive and emotional injuries, and will require additional surgery.

PHYSICIAN’S DEFENSE The patient’s anatomy is abnormal. A perforation is a known complication of a D&C.

VERDICT A $350,000 Wisconsin settlement was reached.

Failure to monitor a high-risk patient

A WOMAN WITH A HEART CONDITION who routinely took a beta-blocker plus migraine medication also had lupus. Her pregnancy was therefore at high risk for developing intrauterine growth restriction. Her US Navy ObGyn was advised by a maternal-fetal medicine (MFM) specialist to monitor the pregnancy closely with frequent ultrasonography and other tests that were never performed.

The baby was born by emergency cesarean delivery at 36 weeks’ gestation. The child suffered severe hypoxia and a brain hemorrhage just before delivery, which caused serious, permanent physical and neurologic injuries. He needs 24-hour care, is confined to a wheelchair, and requires a feeding tube.

PATIENT’S CLAIM The ObGyn failed to monitor the mother for fetal growth restriction as recommended by the MFM specialist.

DEFENDANTS’ DEFENSE There was no negligence; the mother was treated properly.

VERDICT After a $28 million Virginia verdict was awarded, the parties continued to dispute whether the judgment would be paid under California law (where the child was born) or Virginia law (where the case was filed). Prior to a rehearing, a $25 million settlement was reached.

Uterine cancer went undiagnosed

A WOMAN IN HER 50s saw her gynecologist in March 2004 to report vaginal staining. She did not return to the physician’s office until January 2005, when she reported daily vaginal bleeding. Ultrasonography showed a 4-cm mass in the endometrial cavity, consistent with a large polyp. A hysteroscopy and biopsy revealed that the woman had uterine cancer. She underwent a hysterectomy and radiation therapy, but the cancer metastasized to her lungs and she died in October 2006.

ESTATE’S CLAIM The gynecologist failed to diagnose uterine cancer in a timely manner.

PHYSICIAN’S DEFENSE The patient’s cancer was aggressive; an earlier diagnosis would not have changed the outcome.

VERDICT A $820,000 Massachusetts settlement was reached.

Severe stenosis closes vaginal opening after TVT-O surgery

WHEN A 51-YEAR-OLD WOMAN NOTICED A BULGE in her vagina, she consulted her gynecologist. He determined the cause to be a cystocele and rectocele, and recommended a tension-free vaginal tape–obturator (TVT-O) procedure with anterior and posterior colporrhaphy.

The patient awoke from surgery in severe pain and was told that she had lost a lot of blood. Two weeks later, the physician explained that the stitches, not yet absorbed, were causing an abrasion, and that more vaginal tissue had been removed than planned.

Two more weeks passed, and the patient used a mirror to look at her vagina but could not see the opening. The TVT-O tape had created a ridge of tissue in the anterior vagina, causing severe stenosis. Vaginal dilators were required to expand the vagina. Entrapment of the dorsal clitoral nerve by the TVT-O tape was also discovered. The patient continues to experience dyspareunia and groin pain.

PATIENT’S CLAIM The gynecologist failed to tell her that, 2 months before surgery, the FDA had issued a public health warning about complications associated with transvaginal placement of surgical mesh during prolapse and urinary incontinence repair. Nor was she informed that the defendant had just completed training in TVT-O surgery, was not fully credentialed, and was proctored during the procedure.

PHYSICIAN’S DEFENSE The case was settled before the trial concluded.

VERDICT A $390,000 Virginia settlement was reached.

Lumpectomy, though no mass palpated

A 52-YEAR-OLD WOMAN FOUND A LUMP in her left breast. Her internist ordered mammography, which identified a 2-cm oval, asymmetrical density in the upper inner quadrant of the left breast. The radiologist recommended ultrasonography (US).

The patient consulted a surgical oncologist, who performed fine-needle aspiration. Pathology identified “clusters of malignant cells consistent with carcinoma,” and suggested a confirmatory biopsy. The oncologist recommended lumpectomy and sentinel node biopsy.

On the day of surgery, the patient could not locate the mass. The oncologist testified that he had palpated it. During surgery, gross examination did not show a mass or tumor. Frozen sections of sentinel nodes did not reveal evidence of cancer.

The patient suffered postsurgical seromas and lymphedema. The lymphedema has partially resolved, but causes pain in her left arm and breast.

PATIENT’S CLAIM The surgical oncologist should have performed US before surgery. It was negligent to continue with surgery when there were negative intraoperative findings for cancer or a mass.

PHYSICIAN’S DEFENSE Proper care was provided.

