Somatic Disorders

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

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

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

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

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

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

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

This nervous system is located inside the wall of the GI tract, extending from the esophagus to the rectum. Technically, it is known as the enteric nervous system, or ENS, but it has been given other labels, too: “second brain,”² “abdominal brain,” “other brain,” and “back-up brain.” Its neurologic disorders include abdomi­nal epilepsy, abdominal migraine, and autism with intestinal symptoms, such as chronic enterocolitis.³

Impressive brain-like features
The ENS includes 100 million neu­rons (same as the spinal cord) with glia-like support cells. It contains >30 neurotransmitters, including several closely linked to psychopathology (serotonin, dopamine, γ-aminobutyric acid, and acetylcholine). The ENS is not part of the autonomic nervous system. It communicates with the brain via the vagus nerve.

A vast system of gut bacteria
The ENS maintains close links with, and is influenced by, the microbiome, an extensive universe of commensal (that is, symbiotic) bacteria in the gut that play a vital role in immune health, brain function, and signaling systems within the CNS. The role of the micro­biome in neuropsychiatric disorders has become a sizzling area of research.

The numbers of the microbiome are astonishing, including approximately 1,000 species of bacteria; 100 trillion total bacterial organisms (outnum­bering cells of the body by 100-fold); 4 million bacterial genes (compared with 26,000 genes in the host human genome); and a density as high as 1 tril­lion bacteria in a cubic milliliter—higher than any known microbial system.⁴

Significant GI−brain connections
It is of great relevance to psychiatry that 90% of the body’s serotonin and 50% of dopamine are found in the GI brain. Selective serotonin reuptake inhibitors often are associated with GI symptoms, such as nausea and diarrhea; antipsychotics, which are dopamine antagonists, are known for antiemetic effects. Clozapine’s potent anticholiner­gic effects can cause serious ileus.

Things get more interesting when one considers the association of GI dis­orders and psychiatric symptoms:

Irritable bowel syndrome is associated with panic disorder, generalized anxiety disorder, social phobia, dysthymia, and major depression.

Inflammatory bowel disease (IBD)— such as Crohn’s disease and ulcerative colitis (prevalence ranging from 6% in Canada to 14% in the United States to 46% in Mexico⁵)—is commonly associ­ated with mood and anxiety disorders and personality changes. The psychi­atric manifestations of IBD are so com­mon that the authors of a recent article in World Journal of Gastroenterology urged gastroenterologists to collaborate with psychiatrists when managing IBD.⁶

Celiac disease has been repeatedly associated with several neuropsychiat­ric disorders, including ataxia, epilepsy, peripheral neuropathy, headache, anxi­ety, attention-deficit/hyperactivity dis­order, autism spectrum disorder, and schizophrenia.

New, exciting challenges for medical science
There potentially are important impli­cations for possible exploitation of the ENS and the microbiome in the diag­nosis and treatment of neuropsychiatric disorders. For example, consider these speculative challenges:
   • Can intestinal biopsy reveal neu­rotransmitter pathology in schizophrenia?
   • Can early dopamine deficiency predict Parkinson’s disease, enabling early intervention?
   • Can β-amyloid deposits, the degenerative neurologic stigmata of Alzheimer’s disease, be detected in abdominal neurons years before onset of symptoms to allow early intervention?
   • Can the ENS become a therapeutic pathway by targeting the various neu­rotransmitters found there or by engag­ing the enormous human microbiome to manipulate its beneficial properties?
   • Can foods or probiotic supple­ments be prescribed as microbiomal adjuncts to improve the mood and anxi­ety spectrum?

One recommendation I came across is that ingesting 10 to 100 million ben­eficial bacteria, such as Lactobacillus plan­tarum and Bifidobacterium infantis, might be helpful. Such prescriptions obviously are speculative but also are reasonably testable hypotheses of ways to exploit the “other brain” and the microbiome.

We must summon the guts to seize this opportunity
An independent second brain and a remarkable microbiome appear to be significant evolutionary adaptations and advantages for humans. For too long, neuropsychiatric researchers have ignored the ENS and the micro­biome; now, they must focus on how to exploit these entities to yield inno­vative diagnostic and therapeutic advances. Integrating the ENS and the microbiome and enmeshing them into neuropsychiatric research and clinical applications hold great promise.

The field of psychoneurogastroen­terology is in its infancy, but its growth and relevance will be momentous for neuropsychiatry. A major intellectual peristalsis is underway.

CASE Difficulty walking
Ms. M, age 15, is a pregnant, Spanish-speaking Guatemalan woman who is brought to obstet­rics triage in a large academic medical center at 35 weeks gestational age. She complains of dizziness, tinnitus, left orbital headache, and difficulty walking.

The neurology service finds profound trun­cal ataxia, astasia-abasia, and buckling of the knees; a normal brain and spine MRI are not consistent with a neurologic etiology. Otolaryngology service evaluates Ms. M to rule out a cholesteatoma and suggests a head CT and endoscopy, which are normal.

Ms. M’s symptoms resolve after 3 days, although the gait disturbances persist. When no clear cause is found for her difficulty walk­ing, the psychiatry service is consulted to evalu­ate whether an underlying psychiatric disorder is contributing to symptoms.

What could be causing Ms. M’s symptoms?
   a) malingering
   b) factitious disorder
   c) undiagnosed neurologic disorder
   d) conversion disorder

The authors’ observations
Women are vulnerable to a variety of psy­chiatric illnesses during pregnancy¹ that have deleterious effects on mother, baby, and family.^2-6 Although there is a burgeoning literature on affective and anxiety disorders occurring in pregnancy, there is a dearth of information about somatoform disorders.


HISTORY Abandonment
Ms. M reports that, although her boyfriend deserted her after learning about the unexpected pregnancy, she will welcome the baby and looks forward to motherhood. She seems unaware of the responsibilities of being a mother.

Ms. M acknowledges a history of depression and self-harm a few years earlier, yet says she feels better now and thinks that psychiatric care is unnecessary. Because she does not endorse a history of trauma or symptoms suggesting an affective, anxiety, or psychotic illness, the psy­chiatrist does not recommend treatment with psychotropic medication. 

At age 5, Ms. M’s parents sent her to the United States with her aunt, hoping that she would have a better life than she would have had in Guatemala. Her aunt reports that Ms. M initially had difficulty adjusting to life in the United States without her parents, yet she has made substantial strides over the years and is now quite accustomed to the country. Her aunt describes Ms. M as an independent high school student who earns good grades.

