BRIEF REPORT
Lactulose-Associated Lithium Toxicity A Case Series Andrew Bregman, MD, MAS,* Kathy Fritz, MS, RPh,† and Glen L. Xiong, MD* Background: Lactulose is commonly used for constipation and hepatic encephalopathy. Its adverse effects of dehydration and serum electrolyte imbalances are widely known. Objective: This study aimed to describe a case series of 3 patients receiving lactulose who developed lithium toxicity. Methods: The authors described a case series of 3 patients admitted to a large county psychiatric hospital who developed lithium toxicity while taking lactulose for constipation or hyperammonemia. Results: In all 3 cases of lithium toxicity, the patients were prescribed with lithium for acute mania and lactulose for constipation or hyperammonemia. One case required the patient to be transferred to a local emergency department for further treatment. Conclusions: This case series shows the interaction between lithium and lactulose. It is postulated that lactulose’s effects of volume depletion can lead to poor renal excretion of lithium. Key Words: lithium toxicity, lactulose, drug interaction (J Clin Psychopharmacol 2014;34: 742–743)
S
ince its approval by the Food and Drug Administration in 1970,1 lithium has proven to be one of the most effective therapies for bipolar disorder.2 Yet, despite its classification as a first-line treatment,3 its narrow therapeutic index, drug-to-drug interactions, and the potentially severe consequences of lithium toxicity make it a challenging medication to prescribe and manage. In an acute overdose, lithium can have serious gastrointestinal, cardiac, and neurologic consequences. The effects of toxicity include vomiting, diarrhea, cardiac arrhythmia, ataxia, confusion, tremor, seizure, and encephalopathy. Excreted almost entirely by the kidneys,4 nearly any cause of volume depletion (dehydration) or renal impairment can lead to increased serum lithium levels.5 A large body of evidence has documented the interactions between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, and angiotensinconverting enzyme inhibitors.6–8 To our knowledge, however, no published report has described the interaction between lithium and laxative use. Constipation is a common complaint in both inpatient and outpatient settings, and especially in patients on antipsychotics.9 In the hospital, bowel regimens are a key component of patient care. Osmotic laxatives are frequently used to treat constipation. They are often preferred for patients who decline suppositories and enemas. Although the products that are classified as osmotic laxatives are varied, in general, they all work by increasing the
From the *Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California at Davis; and †Sacramento County Mental Health Treatment Center, Sacramento, CA. Received March 20, 2014; accepted after revision June 8, 2014. Reprints: Glen L. Xiong, MD, Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California at Davis, 2230 Stockton Blvd, Sacramento, CA 95817 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000206
742
www.psychopharmacology.com
amount of water that is secreted within the intestines. This effect helps to produce softer, easier-to-pass stool. Some osmotic laxatives are available over the counter, whereas others require a prescription. Lactulose, a disaccharide osmotic laxative, is frequently prescribed for constipation and hyperammonemia caused by hepatic encephalopathy. Lactulose is not absorbed by the digestive system and thus is available to be metabolized by microbes in the intestines. This fermentation process produces fatty acids that pull water into the colon and increase the speed of intestinal contractions.10 Presumably through gastrointestinal water secretion and consequent increased proximal tubule water and lithium reabsorption, it is our belief that coadministration of lithium with lactulose can lead to increased serum lithium concentrations. Here, we report 3 cases of supratherapeutic serum lithium concentrations, defined as levels greater than 1.5 mEq/L, recorded at a community psychiatric hospital. The data were gathered by a retrospective review of adverse events from 2010 to 2013. For each case reported later, lactulose was coadministered with lithium at some point during the patient’s hospitalization. After each case, the Naranjo probability scale11 was applied to better assess for an adverse drug reaction.