VERDICT A $950,000 Illinois verdict was returned.

Genetic testing fails to identify cystic fibrosis in one twin

AFTER HAVING ONE CHILD with cystic fibrosis (CF), parents underwent genetic testing. Embryos were prepared for in vitro fertilization (IVF) and sent to a genetic-testing laboratory. The lab reported that the embryos were negative for CF. Two embryos were implanted, and the mother gave birth to twins, one of which has CF.

PARENTS’ CLAIM Multiple errors by the genetic-testing laboratory led to an incorrect report on the embryos. The parents claimed wrongful birth.

DEFENDANTS’ DEFENSE The testing laboratory and physician owner argued that amniocentesis should have been performed during the pregnancy to rule out CF.

VERDICT The trial judge denied the use of the amniocentesis defense because an abortion would have been the only option available, and abortion is against the public policy of Tennessee. The court entered summary judgment on liability for the parents.

A $13 million verdict was returned, including $7 million to the parents for emotional distress.

Ms. Witt reports no financial relationships relevant to this article.

Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:

• the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
• a new code for bladder injection
• bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).

In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.

Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.

Providers can now characterize their level of service by how long it took to provide

As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.

The typical times are:

• 99234, 40 minutes
• 99235, 50 minutes
• 99236, 55 minutes.

Chemodenervation of the bladder gets its own code

A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.

Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:

• 596.51, hypertonicity of bladder
• 596.54, neurogenic bladder NOS
• 596.55, detrusor sphincter dyssynergia
• 596.59, other functional disorder of bladder
• 788.41, urinary frequency.

Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.

Qualified providers now include nonphysicians as well as physicians

CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.

CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.

Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.

As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.

Three new codes for the flu vaccine

Two of the new codes are CPT codes, and the other is for Medicare:

• 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
• 90672, Influenza virus vaccine, live, for intranasal use
• Q2034, Agriflu.

Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.

CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.

Medicare refines billing for MPA administration

When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.

The deleted codes are:

• J1051, medroxyprogesterone acetate, 50 mg
• J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
• J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.

The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.

Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.

We want to hear from you! Tell us what you think.

Ms. Witt reports no financial relationships relevant to this article.

Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:

• the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
• a new code for bladder injection
• bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).

In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.

Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.

Providers can now characterize their level of service by how long it took to provide

As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.

The typical times are:

• 99234, 40 minutes
• 99235, 50 minutes
• 99236, 55 minutes.

Chemodenervation of the bladder gets its own code

A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.

Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:

• 596.51, hypertonicity of bladder
• 596.54, neurogenic bladder NOS
• 596.55, detrusor sphincter dyssynergia
• 596.59, other functional disorder of bladder
• 788.41, urinary frequency.

Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.

Qualified providers now include nonphysicians as well as physicians

CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.

CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.

Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.

As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.

Three new codes for the flu vaccine

Two of the new codes are CPT codes, and the other is for Medicare:

• 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
• 90672, Influenza virus vaccine, live, for intranasal use
• Q2034, Agriflu.

Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.

CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.

Medicare refines billing for MPA administration

When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.

The deleted codes are:

• J1051, medroxyprogesterone acetate, 50 mg
• J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
• J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.

The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.

Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.

We want to hear from you! Tell us what you think.

Ms. Witt reports no financial relationships relevant to this article.

Among changes to Current Procedural Terminology (CPT) that took effect on January 1 are several of interest to our specialty:

• the addition of “typical” times to the evaluation and management (E/M) codes for same-day admission and discharge
• a new code for bladder injection
• bundling of imaging guidance associated with percutaneous implantation of a neurostimulator electrode array, if performed, using code 64561, Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement).

In addition, CPT made it clear that all E/M codes can be reported by qualified nonphysician health-care providers, as well as physicians. As for Medicare, coding for administration of depot medroxyprogesterone acetate (Depo-Provera) has been modified, as has the billing process for interpretation of ultrasonography performed outside of the office.

Because of requirements in the Health Insurance Portability and Accountability Act (HIPAA), insurers were required to accept the new codes and revisions on January 1.

Providers can now characterize their level of service by how long it took to provide

As I mentioned, typical times have been added to the set of observation and inpatient care codes that involve admission and discharge on the same date of service. Until now, these codes did not have a pre-assigned typical time, and the provider had to select the level of service based solely on three key components: history, examination, and medical decision-making. The addition of times allows the provider to select the level of service based on counseling or coordination of care, if that activity dominated the visit.

The typical times are:

• 99234, 40 minutes
• 99235, 50 minutes
• 99236, 55 minutes.