During the interview, the psychiatrist observes that Ms. M exhibits childlike manner­isms, including sleeping with stuffed toys and coloring in Disney books with crayons. She also is indifferent to her gait difficulty, pregnancy, and psychosocial stressors. Her affect is incon­sistent with the content of her speech and she is alexithymic.

Ms. M’s aunt reports that her niece is becom­ing more dependent on her, which is not con­sistent with her baseline. Her aunt also notes that several years earlier, Ms. M’s nephew was diagnosed with a cholesteatoma after he pre­sented with similar symptoms.

The combination of (1) Ms. M’s clinical pre­sentation, which was causing her significant impairment in her social functioning, (2) the incompatibility of symptoms with any recog­nized neurologic and medical disease, and (3) prior family experience with cholesteatoma leads the consulting psychiatrist to suspect conversion disorder. Ms. M’s alexithymia, indif­ference to her symptoms, and recent aban­donment by the baby’s father also support a conversion disorder diagnosis.

From a psychodynamic perspective, the ataxia appears to be her way of protecting her­self from the abandonment she is experiencing by being left again to “stand alone” by her boy­friend as she had been when her parents sent her to the United States. Her regressive behav­ior could be her way of securing her aunt’s love and support.

The authors’ observations
This is the first case of psychogenic gait dis­turbance during pregnancy described in the literature. Authors have reported on pseu­dotoxemia,⁷ hyperemesis gravidarum,⁸ and pesudocyesis,9 yet there is a paucity of infor­mation on psychogenic gait disturbance during pregnancy. Ms. M’s case elucidates many of the clinical quandaries that occur when managing psychiatric illness—and, more specifically, conversion disorder— during pregnancy. Many women are hesi­tant to seek psychiatric treatment during pregnancy because of shame, stigma, and fear of loss of personal or parental rights^10,11; it is not surprising that emotionally dis­tressed women communicate their feel­ings or troubled thoughts through physical symptoms.

Likely diagnosis
Conversion disorder is the presence of neurologic symptoms in the absence of a neurologic diagnosis that fully explains those symptoms. Conversion disorder, previously known as hysteria, is called functional neurologic symptom disorder in DSM-5 (Box).¹² Symptoms are not feigned; instead, they represent “conver­sion” of emotional distress into neurologic symptoms.^13,14 Although misdiagnosing conversion disorder in patients with true neurologic disease is uncommon, clini­cians often are uncomfortable making the diagnosis until all medical causes have been ruled out.¹⁴ It is not always possible to find a psychological explanation for conversion disorder, but a history of child­hood abuse, particularly sexual abuse, could play a role.¹⁴

How would you treat Ms. M?
   a) destigmatize psychiatric illness and provide psychoeducation regarding treat­ment benefits
   b) identify and treat any comorbid psychiat­ric disorders
   c) maintain a proactive and multidisci­plinary approach that includes assess­ment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy
  d) all of the above


TREATMENT Close follow-up
The psychiatrist recommends continued close psychiatric follow-up as well as multidisci­plinary involvement, including physical ther­apy, neurology, and obstetrics.

Ms. M initially is resistant to psychiatric follow-up because she says that “people on the street” told her that, if she saw a psychia­trist, her baby would be taken away. After the psychiatrist explains that it is unlikely her baby would be taken away, Ms. M immediately appears relieved, smiles, and readily agrees to outpatient psychotherapy.

Over the next 24 hours, she continues to work with a physical therapist and her gait sig­nificantly improves. She is discharged home 2 days later with a walking aid (Zimmer frame) for assistance.

Four days later, however, Ms. M is readmit­ted with worsening ataxia. Her aunt reports that, at home, Ms. M’s regressed behaviors are worsening; she is sleeping in bed with her and had several episodes of enuresis at home.

Ms. M continues to deny psychiatric symp­toms or anxiety about the delivery. Although she shows some improvement when work­ing with physical therapists, they note that Ms. M is still unable to ambulate or stand on her own. The psychiatrist is increasingly con­cerned about her regressed behavior and con­tinued ataxia.

A family meeting is held and the psychia­trist and social worker educate Ms. M and her aunt about conversion disorder, including how some emotionally distressed women communicate their feelings or troubled thoughts through physical symptoms and how that may apply to Ms. M. During the meeting, the team also destigmatizes psy­chiatric illness and treatment and provides psychoeducation regarding its benefits. The psychiatrist and social worker also provide a psychodynamic interpretation that her ataxia could be a way of protecting herself against the abandonment she is experiencing by being left to “stand alone” by her boyfriend— as she had been when her parents sent her to the United States, and that her behavior could be her way of securing her aunt’s love and support.Ms. M and her aunt both readily agree with this interpretation. The aunt notes that her niece is more anxious about motherhood than she acknowledges and is concerned that Ms. M expects her to be the primary care­giver for the baby. Those present note that Ms. M is becoming increasingly dependent on her aunt, and that it is important for her to retain her independence, especially once she becomes a mother.

Ms. M immediately begins to display more affect; she smiles and reports feeling relieved. Similar to the previous admission, her gait sig­nificantly improves over the next 2 days and she is discharged home with a walking aid.

The authors’ observations
A broad differential diagnosis and early multidisciplinary involvement might facilitate earlier diagnosis and treatment.¹⁶ Assessment of psychosocial stressors in the patient’s personal and family life, includ­ing circumstances around the pregnancy and the meaning of motherhood, as well as investigation of what the patient may gain from the sick role, are paramount. In Ms. M’s case, cultural background, sepa­ration from her parents at a young age, and recent abandonment by her boyfriend have contributed to her inability to “stand alone,” which manifested as ataxia. Young age, regressed behavior, and her minimi­zation of stressors also point to her dif­ficulty acknowledging and coping with psychosocial stressors.

Successful delivery of the diagnosis is key to treatment success. After building a therapeutic alliance, a multidisciplinary discussion should take place that allows the patient to understand the diagnosis and treatment plan.^17,18 The patient and family should be reassured that the fetus is healthy and all organic causes of symptoms have been investigated.¹⁷ Although man­agement of conversion disorder during pregnancy is similar to that in non-preg­nant women, several additional avenues of investigation should be considered:
   • Explore the psychodynamic basis of the disorder and the role of the pregnancy and motherhood.
   • Identify any comorbid psychiatric disorders, particularly those specific to pregnancy or the postpartum period.
   • Because of the shame and stigma associated with seeking psychiatric treat­ment during pregnancy,^10,11 it is impera­tive to destigmatize treatment and provide psychoeducation regarding its benefits.

