- Email: [email protected]
Lithium Therapy for Bipolar Disorder
Lithium Therapy for Bipolar Disorder
Brent Luu, PharmD, BCPS, BCACP, and George Rodway, PhD, APRN ABSTRACT
The management of bipolar disorder (BD) may be challenging because of the disease state itself. In addition, the maintenance of the drug level of lithium plays a vital role in preventing acute manic or mixed episodes. This article reviews the drug properties of lithium, the current treatment guidelines for BD, and best practices in monitoring lithium therapy, as well as the characteristics and classification of BD. Keywords: bipolar disorder, challenges of bipolar disorders, lithium, mania, properties of lithium Published by Elsevier Inc.
T
he description of bipolar disorder (BD) may be traced back to the early 19th century,1 yet the management of this condition remains challenging and complicated even in the present day. The estimated prevalence of BD in the general population is approximately 4%; however, in the primary care setting, it may be as high as 21% to 26%.2,3 According to the American Psychiatric Association (APA) guidelines, lithium therapy plays a vital role in managing and preventing acute manic or mixed episodes.4 However, its use has declined in recent years because of the availability of newer atypical antipsychotics, the unacquaintedness of the drug, and the “exaggerated fears” of its toxicities.5 More recently, the 2016 British Association for Psychopharmacology (BAP) evidenced-based guidelines for treating BD still recommended lithium to be used together with dopamine antagonists or partial agonists for acute breakthrough mania when monotherapy of haloperidol, olanzapine, risperidone, or quetiapine was suboptimal. Additionally, the guidelines suggest lithium to be the most effective therapy in preventing relapse and hospitalization for BD type I.6 The 2017 International College of Neuropsychopharmacology guidelines also recommended that lithium be considered as first-line therapy during the maintenance phase of BD.7 In fact, lithium may have neuroprotective properties, which have been reported on multiple occasions. In an animal model, lithium has significantly delayed the onset of status epilepticus in mice when the condition was induced by a pilocarpine injection.8 Most www.npjournal.org
recently, Berk et al9 have used structural magnetic resonance imaging to show that lithium was more effective than quetiapine in slowing the reduction of white matter volume after 12 months of therapy. Because of the significant impact of lithium in the treatment of BD, it is prudent for prescribers to understand and be familiar with the properties of this agent and appropriately monitor for therapeutic efficacy and patient safety. This article provides a review of BD and its treatment guidelines. Additionally, it highlights the pertinent characteristics of lithium so prescribers may become more acquainted with this useful agent. BD OVERVIEW
BD, formerly known as manic-depressive disorder, is characterized by the recurrent episodes of depression and mania. BD may be generally classified into 5 different subtypes depending on the patterns of the episodic depression and mania. Bipolar type I is defined as patients who have at least 1 episode of mania with a minimum duration of 1 week with or without episodes of major depression. Bipolar type II is characterized by the presence of episodes of hypomania accompanied by at least 1 episode of major depression with no psychosis. Cyclothymia involves cyclic periods of 1 or more hypomania and depressive symptoms that do not meet criteria for major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. The rapid cycling type describes a condition in which the patients have 4 or more episodes of well-defined The Journal for Nurse Practitioners - JNP
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depression or mania during a year. These patients usually have periods of remission for at least 2 months and switch from one to the opposite pole. The mixed episodes type involves patients who have concurrent symptoms of mania and depression. During the manic phase, they also experience at least 2 of the 6 dysphoric symptoms, which include anhedonia, guilt, depressed mood, anxiety, fatigue, and suicidal ideation (Figure). Although BD is defined and recognized during the manic phase, patients with BD commonly present with depression; therefore, patients who have episodes of major depression should also be screened for a history of mania or hypomania.10 The etiology of BD is primarily genetic in nature. Overexpression of the ankyrin 3 gene has been shown to have a strong association with BD and schizophrenia, especially in the adolescent population. Meanwhile, individuals who have a low-frequency or loss-offunction mutation of this gene are protected against BD or schizophrenia, although the protective effect is stronger with type I than type II BD.11-13 Furthermore, there may also be some environmental and biological components associated. Other factors such as early childhood abuse and neglect and/or Figure. A summary of the different subtypes of BD.