CASES Case 1
“Mr B,” a 47-year-old conserved man, transferred to our psychiatric facility after a self-inflicted stab wound to the abdomen requiring operative repair. He carried a diagnosis of schizoaffective disorder with numerous past self-injurious behaviors. On arrival, he was minimally engaged and demonstrated poor insight, giving only brief, inconsistent reasoning behind his suicide attempt. From the outside hospital, he was on 300 mg of lithium twice daily (BID), 1500 mg of divalproate extended release nightly, and 400 mg of quetiapine BID. These medications were continued on admission and he was started on 30 mL of lactulose BID (10 g/15 mL solution) for constipation. After 2 doses of lactulose, the medication was discontinued because of reported diarrhea, and on hospital day 3, his lithium level was found to be 1.6 mEq/L with a serum creatinine level of 0.57 mg/dL (reference range, 0.50–1.10 mg/dL). He was given no antihypertensive medications or NSAID. He demonstrated no physical signs of lithium toxicity and no changes were made other than the discontinued lactulose. Repeated lithium level was 1.2 mEq/L and no adverse outcomes were reported. This case received a 6 on the Naranjo adverse drug reaction probability scale.
Case 2
“Ms E,” a 45-year-old woman with a history of depression treated with a selective serotonin reuptake inhibitor, was admitted to the psychiatric hospital with paranoia, grandiosity, pressured speech, flight of ideas, irritability, and suicidal ideation. The patient was determined to be in an acute manic episode and diagnosed with bipolar type I with psychotic features. Her baseline serum
Journal of Clinical Psychopharmacology • Volume 34, Number 6, December 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology • Volume 34, Number 6, December 2014
creatinine level was measured at 0.76 mg/dL. She was started on a combination of 300 mg of lithium carbonate orally (PO) BID and 2 mg of risperidone PO nightly for mania as well as 25 mg of lisinopril and 25 mg of hydrochlorothiazide daily for hypertension. Although the potential drug-to-drug interactions between the antihypertensives and lithium were alerted to both the psychiatric team and the medical provider, the decision was to start a low dose and carefully monitor her lithium level, rather than to discontinue these medications. Five days after the initiation of the lithium therapy, her lithium level returned at 0.5 mEq/L. Because she still appeared manic on examination, her lithium dose was increased to 450 mg in the morning and 600 mg at night. Two days after this increase, she was started on 30 mL of lactulose for constipation. After receiving 3 doses for 3 days, the patient developed 3 episodes of diarrhea and lactulose was discontinued. She was not given any NSAID medications. Her repeated lithium level 9 days after the increase to 1050 mg daily was 2.4 mEq/L. She reported mild fatigue but no tremors, change in cognition, or other signs of overt lithium toxicity. She was sent to the nearest emergency department where she was admitted and observed in the hospital for 3 days. Her lithium therapy and antihypertensives were stopped, she received more than 4 L of normal saline, and she was discharged with a lithium level of 0.6 mEq/L. This case received a 3 on the Naranjo probability scale.
Case 3
“Ms O,” a 48-year-old woman with a history of bipolar disorder, was brought to the emergency department after having multiple “fainting spells” while visiting her outpatient psychiatrist. The patient had reportedly stopped her lithium home medication 1 week prior and her lithium level in the emergency department was 0.1 mEq/L, with a baseline serum creatinine level of 0.75 mg/dL. At that time, she had significant affective lability, pressured speech, and delusional thought content. She was transferred to our psychiatric facility where she was determined to be in an acute manic episode and started on 600 mg of lithium PO BID and 400 mg of quetiapine BID. She was also found to be hypertensive and started on 20 mg of benazepril daily. On hospital day 5, her lithium level returned to 0.8 mEq/L and her dose was increased to 900 mg BID. On hospital day 11, the patient received 5 doses of 30 mL of lactulose for constipation for a 2-day period. On hospital day 16, she developed a fine tremor and drowsiness and her lithium level was 1.6 mEq/L. Her dose was reduced to 300 mg in the morning and 600 mg in the evening, and her lithium level returned to normal at 0.8 mEq/L. No NSAIDs were prescribed for this patient. This case received a 4 on the Naranjo probability scale.