A treatment plan can then be developed that involves psychotherapy, psychoedu­cation, stress management, and, when appropriate, pharmacotherapy.¹⁷

Providing psychoeducation about postpartum depression and other perina­tal psychiatric illness could be beneficial. Physical therapy often is culturally accept­able and can help re-establish healthy patterns of motor function.¹⁹ Ms. M’s gait  showed some improvement with physical therapy as part of the multidisciplinary approach, which also should include a thorough medical workup. Appropriate psychiatric treatment can help patients give up the sick role and return to their previous level of functioning.¹⁷

Maintain close communication with the outpatient perinatal care team as they mon­itor the patient’s parenting capacity. The outpatient perinatal care team also should engage pregnant or postpartum women in prioritizing their emotional well-being and encourage outpatient mental health treatment. Despite a dearth of data on the regressive symptoms and prognosis for future pregnancies, it is important to mon­itor maternal capacity and discuss the pos­sibility of symptom recurrence.


OUTCOME Healthy baby
Three days later, Ms. M returns in labor with improved gait yet still using a walking aid. She has a normal vaginal delivery of a healthy baby boy at 37 weeks’ gestational age.

After the birth, Ms. M reports feeling well and enjoying motherhood, and denies psy­chiatric symptoms. She is ambulating without assistance within hours of delivery. This spon­taneous resolution of symptoms could have been because of the psychodynamically ori­ented multidisciplinary approach to her care, which may have helped her realize that she did not have to “stand alone” as she embarked on motherhood.

Before being discharged home, Ms. M and her aunt meet with the inpatient obstetric social worker to assess Ms. M’s ability to care for the baby and discuss the importance of continued emotional support. The social worker does not contact the Department of Children and Families because Ms. M is walking independently and not endorsing or exhibiting regressive behaviors. Ms. M also reports that she will ask her aunt to take care of the baby should ataxia recur. Her aunt reassures the social workers that she will encourage Ms. M to attend outpatient psy­chotherapy and will contact the social worker if she becomes concerned about Ms. M’s or the baby’s well-being.

During her postpartum obstetric visit, Ms. M is walking independently and does not exhibit or endorse neurologic symptoms. The social worker provides psychoeducation about the importance of outpatient psycho­therapy and schedules an initial appointment; Ms. M does not attend outpatient psychother­apy after discharge.

Bottom Line
Consider conversion disorder in obstetric patients who present with ataxia without a neurologic cause. Management involves a proactive and multidisciplinary approach that includes a thorough medical workup and assessment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy. Early identification and delivery of the diagnosis, destigmatization, and provision of appropriate psychiatric treatment can facilitate treatment success.

Disclosures
Dr. Byatt has received grant funding/support for this project from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR000160. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Toor reports no financial relationships with any company whose products are mentioned in this article or manufacturers of competing products.

CASE Difficulty walking
Ms. M, age 15, is a pregnant, Spanish-speaking Guatemalan woman who is brought to obstet­rics triage in a large academic medical center at 35 weeks gestational age. She complains of dizziness, tinnitus, left orbital headache, and difficulty walking.

The neurology service finds profound trun­cal ataxia, astasia-abasia, and buckling of the knees; a normal brain and spine MRI are not consistent with a neurologic etiology. Otolaryngology service evaluates Ms. M to rule out a cholesteatoma and suggests a head CT and endoscopy, which are normal.

Ms. M’s symptoms resolve after 3 days, although the gait disturbances persist. When no clear cause is found for her difficulty walk­ing, the psychiatry service is consulted to evalu­ate whether an underlying psychiatric disorder is contributing to symptoms.

What could be causing Ms. M’s symptoms?
   a) malingering
   b) factitious disorder
   c) undiagnosed neurologic disorder
   d) conversion disorder

The authors’ observations
Women are vulnerable to a variety of psy­chiatric illnesses during pregnancy¹ that have deleterious effects on mother, baby, and family.^2-6 Although there is a burgeoning literature on affective and anxiety disorders occurring in pregnancy, there is a dearth of information about somatoform disorders.


HISTORY Abandonment
Ms. M reports that, although her boyfriend deserted her after learning about the unexpected pregnancy, she will welcome the baby and looks forward to motherhood. She seems unaware of the responsibilities of being a mother.

Ms. M acknowledges a history of depression and self-harm a few years earlier, yet says she feels better now and thinks that psychiatric care is unnecessary. Because she does not endorse a history of trauma or symptoms suggesting an affective, anxiety, or psychotic illness, the psy­chiatrist does not recommend treatment with psychotropic medication. 

At age 5, Ms. M’s parents sent her to the United States with her aunt, hoping that she would have a better life than she would have had in Guatemala. Her aunt reports that Ms. M initially had difficulty adjusting to life in the United States without her parents, yet she has made substantial strides over the years and is now quite accustomed to the country. Her aunt describes Ms. M as an independent high school student who earns good grades.

During the interview, the psychiatrist observes that Ms. M exhibits childlike manner­isms, including sleeping with stuffed toys and coloring in Disney books with crayons. She also is indifferent to her gait difficulty, pregnancy, and psychosocial stressors. Her affect is incon­sistent with the content of her speech and she is alexithymic.

Ms. M’s aunt reports that her niece is becom­ing more dependent on her, which is not con­sistent with her baseline. Her aunt also notes that several years earlier, Ms. M’s nephew was diagnosed with a cholesteatoma after he pre­sented with similar symptoms.

The combination of (1) Ms. M’s clinical pre­sentation, which was causing her significant impairment in her social functioning, (2) the incompatibility of symptoms with any recog­nized neurologic and medical disease, and (3) prior family experience with cholesteatoma leads the consulting psychiatrist to suspect conversion disorder. Ms. M’s alexithymia, indif­ference to her symptoms, and recent aban­donment by the baby’s father also support a conversion disorder diagnosis.

From a psychodynamic perspective, the ataxia appears to be her way of protecting her­self from the abandonment she is experiencing by being left again to “stand alone” by her boy­friend as she had been when her parents sent her to the United States. Her regressive behav­ior could be her way of securing her aunt’s love and support.

The authors’ observations
This is the first case of psychogenic gait dis­turbance during pregnancy described in the literature. Authors have reported on pseu­dotoxemia,⁷ hyperemesis gravidarum,⁸ and pesudocyesis,9 yet there is a paucity of infor­mation on psychogenic gait disturbance during pregnancy. Ms. M’s case elucidates many of the clinical quandaries that occur when managing psychiatric illness—and, more specifically, conversion disorder— during pregnancy. Many women are hesi­tant to seek psychiatric treatment during pregnancy because of shame, stigma, and fear of loss of personal or parental rights^10,11; it is not surprising that emotionally dis­tressed women communicate their feel­ings or troubled thoughts through physical symptoms.