Chemodenervation of the bladder gets its own code

A new code, 52287, cystourethroscopy, with injection(s) for chemodenervation of the bladder, has been added to CPT. This procedure is performed to treat idiopathic overactive bladder that can’t be managed any other way. It typically involves the injection of botulinum. Before January 1, this procedure was reported using codes 52000 and 64614, but this approach represented an inexact match.

Payers will be looking closely at diagnostic coding for this procedure. The most frequently accepted diagnostic codes are:

• 596.51, hypertonicity of bladder
• 596.54, neurogenic bladder NOS
• 596.55, detrusor sphincter dyssynergia
• 596.59, other functional disorder of bladder
• 788.41, urinary frequency.

Because costs will vary, depending on the chemotoxin used, the agent may be reported separately using the descriptive “J” code or another Medicare-designated alphanumeric code, such as J0585, injection of botulinum toxin type A, 1 unit.

Qualified providers now include nonphysicians as well as physicians

CPT has clarified that all E/M codes can be reported not only by physicians but by qualified nonphysicians as well.

CPT also changed wording in each of the codes so that the use of counseling time applies to all providers when counseling dominates the visit. In other words, if a payer allows someone other than a physician to provide and bill for a service, the CPT E/M codes can be used by all providers who qualify and have documented the service. These changes have no effect on the codes themselves.

Please note, however, that registered nurses and licensed practical nurses are not normally recognized as billing providers and will still be restricted to code 99211, Office or other outpatient visit for the evaluation and management of an established patient, that may not require the presence of a physician. Usually, with this code, presenting problems are minimal. Typically, 5 minutes are spent performing or supervising these services. This code is often referred to as the “nurse-only” code.

As a result of this clarification, references to physicians have been removed from CPT code 59300, Episiotomy or vaginal repair, by other than attending. This change signifies that this code may be reported by any qualified provider who did not perform the delivery or was not covering for a physician group who billed for the delivery.

Three new codes for the flu vaccine

Two of the new codes are CPT codes, and the other is for Medicare:

• 90653, Influenza vaccine, inactivated, subunit, adjuvanted, for intramuscular use
• 90672, Influenza virus vaccine, live, for intranasal use
• Q2034, Agriflu.

Keep in mind that the administration of the flu vaccine is reported differently for Medicare, compared with private payers. Administration code G0008 and diagnosis code V04.81 would be reported in conjunction with the appropriate vaccine code for Medicare. CPT requires that code 90471 be reported for administration.

CPT also revised all flu vaccine codes (90655–90660) to include the term “trivalent” to signify that all flu vaccines are made up of three strains of the virus.

Medicare refines billing for MPA administration

When billing for MPA or MPA in combination with estradiol, be aware that Medicare has eliminated the J codes for these drugs, replacing them with a single new code.

The deleted codes are:

• J1051, medroxyprogesterone acetate, 50 mg
• J1055, medroxyprogesterone acetate, 150 mg, for contraceptive use
• J1056, medroxyprogesterone acetate/ estradiol cypionate, 5 mg/25 mg.

The new code is J1050, medroxyprogesterone acetate, 1 mg. To use it, you must indicate the dosage as a quantity. For example, if you injected 150 mg, you would use code J1050 x 150 on the claim. The diagnosis code will indicate the reason for the injection—that is, medical treatment or contraception. In the event that the combination drug is being administered, separate billing of J1000, Injection, depo-estradiol cypionate, up to 5 mg, would need to be reported in addition to J1050.

Medicare has also issued a national policy on Place of Service (POS) billing because the office of the inspector general has found that physicians and other suppliers frequently report an incorrect POS, and Medicare pays more for some sites. Medicare rules for the billing of POS for the professional component of an imaging service are changing, effective April 1, 2013. This rule was postponed from its original date of October 1, 2012. Under this rule, when the professional and technical components of a service are performed in different locations, the appropriate POS to report for the interpretive aspect is the location where the technical component was performed. This change would apply to an ObGyn practice that contracts out for the technical component of an ultrasound but performs the interpretation in the office. In that case, the POS should not be listed as “office” or POS 11, but should match the POS of the imaging contractor.

We want to hear from you! Tell us what you think.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.¹ Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.² When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.^3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.^6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).^6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.^6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.¹⁰ Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.^4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 1^3-11 and Table 2^3-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.^6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.⁵

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.^10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.¹⁴ When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.¹⁵

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.¹¹ When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.^10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.^4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.¹⁰ For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.^11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.^4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.¹⁰ Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.¹¹

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

• Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
• Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.

