Bipolar Disorder

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

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.