Likely diagnosis
Conversion disorder is the presence of neurologic symptoms in the absence of a neurologic diagnosis that fully explains those symptoms. Conversion disorder, previously known as hysteria, is called functional neurologic symptom disorder in DSM-5 (Box).¹² Symptoms are not feigned; instead, they represent “conver­sion” of emotional distress into neurologic symptoms.^13,14 Although misdiagnosing conversion disorder in patients with true neurologic disease is uncommon, clini­cians often are uncomfortable making the diagnosis until all medical causes have been ruled out.¹⁴ It is not always possible to find a psychological explanation for conversion disorder, but a history of child­hood abuse, particularly sexual abuse, could play a role.¹⁴

How would you treat Ms. M?
   a) destigmatize psychiatric illness and provide psychoeducation regarding treat­ment benefits
   b) identify and treat any comorbid psychiat­ric disorders
   c) maintain a proactive and multidisci­plinary approach that includes assess­ment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy
  d) all of the above


TREATMENT Close follow-up
The psychiatrist recommends continued close psychiatric follow-up as well as multidisci­plinary involvement, including physical ther­apy, neurology, and obstetrics.

Ms. M initially is resistant to psychiatric follow-up because she says that “people on the street” told her that, if she saw a psychia­trist, her baby would be taken away. After the psychiatrist explains that it is unlikely her baby would be taken away, Ms. M immediately appears relieved, smiles, and readily agrees to outpatient psychotherapy.

Over the next 24 hours, she continues to work with a physical therapist and her gait sig­nificantly improves. She is discharged home 2 days later with a walking aid (Zimmer frame) for assistance.

Four days later, however, Ms. M is readmit­ted with worsening ataxia. Her aunt reports that, at home, Ms. M’s regressed behaviors are worsening; she is sleeping in bed with her and had several episodes of enuresis at home.

Ms. M continues to deny psychiatric symp­toms or anxiety about the delivery. Although she shows some improvement when work­ing with physical therapists, they note that Ms. M is still unable to ambulate or stand on her own. The psychiatrist is increasingly con­cerned about her regressed behavior and con­tinued ataxia.

A family meeting is held and the psychia­trist and social worker educate Ms. M and her aunt about conversion disorder, including how some emotionally distressed women communicate their feelings or troubled thoughts through physical symptoms and how that may apply to Ms. M. During the meeting, the team also destigmatizes psy­chiatric illness and treatment and provides psychoeducation regarding its benefits. The psychiatrist and social worker also provide a psychodynamic interpretation that her ataxia could be a way of protecting herself against the abandonment she is experiencing by being left to “stand alone” by her boyfriend— as she had been when her parents sent her to the United States, and that her behavior could be her way of securing her aunt’s love and support.Ms. M and her aunt both readily agree with this interpretation. The aunt notes that her niece is more anxious about motherhood than she acknowledges and is concerned that Ms. M expects her to be the primary care­giver for the baby. Those present note that Ms. M is becoming increasingly dependent on her aunt, and that it is important for her to retain her independence, especially once she becomes a mother.

Ms. M immediately begins to display more affect; she smiles and reports feeling relieved. Similar to the previous admission, her gait sig­nificantly improves over the next 2 days and she is discharged home with a walking aid.

The authors’ observations
A broad differential diagnosis and early multidisciplinary involvement might facilitate earlier diagnosis and treatment.¹⁶ Assessment of psychosocial stressors in the patient’s personal and family life, includ­ing circumstances around the pregnancy and the meaning of motherhood, as well as investigation of what the patient may gain from the sick role, are paramount. In Ms. M’s case, cultural background, sepa­ration from her parents at a young age, and recent abandonment by her boyfriend have contributed to her inability to “stand alone,” which manifested as ataxia. Young age, regressed behavior, and her minimi­zation of stressors also point to her dif­ficulty acknowledging and coping with psychosocial stressors.

Successful delivery of the diagnosis is key to treatment success. After building a therapeutic alliance, a multidisciplinary discussion should take place that allows the patient to understand the diagnosis and treatment plan.^17,18 The patient and family should be reassured that the fetus is healthy and all organic causes of symptoms have been investigated.¹⁷ Although man­agement of conversion disorder during pregnancy is similar to that in non-preg­nant women, several additional avenues of investigation should be considered:
   • Explore the psychodynamic basis of the disorder and the role of the pregnancy and motherhood.
   • Identify any comorbid psychiatric disorders, particularly those specific to pregnancy or the postpartum period.
   • Because of the shame and stigma associated with seeking psychiatric treat­ment during pregnancy,^10,11 it is impera­tive to destigmatize treatment and provide psychoeducation regarding its benefits.

A treatment plan can then be developed that involves psychotherapy, psychoedu­cation, stress management, and, when appropriate, pharmacotherapy.¹⁷

Providing psychoeducation about postpartum depression and other perina­tal psychiatric illness could be beneficial. Physical therapy often is culturally accept­able and can help re-establish healthy patterns of motor function.¹⁹ Ms. M’s gait  showed some improvement with physical therapy as part of the multidisciplinary approach, which also should include a thorough medical workup. Appropriate psychiatric treatment can help patients give up the sick role and return to their previous level of functioning.¹⁷

Maintain close communication with the outpatient perinatal care team as they mon­itor the patient’s parenting capacity. The outpatient perinatal care team also should engage pregnant or postpartum women in prioritizing their emotional well-being and encourage outpatient mental health treatment. Despite a dearth of data on the regressive symptoms and prognosis for future pregnancies, it is important to mon­itor maternal capacity and discuss the pos­sibility of symptom recurrence.


OUTCOME Healthy baby
Three days later, Ms. M returns in labor with improved gait yet still using a walking aid. She has a normal vaginal delivery of a healthy baby boy at 37 weeks’ gestational age.

After the birth, Ms. M reports feeling well and enjoying motherhood, and denies psy­chiatric symptoms. She is ambulating without assistance within hours of delivery. This spon­taneous resolution of symptoms could have been because of the psychodynamically ori­ented multidisciplinary approach to her care, which may have helped her realize that she did not have to “stand alone” as she embarked on motherhood.

