Bipolar Disorder

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.

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.

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.