DISCUSSION This case series of 3 patients with lithium toxicity after concurrent lactulose use adds to the data of potential risk factors for lithium toxicity. In each case, lactulose was added during admission for a brief period shortly before the supratherapeutic lithium levels were drawn. After applying the Naranjo adverse drug reaction probability scale to each vignette, we can further clarify the likelihood of this drug-to-drug interaction. Case 1 is the most convincing with a score of 6, classifying the event as a “probable” adverse drug reaction. Both case 2 and case 3 were classified as “possible” adverse drug reaction events with scores of 3 and 4, respectively. There are several limitations in this series,
© 2014 Lippincott Williams & Wilkins
Lactulose-Associated Lithium Toxicity
however. In the first case, patient Mr B, there was no baseline creatinine level on admission, but his serum creatinine was normal at the time of his supratherapeutic lithium level. Although both Ms E (case 2) and Ms O (case 3) were also prescribed with an angiotensin-converting enzyme inhibitor, no changes to their antihypertensive medications were made during their hospitalizations and both had nontoxic lithium levels before the addition of lactulose. Clinicians should be alerted to the potential for increasing serum lithium levels in patients who are prescribed with lactulose concurrently with lithium. The most likely mechanism for this observed interaction is through increased gastrointestinal water loss and volume depletion. Decreased circulating volume stimulates proximal tubule sodium reabsorption, which results in an increase in proximal lithium reabsorption and serum lithium levels. This theory can then be reasonably expanded to other potent osmotic laxatives, as well, because osmotic laxatives can cause severe dehydration.12 Whether in the hospital or in psychiatric inpatient or outpatient settings, careful monitoring of patients on concurrent lithium and laxative therapy is necessary, with particular attention needed to maintain adequate patient hydration. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. REFERENCES 1. Mitchell PB, Hadzi-Pavlovic D. Lithium treatment for bipolar disorder. Bull World Health Organ. 2000;78:515–517. 2. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217–222. 3. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159:1–50. 4. Price LH, Heninger GR. Lithium in the treatment of mood disorders. N Engl J Med. 1994;331:591–598. 5. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. 1999;10:666–674. 6. Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003;64:1328–1334. 7. Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use. JAMA. 1979;241:1134. 8. Finley PR, O'Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol. 1996;16:68–71. 9. De Hert M, Dockx L, Bernagie C, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC Gastroenterol. 2011;11:17. 10. Riggio O, Varriale M, Testore GP, et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol. 1990;12:433–436. 11. Naranjo CA, Busto U, Sellers M, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245. 12. Baker EH, Sandle GI. Complications of laxative abuse. Annu Rev Med. 1996;47:127–134.
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
743
Lactulose-Associated Lithium Toxicity A Case Series Andrew Bregman, MD, MAS,* Kathy Fritz, MS, RPh,† and Glen L. Xiong, MD* Background: Lactulose is commonly used for constipation and hepatic encephalopathy. Its adverse effects of dehydration and serum electrolyte imbalances are widely known. Objective: This study aimed to describe a case series of 3 patients receiving lactulose who developed lithium toxicity. Methods: The authors described a case series of 3 patients admitted to a large county psychiatric hospital who developed lithium toxicity while taking lactulose for constipation or hyperammonemia. Results: In all 3 cases of lithium toxicity, the patients were prescribed with lithium for acute mania and lactulose for constipation or hyperammonemia. One case required the patient to be transferred to a local emergency department for further treatment. Conclusions: This case series shows the interaction between lithium and lactulose. It is postulated that lactulose’s effects of volume depletion can lead to poor renal excretion of lithium. Key Words: lithium toxicity, lactulose, drug interaction (J Clin Psychopharmacol 2014;34: 742–743)
S
ince its approval by the Food and Drug Administration in 1970,1 lithium has proven to be one of the most effective therapies for bipolar disorder.2 Yet, despite its classification as a first-line treatment,3 its narrow therapeutic index, drug-to-drug interactions, and the potentially severe consequences of lithium toxicity make it a challenging medication to prescribe and manage. In an acute overdose, lithium can have serious gastrointestinal, cardiac, and neurologic consequences. The effects of toxicity include vomiting, diarrhea, cardiac arrhythmia, ataxia, confusion, tremor, seizure, and encephalopathy. Excreted almost entirely by the kidneys,4 nearly any cause of volume depletion (dehydration) or renal impairment can lead to increased serum lithium levels.5 A large body of evidence has documented the interactions between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, and angiotensinconverting enzyme inhibitors.6–8 To our knowledge, however, no published report has described the interaction between lithium and laxative use. Constipation is a common complaint in both inpatient and outpatient settings, and especially in patients on antipsychotics.9 In the hospital, bowel regimens are a key component of patient care. Osmotic laxatives are frequently used to treat constipation. They are often preferred for patients who decline suppositories and enemas. Although the products that are classified as osmotic laxatives are varied, in general, they all work by increasing the