Before being discharged home, Ms. M and her aunt meet with the inpatient obstetric social worker to assess Ms. M’s ability to care for the baby and discuss the importance of continued emotional support. The social worker does not contact the Department of Children and Families because Ms. M is walking independently and not endorsing or exhibiting regressive behaviors. Ms. M also reports that she will ask her aunt to take care of the baby should ataxia recur. Her aunt reassures the social workers that she will encourage Ms. M to attend outpatient psy­chotherapy and will contact the social worker if she becomes concerned about Ms. M’s or the baby’s well-being.

During her postpartum obstetric visit, Ms. M is walking independently and does not exhibit or endorse neurologic symptoms. The social worker provides psychoeducation about the importance of outpatient psycho­therapy and schedules an initial appointment; Ms. M does not attend outpatient psychother­apy after discharge.

Bottom Line
Consider conversion disorder in obstetric patients who present with ataxia without a neurologic cause. Management involves a proactive and multidisciplinary approach that includes a thorough medical workup and assessment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy. Early identification and delivery of the diagnosis, destigmatization, and provision of appropriate psychiatric treatment can facilitate treatment success.

Disclosures
Dr. Byatt has received grant funding/support for this project from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR000160. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Toor reports no financial relationships with any company whose products are mentioned in this article or manufacturers of competing products.

CASE Difficulty walking
Ms. M, age 15, is a pregnant, Spanish-speaking Guatemalan woman who is brought to obstet­rics triage in a large academic medical center at 35 weeks gestational age. She complains of dizziness, tinnitus, left orbital headache, and difficulty walking.

The neurology service finds profound trun­cal ataxia, astasia-abasia, and buckling of the knees; a normal brain and spine MRI are not consistent with a neurologic etiology. Otolaryngology service evaluates Ms. M to rule out a cholesteatoma and suggests a head CT and endoscopy, which are normal.

Ms. M’s symptoms resolve after 3 days, although the gait disturbances persist. When no clear cause is found for her difficulty walk­ing, the psychiatry service is consulted to evalu­ate whether an underlying psychiatric disorder is contributing to symptoms.

What could be causing Ms. M’s symptoms?
   a) malingering
   b) factitious disorder
   c) undiagnosed neurologic disorder
   d) conversion disorder

The authors’ observations
Women are vulnerable to a variety of psy­chiatric illnesses during pregnancy¹ that have deleterious effects on mother, baby, and family.^2-6 Although there is a burgeoning literature on affective and anxiety disorders occurring in pregnancy, there is a dearth of information about somatoform disorders.


HISTORY Abandonment
Ms. M reports that, although her boyfriend deserted her after learning about the unexpected pregnancy, she will welcome the baby and looks forward to motherhood. She seems unaware of the responsibilities of being a mother.

Ms. M acknowledges a history of depression and self-harm a few years earlier, yet says she feels better now and thinks that psychiatric care is unnecessary. Because she does not endorse a history of trauma or symptoms suggesting an affective, anxiety, or psychotic illness, the psy­chiatrist does not recommend treatment with psychotropic medication. 

At age 5, Ms. M’s parents sent her to the United States with her aunt, hoping that she would have a better life than she would have had in Guatemala. Her aunt reports that Ms. M initially had difficulty adjusting to life in the United States without her parents, yet she has made substantial strides over the years and is now quite accustomed to the country. Her aunt describes Ms. M as an independent high school student who earns good grades.

During the interview, the psychiatrist observes that Ms. M exhibits childlike manner­isms, including sleeping with stuffed toys and coloring in Disney books with crayons. She also is indifferent to her gait difficulty, pregnancy, and psychosocial stressors. Her affect is incon­sistent with the content of her speech and she is alexithymic.

Ms. M’s aunt reports that her niece is becom­ing more dependent on her, which is not con­sistent with her baseline. Her aunt also notes that several years earlier, Ms. M’s nephew was diagnosed with a cholesteatoma after he pre­sented with similar symptoms.

The combination of (1) Ms. M’s clinical pre­sentation, which was causing her significant impairment in her social functioning, (2) the incompatibility of symptoms with any recog­nized neurologic and medical disease, and (3) prior family experience with cholesteatoma leads the consulting psychiatrist to suspect conversion disorder. Ms. M’s alexithymia, indif­ference to her symptoms, and recent aban­donment by the baby’s father also support a conversion disorder diagnosis.

From a psychodynamic perspective, the ataxia appears to be her way of protecting her­self from the abandonment she is experiencing by being left again to “stand alone” by her boy­friend as she had been when her parents sent her to the United States. Her regressive behav­ior could be her way of securing her aunt’s love and support.

The authors’ observations
This is the first case of psychogenic gait dis­turbance during pregnancy described in the literature. Authors have reported on pseu­dotoxemia,⁷ hyperemesis gravidarum,⁸ and pesudocyesis,9 yet there is a paucity of infor­mation on psychogenic gait disturbance during pregnancy. Ms. M’s case elucidates many of the clinical quandaries that occur when managing psychiatric illness—and, more specifically, conversion disorder— during pregnancy. Many women are hesi­tant to seek psychiatric treatment during pregnancy because of shame, stigma, and fear of loss of personal or parental rights^10,11; it is not surprising that emotionally dis­tressed women communicate their feel­ings or troubled thoughts through physical symptoms.

Likely diagnosis
Conversion disorder is the presence of neurologic symptoms in the absence of a neurologic diagnosis that fully explains those symptoms. Conversion disorder, previously known as hysteria, is called functional neurologic symptom disorder in DSM-5 (Box).¹² Symptoms are not feigned; instead, they represent “conver­sion” of emotional distress into neurologic symptoms.^13,14 Although misdiagnosing conversion disorder in patients with true neurologic disease is uncommon, clini­cians often are uncomfortable making the diagnosis until all medical causes have been ruled out.¹⁴ It is not always possible to find a psychological explanation for conversion disorder, but a history of child­hood abuse, particularly sexual abuse, could play a role.¹⁴

How would you treat Ms. M?
   a) destigmatize psychiatric illness and provide psychoeducation regarding treat­ment benefits
   b) identify and treat any comorbid psychiat­ric disorders
   c) maintain a proactive and multidisci­plinary approach that includes assess­ment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy
  d) all of the above


TREATMENT Close follow-up
The psychiatrist recommends continued close psychiatric follow-up as well as multidisci­plinary involvement, including physical ther­apy, neurology, and obstetrics.

Ms. M initially is resistant to psychiatric follow-up because she says that “people on the street” told her that, if she saw a psychia­trist, her baby would be taken away. After the psychiatrist explains that it is unlikely her baby would be taken away, Ms. M immediately appears relieved, smiles, and readily agrees to outpatient psychotherapy.