Drug Brand Names

• Albuterol/ipratropium • Combivent
• Almotriptan • Axert
• Alosetron • Lotronex
• Aminophylline • Phyllocontin, Truphylline
• Amitriptyline • Elavil
• Amlodipine • Norvasc
• Asenapine • Saphris
• Betaxolol • Kerlone
• Carbamazepine • Carbatrol, Tegretol
• Carvedilol • Coreg
• Chlorpromazine • Thorazine
• Chlorzoxazone • Parafon Forte
• Cimetidine • Tagamet
• Ciprofloxacin • Cipro
• Clomipramine • Anafranil
• Clopidogrel • Plavix
• Clozapine • Clozaril
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Diazepam • Valium
• Diclofenac • Voltaren
• Diphenhydramine • Benadryl
• Doxepin • Silenor, Sinequan
• Duloxetine • Cymbalta
• Estradiol • Estrace
• Estrogens (conjugated) • Cenestin, Premarin
• Estropipate • Ogen
• Febuxostat • Uloric
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Guanabenz • Wytensin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Maprotiline • Ludiomil
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Nabumetone • Relafen
• Naratriptan • Amerge
• Nicardipine • Cardene
• Nifedipine • Adalat, Procardia
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Ondansetron • Zofran
• Palonosetron • Aloxi
• Perphenazine • Trilafon
• Pimozide • Orap
• Primidone • Mysoline
• Progesterone • Prometrium
• Propofol • Diprivan
• Propranolol • Inderal
• Ramelteon • Rozerem
• Ranitidine • Zantac
• Rasagiline • Azilect
• Rifampin • Rifadin, Rimactane
• Riluzole • Rilutek
• Rivastigmine • Exelon
• Ropinirole • Requip
• Selegiline • Eldepryl, EMSAM, others
• Theophylline • Elixophyllin
• Thioridazine • Mellaril
• Thiothixene • Navane
• Tizanidine • Zanaflex
• Trazodone • Desyrel, Oleptro
• Triamterene • Dyrenium
• Trifluoperazine • Stelazine
• Verapamil • Calan, Verelan
• Warfarin • Coumadin, Jantoven
• Zileuton • Zyflo
• Ziprasidone • Geodon
• Zolmitriptan • Zomig
• Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:

• deficiencies may play a causative role in mental illness and exacerbate symptoms
• psychiatric symptoms can result in poor nutrition
• vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.

Additionally, genetic differences may compromise vitamin and essential nutrient pathways.

Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com

To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,¹) and 3 fat-soluble vitamins (A, D, and E; Table 2,¹) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.

Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources

Water-soluble vitamins

Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.² Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.³ Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.

Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.

Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.⁴ Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.⁵ Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.

Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,⁶ and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients⁷ and predicts depression in prospective trials.⁸ Deficiency is common (24% to 56%) among patients receiving hemodialysis.⁹ Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.¹⁰ Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.

Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.¹¹ In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.¹² A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.¹³ Patients without deficiency but with folate levels near the low end of the normal range also report low mood.¹⁴ Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.¹⁵

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.¹⁶ Clinical trials have shown that several forms of folate can enhance antidepressant treatment.¹⁷ Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.¹⁸

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality.^19,20

Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients¹¹ and compromises antidepressant response,²¹ whereas higher vitamin B12 levels are associated with better treatment outcomes.²² B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.^23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.²⁶

B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.

Psychiatric symptoms of B12 deficiency may present before hematologic findings.²³ Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.

Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.

Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.²⁷ Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.

Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.²⁸ Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.²⁹ Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.

Fat-soluble vitamins

Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.³⁰ Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.

Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.

Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.

Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.

Although vitamin D is known for its role in bone growth and mineralization,³¹ increasing evidence reveals vitamin D’s role in brain function and development.³² Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra—all regions theorized to be linked to depression pathophysiology.³³ A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of Current Psychiatry.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or “UVB-irradiated” mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E—4 tocopherols and 4 tocotrienols—that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB.³⁴ Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake.³⁵ Low vitamin status has been found in up to 70% of older adults.³⁶ Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E.¹ The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake.^37,38 Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients’ dietary patterns and vitamin status, particularly older adults and those with:

• lower socioeconomic status or food insecurity
• a history of treatment resistance
• restrictive dietary patterns such as veganism
• alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient’s blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient’s primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient’s eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Related Resources

• Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf" target="_blank">www.iom.edu/Activities/Nutrition/
  SummaryDRIs/~/media/Files
  /Activity%20Files/Nutrition
  /DRIs/5_Summary%20Table%20Tables%201-4.pdf.
• The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.
• Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.
• Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

• Isotretinoin • Accutane
• L-methylfolate • Deplin
• Omeprazole • Prilosec

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.