From the *Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California at Davis; and †Sacramento County Mental Health Treatment Center, Sacramento, CA. Received March 20, 2014; accepted after revision June 8, 2014. Reprints: Glen L. Xiong, MD, Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California at Davis, 2230 Stockton Blvd, Sacramento, CA 95817 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000206
742
www.psychopharmacology.com
amount of water that is secreted within the intestines. This effect helps to produce softer, easier-to-pass stool. Some osmotic laxatives are available over the counter, whereas others require a prescription. Lactulose, a disaccharide osmotic laxative, is frequently prescribed for constipation and hyperammonemia caused by hepatic encephalopathy. Lactulose is not absorbed by the digestive system and thus is available to be metabolized by microbes in the intestines. This fermentation process produces fatty acids that pull water into the colon and increase the speed of intestinal contractions.10 Presumably through gastrointestinal water secretion and consequent increased proximal tubule water and lithium reabsorption, it is our belief that coadministration of lithium with lactulose can lead to increased serum lithium concentrations. Here, we report 3 cases of supratherapeutic serum lithium concentrations, defined as levels greater than 1.5 mEq/L, recorded at a community psychiatric hospital. The data were gathered by a retrospective review of adverse events from 2010 to 2013. For each case reported later, lactulose was coadministered with lithium at some point during the patient’s hospitalization. After each case, the Naranjo probability scale11 was applied to better assess for an adverse drug reaction.
CASES Case 1
“Mr B,” a 47-year-old conserved man, transferred to our psychiatric facility after a self-inflicted stab wound to the abdomen requiring operative repair. He carried a diagnosis of schizoaffective disorder with numerous past self-injurious behaviors. On arrival, he was minimally engaged and demonstrated poor insight, giving only brief, inconsistent reasoning behind his suicide attempt. From the outside hospital, he was on 300 mg of lithium twice daily (BID), 1500 mg of divalproate extended release nightly, and 400 mg of quetiapine BID. These medications were continued on admission and he was started on 30 mL of lactulose BID (10 g/15 mL solution) for constipation. After 2 doses of lactulose, the medication was discontinued because of reported diarrhea, and on hospital day 3, his lithium level was found to be 1.6 mEq/L with a serum creatinine level of 0.57 mg/dL (reference range, 0.50–1.10 mg/dL). He was given no antihypertensive medications or NSAID. He demonstrated no physical signs of lithium toxicity and no changes were made other than the discontinued lactulose. Repeated lithium level was 1.2 mEq/L and no adverse outcomes were reported. This case received a 6 on the Naranjo adverse drug reaction probability scale.
Case 2
“Ms E,” a 45-year-old woman with a history of depression treated with a selective serotonin reuptake inhibitor, was admitted to the psychiatric hospital with paranoia, grandiosity, pressured speech, flight of ideas, irritability, and suicidal ideation. The patient was determined to be in an acute manic episode and diagnosed with bipolar type I with psychotic features. Her baseline serum
Journal of Clinical Psychopharmacology • Volume 34, Number 6, December 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology • Volume 34, Number 6, December 2014
creatinine level was measured at 0.76 mg/dL. She was started on a combination of 300 mg of lithium carbonate orally (PO) BID and 2 mg of risperidone PO nightly for mania as well as 25 mg of lisinopril and 25 mg of hydrochlorothiazide daily for hypertension. Although the potential drug-to-drug interactions between the antihypertensives and lithium were alerted to both the psychiatric team and the medical provider, the decision was to start a low dose and carefully monitor her lithium level, rather than to discontinue these medications. Five days after the initiation of the lithium therapy, her lithium level returned at 0.5 mEq/L. Because she still appeared manic on examination, her lithium dose was increased to 450 mg in the morning and 600 mg at night. Two days after this increase, she was started on 30 mL of lactulose for constipation. After receiving 3 doses for 3 days, the patient developed 3 episodes of diarrhea and lactulose was discontinued. She was not given any NSAID medications. Her repeated lithium level 9 days after the increase to 1050 mg daily was 2.4 mEq/L. She reported mild fatigue but no tremors, change in cognition, or other signs of overt lithium toxicity. She was sent to the nearest emergency department where she was admitted and observed in the hospital for 3 days. Her lithium therapy and antihypertensives were stopped, she received more than 4 L of normal saline, and she was discharged with a lithium level of 0.6 mEq/L. This case received a 3 on the Naranjo probability scale.