Over the next 24 hours, she continues to work with a physical therapist and her gait sig­nificantly improves. She is discharged home 2 days later with a walking aid (Zimmer frame) for assistance.

Four days later, however, Ms. M is readmit­ted with worsening ataxia. Her aunt reports that, at home, Ms. M’s regressed behaviors are worsening; she is sleeping in bed with her and had several episodes of enuresis at home.

Ms. M continues to deny psychiatric symp­toms or anxiety about the delivery. Although she shows some improvement when work­ing with physical therapists, they note that Ms. M is still unable to ambulate or stand on her own. The psychiatrist is increasingly con­cerned about her regressed behavior and con­tinued ataxia.

A family meeting is held and the psychia­trist and social worker educate Ms. M and her aunt about conversion disorder, including how some emotionally distressed women communicate their feelings or troubled thoughts through physical symptoms and how that may apply to Ms. M. During the meeting, the team also destigmatizes psy­chiatric illness and treatment and provides psychoeducation regarding its benefits. The psychiatrist and social worker also provide a psychodynamic interpretation that her ataxia could be a way of protecting herself against the abandonment she is experiencing by being left to “stand alone” by her boyfriend— as she had been when her parents sent her to the United States, and that her behavior could be her way of securing her aunt’s love and support.Ms. M and her aunt both readily agree with this interpretation. The aunt notes that her niece is more anxious about motherhood than she acknowledges and is concerned that Ms. M expects her to be the primary care­giver for the baby. Those present note that Ms. M is becoming increasingly dependent on her aunt, and that it is important for her to retain her independence, especially once she becomes a mother.

Ms. M immediately begins to display more affect; she smiles and reports feeling relieved. Similar to the previous admission, her gait sig­nificantly improves over the next 2 days and she is discharged home with a walking aid.

The authors’ observations
A broad differential diagnosis and early multidisciplinary involvement might facilitate earlier diagnosis and treatment.¹⁶ Assessment of psychosocial stressors in the patient’s personal and family life, includ­ing circumstances around the pregnancy and the meaning of motherhood, as well as investigation of what the patient may gain from the sick role, are paramount. In Ms. M’s case, cultural background, sepa­ration from her parents at a young age, and recent abandonment by her boyfriend have contributed to her inability to “stand alone,” which manifested as ataxia. Young age, regressed behavior, and her minimi­zation of stressors also point to her dif­ficulty acknowledging and coping with psychosocial stressors.

Successful delivery of the diagnosis is key to treatment success. After building a therapeutic alliance, a multidisciplinary discussion should take place that allows the patient to understand the diagnosis and treatment plan.^17,18 The patient and family should be reassured that the fetus is healthy and all organic causes of symptoms have been investigated.¹⁷ Although man­agement of conversion disorder during pregnancy is similar to that in non-preg­nant women, several additional avenues of investigation should be considered:
   • Explore the psychodynamic basis of the disorder and the role of the pregnancy and motherhood.
   • Identify any comorbid psychiatric disorders, particularly those specific to pregnancy or the postpartum period.
   • Because of the shame and stigma associated with seeking psychiatric treat­ment during pregnancy,^10,11 it is impera­tive to destigmatize treatment and provide psychoeducation regarding its benefits.

A treatment plan can then be developed that involves psychotherapy, psychoedu­cation, stress management, and, when appropriate, pharmacotherapy.¹⁷

Providing psychoeducation about postpartum depression and other perina­tal psychiatric illness could be beneficial. Physical therapy often is culturally accept­able and can help re-establish healthy patterns of motor function.¹⁹ Ms. M’s gait  showed some improvement with physical therapy as part of the multidisciplinary approach, which also should include a thorough medical workup. Appropriate psychiatric treatment can help patients give up the sick role and return to their previous level of functioning.¹⁷

Maintain close communication with the outpatient perinatal care team as they mon­itor the patient’s parenting capacity. The outpatient perinatal care team also should engage pregnant or postpartum women in prioritizing their emotional well-being and encourage outpatient mental health treatment. Despite a dearth of data on the regressive symptoms and prognosis for future pregnancies, it is important to mon­itor maternal capacity and discuss the pos­sibility of symptom recurrence.


OUTCOME Healthy baby
Three days later, Ms. M returns in labor with improved gait yet still using a walking aid. She has a normal vaginal delivery of a healthy baby boy at 37 weeks’ gestational age.

After the birth, Ms. M reports feeling well and enjoying motherhood, and denies psy­chiatric symptoms. She is ambulating without assistance within hours of delivery. This spon­taneous resolution of symptoms could have been because of the psychodynamically ori­ented multidisciplinary approach to her care, which may have helped her realize that she did not have to “stand alone” as she embarked on motherhood.

Before being discharged home, Ms. M and her aunt meet with the inpatient obstetric social worker to assess Ms. M’s ability to care for the baby and discuss the importance of continued emotional support. The social worker does not contact the Department of Children and Families because Ms. M is walking independently and not endorsing or exhibiting regressive behaviors. Ms. M also reports that she will ask her aunt to take care of the baby should ataxia recur. Her aunt reassures the social workers that she will encourage Ms. M to attend outpatient psy­chotherapy and will contact the social worker if she becomes concerned about Ms. M’s or the baby’s well-being.

During her postpartum obstetric visit, Ms. M is walking independently and does not exhibit or endorse neurologic symptoms. The social worker provides psychoeducation about the importance of outpatient psycho­therapy and schedules an initial appointment; Ms. M does not attend outpatient psychother­apy after discharge.

Bottom Line
Consider conversion disorder in obstetric patients who present with ataxia without a neurologic cause. Management involves a proactive and multidisciplinary approach that includes a thorough medical workup and assessment of psychosocial stressors and psychodynamic factors, particularly those related to the pregnancy. Early identification and delivery of the diagnosis, destigmatization, and provision of appropriate psychiatric treatment can facilitate treatment success.

Disclosures
Dr. Byatt has received grant funding/support for this project from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR000160. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Toor reports no financial relationships with any company whose products are mentioned in this article or manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Akathisia—from the Greek for “inability to sit”—is a neuropsychiatric syndrome characterized by subjective and objective psychomotor restlessness. Patients typi­cally experience feelings of unease, inner restlessness mainly involving the legs, and a compulsion to move. Most engage in repetitive movement. They might swing or cross and uncross their legs, shift from one foot to the other, continuously pace, or persistently fidget.

In clinical settings, akathisia usually is a side effect of medi­cation. Antipsychotics, serotonin reuptake inhibitors, and buspirone are common triggers, but akathisia also has been associated with some antiemetics, preoperative sedatives, calcium channel blockers, and antivertigo agents. It also can be caused by withdrawal from an antipsychotic or related to a substance use disorder, especially cocaine. Akathisia can be acute or chronic, occurring in a tardive form with symptoms that last >6 months.^1-3

Much isn’t known about drug-induced akathisia
Our understanding of the pathophysiology of akathisia is incomplete. Some have suggested that it results from an imbal­ance between the dopaminergic/cholinergic and dopaminer­gic/serotonergic systems⁴; others, that the cause is a mismatch between the core and the shell of the nucleus accumbens, due in part to overstimulation of the locus ceruleus.⁵

More recently, researchers established a positive asso­ciation between higher scores on the Liverpool University Neuroleptic Side Effects Rating Scale and D2/D3 receptor occupancy in the ventral striatum (nucleus accumbens and olfactory tubercle).⁶ The D2/D3 receptor occupancy model might explain withdrawal symptoms associated with cocaine,⁷ as well as rela­tive worsening of symptoms after tapering or discontinuing stimulants in attention-deficit/hyperactivity disorder (ADHD).

Elements of a clinical evaluation
When akathisia is suspected, evaluation by a clinician familiar with its phenom­enology is crucial. A validated tool, such as the Barnes Akathisia Rating Scale (at out cometracker.org/library/BAS.pdf) can aid in the detection and assessment of severity.⁸

In evaluating patients, keep in mind that the inner restlessness that characterizes akathisia can affect the trunk, hands, and arms, as well as the legs, and can cause dys­phoria and anxiety. Akathisia has been linked to an increased likelihood of developing sui­cidal ideation and behavior.⁹

Less common subjective symptoms include rage, fear, nausea, and worsening of psychotic symptoms. Because of its asso­ciation with aggression and agitation, drug-induced akathisia has been cited—with little success—as the basis for an insanity defense by people who have committed a violent act.¹⁰

Or is akathisia another psychiatric disorder?
Akathisia might go undetected for several reasons. One key factor: Its symptoms resem­ble and often overlap with those of other psy­chiatric disorders, such as mania, psychosis, agitated depression, and ADHD. In addition, akathisia often occurs concurrently with, and is masked by, akinesia, a common extrapy­ramidal side effect of many antipsychotics. Such patients might have the inner feeling of restlessness and urge to move but do not exhibit characteristic limb movements. In some cases, cognitive or intellectual limita­tions prevent patients from communicating the inner turmoil they feel.¹¹

Medication nonadherence further compli­cates the picture, sometimes prompting a cli­nician to increase the dosage of the drug that is causing akathisia (Box 1¹²).

Managing drug-induced akathisia
Akathisia usually resolves when the drug causing it is discontinued; decreasing the dosage might alleviate the symptoms. Whenever akathisia is detected, careful revision of the current drug regimen— substituting an antipsychotic with a lower prevalence of akathisia, for example— should be considered (Box 2^13-16). Treatment of drug-induced akathisia, which should be tailored to the patient’s psycho­pathology and comorbidities, is needed as well (Table^17-25).

Low-dose mirtazapine (15 mg/d) was found to be as effective as propranolol, 80 mg/d, in a placebo-controlled study, and to be more effective than a beta blocker in treating akathisia induced by a first-gener­ation antipsychotic. The authors concluded that both propranolol and mirtazapine should be first-line therapy.²³ Others have suggested that these results be interpreted with caution because mirtazapine (at a higher dosage) has been linked to akathi­sia.³³ Mirtazapine blocks α-adrenergic receptors, resulting in antagonism of 5-HT2 and 5-HT3 receptors and consequent enhancement of 5-HT1A serotonergic trans­mission.³⁴ In one study, it was shown to reduce binding of the D2/D3 receptor ago­nist quinpirole.³⁵

Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.³⁷ The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.^14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used³⁸; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.³⁹

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.²⁵

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.⁴⁰ Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,^12,17,33 their association with cognitive side effects suggests a need for caution.¹⁸

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms^2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.⁴¹

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.⁴² However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.⁴³ Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.¹⁹

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.¹⁷ Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.⁴⁴

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,^1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.⁴⁵ D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.²²


Bottom Line
Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names
Aripiprazole • Abilify                  Haloperidol • Haldol
Baclofen • Lioresal                     Iloperidone • Fanapt
Benztropine • Cogentin              Lurasidone • Latuda
Biperiden • Akineton                  Mirtazapine • Remeron
Buspirone • BuSpar                   Pramipexole • Mirapex
Cabergoline • Dostinex              Propranolol • Inderal
Carbamazepine • Tegretol          Quetiapine • Seroquel
Clonazepam • Klonopin              Ropinirole • Requip
Clonidine • Catapres                  Rotigotine • Neupro
Clozapine • Clozaril                    Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin          Trihexyphenidyl • Artane
Diphenhydramine • Benadryl       Valproic acid • Depakene
Gabapentin • Neurontin               Zolmitriptan • Zomig


Acknowledgement
Mandy Evans, MD, assisted with editing the manuscript of this article.

Disclosure
Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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

Police bring Ms. R, age 35, to the psychiat­ric ER after they find her asleep in a park. She is awake but drowsy, and states that she has a history of bipolar disorder. She claims that she had been stable on valproic acid (VPA), 1,500 mg/d, bupropion XL, 300 mg/d, quetiap­ine, 400 mg/d, and trazodone, 100 mg/d, until 2 weeks ago, when her best friend died and she stopped taking her medications all together. The previous evening, feeling “alone, hopeless, and sad,” she attempted suicide by ingesting a handful of VPA and clonazepam, obtained from a friend, and 2 liters of vodka. She complains of nausea, vomiting, and abdominal pain. Ele­vated laboratory chemistries included aspartate aminotransferase (AST), 220 U/L; alanine ami­notransferase (ALT), 182 U/L; alkaline phospha­tase (AP), 75 U/L; γ-glutamyltransferase (GGT), 104 U/L; total bilirubin, 1.4 mg/dL; and an ele­vated VPA serum concentration of 152 μg/mL.