Case 3
“Ms O,” a 48-year-old woman with a history of bipolar disorder, was brought to the emergency department after having multiple “fainting spells” while visiting her outpatient psychiatrist. The patient had reportedly stopped her lithium home medication 1 week prior and her lithium level in the emergency department was 0.1 mEq/L, with a baseline serum creatinine level of 0.75 mg/dL. At that time, she had significant affective lability, pressured speech, and delusional thought content. She was transferred to our psychiatric facility where she was determined to be in an acute manic episode and started on 600 mg of lithium PO BID and 400 mg of quetiapine BID. She was also found to be hypertensive and started on 20 mg of benazepril daily. On hospital day 5, her lithium level returned to 0.8 mEq/L and her dose was increased to 900 mg BID. On hospital day 11, the patient received 5 doses of 30 mL of lactulose for constipation for a 2-day period. On hospital day 16, she developed a fine tremor and drowsiness and her lithium level was 1.6 mEq/L. Her dose was reduced to 300 mg in the morning and 600 mg in the evening, and her lithium level returned to normal at 0.8 mEq/L. No NSAIDs were prescribed for this patient. This case received a 4 on the Naranjo probability scale.
DISCUSSION This case series of 3 patients with lithium toxicity after concurrent lactulose use adds to the data of potential risk factors for lithium toxicity. In each case, lactulose was added during admission for a brief period shortly before the supratherapeutic lithium levels were drawn. After applying the Naranjo adverse drug reaction probability scale to each vignette, we can further clarify the likelihood of this drug-to-drug interaction. Case 1 is the most convincing with a score of 6, classifying the event as a “probable” adverse drug reaction. Both case 2 and case 3 were classified as “possible” adverse drug reaction events with scores of 3 and 4, respectively. There are several limitations in this series,
© 2014 Lippincott Williams & Wilkins
Lactulose-Associated Lithium Toxicity
however. In the first case, patient Mr B, there was no baseline creatinine level on admission, but his serum creatinine was normal at the time of his supratherapeutic lithium level. Although both Ms E (case 2) and Ms O (case 3) were also prescribed with an angiotensin-converting enzyme inhibitor, no changes to their antihypertensive medications were made during their hospitalizations and both had nontoxic lithium levels before the addition of lactulose. Clinicians should be alerted to the potential for increasing serum lithium levels in patients who are prescribed with lactulose concurrently with lithium. The most likely mechanism for this observed interaction is through increased gastrointestinal water loss and volume depletion. Decreased circulating volume stimulates proximal tubule sodium reabsorption, which results in an increase in proximal lithium reabsorption and serum lithium levels. This theory can then be reasonably expanded to other potent osmotic laxatives, as well, because osmotic laxatives can cause severe dehydration.12 Whether in the hospital or in psychiatric inpatient or outpatient settings, careful monitoring of patients on concurrent lithium and laxative therapy is necessary, with particular attention needed to maintain adequate patient hydration. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. REFERENCES 1. Mitchell PB, Hadzi-Pavlovic D. Lithium treatment for bipolar disorder. Bull World Health Organ. 2000;78:515–517. 2. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217–222. 3. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159:1–50. 4. Price LH, Heninger GR. Lithium in the treatment of mood disorders. N Engl J Med. 1994;331:591–598. 5. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. 1999;10:666–674. 6. Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003;64:1328–1334. 7. Jefferson JW, Kalin NH. Serum lithium levels and long-term diuretic use. JAMA. 1979;241:1134. 8. Finley PR, O'Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol. 1996;16:68–71. 9. De Hert M, Dockx L, Bernagie C, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC Gastroenterol. 2011;11:17. 10. Riggio O, Varriale M, Testore GP, et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol. 1990;12:433–436. 11. Naranjo CA, Busto U, Sellers M, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245. 12. Baker EH, Sandle GI. Complications of laxative abuse. Annu Rev Med. 1996;47:127–134.
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
743