Drug-induced hepatotoxicity accounts for approximately 50% of acute liver failure cases, and almost 10% of liver transplants in some facilities.¹ The incidence of drug-induced hepatotoxicity is between 0.001% and 0.1% in patients on standard medication doses.² Drug-induced hepatotoxicity is char­acterized by:
   • abnormalities in laboratory parameters (hepatocellular, cholestatic, or mixed)
   • mechanisms of toxicity (direct, immune-mediated, idiosyncratic, mito­chondrial toxicity)
   • liver biopsy histology (steatosis, sinu­soidal obstruction syndrome).3

Liver function test results of hepatocel­lular injury are characterized by ALT ele­vation and minimal AP elevation, whereas cholestatic injury manifests as high AP. Table 1³ categorizes psychotropics based on type of liver injury and how each injury manifest in liver function tests. Delayed idiosyncratic reactions occur after tak­ing the drug, whereas direct toxicities are dose-dependent and more predictable. By definition, a clinically significant hepato­toxicity is associated with an ALT >3 times the upper limit of normal.³

VPA-induced liver injury occurs in approximately 1 in 37,000 persons taking the drug.⁴ Patients at an increased risk of VPA-induced liver injury include:
   • children
   • patients with mitochondrial enzyme deficiencies
   • Reye’s syndrome
   • Friedreich’s ataxia
   • polypharmacy patients
   • patients with a sibling who has experi­enced VPA toxicity.⁴

Benign enzyme elevations occur in approximately 20% of patients taking VPA.⁵ In Ms. R’s case, concomitant VPA, clonazepam, and alcohol may have led to elevations in ALT, AST, and GGT. Her nausea, vomiting, and abdominal pain are consistent with hepatic dysfunction.

Carnitine is effective in increasing sur­vival of patients with VPA-induced hepa­totoxicity.⁴ Because Ms. R is symptomatic, discontinuing VPA and administering IV L-carnitine is warranted.⁵ L-carnitine can be initiated at 100 mg/kg as an IV bolus, followed by 50 mg/kg as an IV infusion every 8 hours, with a maximum dosage of 3,000 mg.⁶ Patients may require sev­eral days of therapy based on symptoms. L-carnitine should be continued until a patient shows clinical improvement, such as decreases in ALT and AST.

Ms. R experienced a VPA-induced hepa­totoxic reaction. However, continuous mon­itoring is appropriate for all patients who are prescribed any potentially hepatotoxic psychotropic, especially after hepatic inju­ries resolve. This includes mood stabilizers, antipsychotics, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibi­tors, especially when given concomitantly with other hepatotoxic agents.

Table 2 lists dosing recommen­dations for commonly used psychotro­pics in patients with hepatic impairment. Among mood stabilizers, carbamazepine and VPA are associated with the highest incidence of hepatotoxicity.² A follow-up study of more than 1,000,000 VPA prescrip­tions found 29 cases of fatal hepatotoxicity in a 7-year period.⁷ Although there are case reports of hepatotoxicity with oxcarbaze­pine, it may have a better liver safety profile than carbamazepine.² Hepatotoxicity with lamotrigine is rare, although fatal cases have been reported.⁵

When initiating an antipsychotic, a tem­porary, benign increase in liver enzymes can be expected, but typically discontinuation is unnecessary.² Phenothiazines in particular can cause increases in liver enzymes in 20% of patients.² Hepatotoxicity with benzodi­azepines is infrequent, with a few cases of cholestatic injury reported with diazepam, chlordiazepoxide, and flurazepam.²

SSRIs are relatively safe; incidents of hepatic injury are rare. Among SSRIs, parox­etine is most frequently associated with hep­atotoxicity. Abnormal liver function tests have been observed with fluoxetine (0.5% of long-term recipients) and other SSRIs.^1,2,4

Among antidepressants with dual serotonergic action, nefazodone carries a black-box warning for hepatotoxicity and is used rarely, whereas trazodone is not regarded as hepatotoxic.² Antidepressants with dual norepinephrine and serotonin reuptake inhibitor properties carry a higher risk of liver injury, especially duloxetine. Hepatocellular, cholestatic, and mixed types of hepatotoxicity are associated with duloxetine-induced hepatotoxicity.²

Monitoring recommendations
Before prescribing potentially hepatotoxic medications, order baseline liver function tests. During therapy, periodic liver func­tion monitoring is recommended. Elevated transaminase concentrations (>3 × the upper limit of normal), bilirubin (>2 × the upper limit of normal), and prolonged pro­thrombin times are indicators of hepatic injury.² Caution should be taken to prevent polypharmacy with multiple hepatotoxic medications and over-the-counter use of hepatotoxic drugs and supplements.

When choosing a psychotropic, take into account patient-specific factors, such as underlying liver disease and alcohol con­sumption. Patients on potentially hepato­toxic medications should be counseled to recognize and report symptoms of liver dysfunction, including nausea, vomiting, jaundice, and lower-extremity edema.² If liver injury occurs, modify therapy with the potential offending agent and check liver function periodically.

Related Resourcesa
• Bleibel W, Kim S, D’Silva K, et al. Drug-induced liver injury: review article. Dig Dis Sci. 2007;52(10):2463-2471.
• U.S. National Library of Medicine. LiverTox. National Institute of Health. www.livertox.nih.gov.

Drug Brand Names
Amitriptyline • Elavil                                       Lurasidone • Latuda
Molindone • Moban                                         Molindone • Moban
Aripiprazole • Abilify                                       Nefazodone • Serzone
Asenapine • Saphris                                       Nortriptyline • Pamelor
Bupropion XL • Wellbutrin XL                          Olanzapine • Zyprexa
Citalopram • Celexa                                       Oxcarbazepine • Trileptal
Carbamazepine • Tegretol                               Paroxetine • Paxil
Chlordiazepoxide • Librium                              Perphenazine • Trilafon
Chlorpromazine • Thorazine                             Phenobarbital • Luminal
Clonazepam • Klonopin                                   Phenytoin • Dilantin
Clozapine • Clozaril                                         Quetiapine • Seroquel
Desvenlafaxine • Pristiq                                   Risperidone • Risperdal
Diazepam • Valium                                         Sertraline • Zoloft
Duloxetine • Cymbalta                                    Thiothixene • Navane
Escitalopram • Lexapro                                   Trazodone • Desyrel
Fluoxetine • Prozac                                         Trifluoperazine • Stelazine
Fluphenazine • Prolixin                                    Topiramate • Topamax
Flurazepam • Dalmane                                    Valproic acid • Depakote
Haloperidol • Haldol                                        Venlafaxine • Effexor
Iloperidone • Fanapt                                       Ziprasidone • Geodon
Lamotrigine • Lamictal
Levocarnitine • L-carnitine

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