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other psychiatric comorbidities may increase the risk and worsen the course of bipolar illness.6 In fact, childhood trauma has been shown to associate with various degrees of severity of BD, including earlier age at onset, increased risk of suicide attempts, and substance abuse.14 THE PHARMACOLOGIC TREATMENT OF BD
The management of BD may be summarized into 2 phases, acute treatment and long-term prevention. During the acute treatment phase, patients may present with either mania or depression or mixed episodes. According to the APA guidelines, a combination of an antipsychotic, preferably secondgeneration antipsychotics or atypical antipsychotics, together with either lithium or valproate may be initiated for patients who have severe acute mania or mixed episodes. However, for patients with mild symptoms, monotherapy of lithium, valproate, or an atypical antipsychotic may be sufficient. Short-term adjunctive therapy with a benzodiazepine may also be added if the patient has a partial response to the previously initiated therapy. However, given the high potential for abuse of benzodiazepines with this population, precautionary measures must always be implemented. Alternatively, carbamazepine or oxcarbazepine may be used in lieu of lithium or valproate; meanwhile, ziprasidone or quetiapine may be substituted for another antipsychotic.4 The 2016 BAP guidelines suggested using haloperidol, olanzapine, risperidone, or quetiapine as first-line therapy to control short-term acute manic symptoms because they have the highest efficacy.6 However, valproate and lithium are also alternative options for patients who have not been on long-term treatment of BD. The addition of short-term benzodiazepine to promote sleep for agitated overactive patients may be considered as an adjunctive therapy. For patients who are inadequately controlled with the first-line therapy, a combination of lithium or valproate together with a dopamine antagonist (ie, haloperidol or olanzapine) or a partial agonist (ie, aripiprazole) is recommended. In cases of more refractory illness, clozapine may also be considered. As for the management of acute depression, the APA recommends either lithium or lamotrigine alone as first-line treatment. However, dual therapy Volume
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of lithium and an antidepressant may be initiated for patients who have a more severe illness. Monotherapy of antidepressant such as a selective serotonin reuptake inhibitor is not recommended because of the limited supportive data. Alternatively, for patients who have a suboptimal response to the maintenance therapy (ie, lithium or lamotrigine by itself or a combination of lithium plus a selective serotonin reuptake inhibitor), the addition of lamotrigine, bupropion, or paroxetine may be warranted if there is no duplication of therapy. In contrast, the BAP recommended quetiapine, lurasidone, or olanzapine as first-line therapy for
acute depressive episodes because they also have antimanic properties. When an antidepressant is considered, it should be used together with an antipsychotic, lithium, or valproate for bipolar type I. Meanwhile, lamotrigine alone may be considered for acute or relapse prevention of depression. In relation to long-term preventive treatment of BD, lithium remains the most effective therapy in preventing relapses and hospital admission in bipolar type I, according to both guidelines. Valproate, carbamazepine, lamotrigine, and antipsychotics are other alternative treatments that may be considered if lithium is contraindicated (Table).6
Table. A Summary of the Pharmacologic Recommendations from the Current Guidelines 2002 APA Guidelines
2016 BAP Guidelines
Acute treatment Haloperidol, olanzapine, risperidone, quetiapine Breakthrough mania Lithium or valproate þ AA Adjunctive therapy Benzodiazepine (to induce sedation or sleep) Alternative Lithium, carbamazepine, or valproate
Manic/mixed episodes phase
Less symptoms Monotherapy B Lithium B Valproate B AA (ie, olanzapine) Severe symptoms Lithium þ AA Valproate þ AA Adjunctive therapy Short-term benzodiazepine Alternative to lithium or valproate Carbamazepine Oxcarbazepine Alternative AA Ziprasidone Quetiapine Refractory symptoms Clozapine
Depressive phase
New onset Lithium or lamotrigine Severe symptoms Lithium þ antidepressant Monotherapy of antidepressant is NOT recommended Fails to respond with first-line therapy Add lamotrigine, bupropion, or paroxetine or other SSRI, SNRI, or MAOI
Initial treatment Lithium or valproate Alternative treatment Lamotrigine, carbamazepine, or oxcarbazepine
Long-term prevention
Quetiapine Olanzapine Lurasidone Antidepressants þ lithium/valproate/ AA Lamotrigine
Lithium Valproate Carbamazepine Lamotrigine AA
AA ¼ atypical antipsychotic; APA ¼ American Psychiatric Association; BAP ¼ British Association for Psychopharmacology; MAOI ¼ monoamine oxidase inhibitors; SNRI ¼ serotonin norepinephrine; SSRI ¼ selective serotonin reuptake inhibitor.
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THE PROPERTIES OF LITHIUM
Lithium carbonate was rediscovered by John Cade for the treatment of BD in 194915; however, it did not gain approval from the Food and Drug Administration until 1970.16 Lithium was observed to have a unique therapeutic profile, including mood-stabilizing effects, as well as antisuicidal and neuroprotective properties.16 It is available in many different salt forms, namely lithium carbonate, lithium citrate, lithium chloride, and lithium sulfate. The chloride and sulfate salt forms are relatively more soluble than the carbonate salt; therefore, their peak plasma concentration can be reached within 1 hour after ingestion compared with 4 hours for the carbonate formulation.5,15,17,18 The 2 available formulations that have been approved in the United States are lithium citrate, an oral solution, and lithium carbonate, which comes as a tablet or capsule. Lithium is a naturally occurring element that forms ions that do not bind to plasma proteins; however, it can cross the blood-brain barrier after absorption. Lithium’s concentration in the brain may peak at approximately 24 hours after administration. The exact mechanism of action of lithium has not been completely elucidated; nevertheless, studies have shown it affects sodium transport in nerve and muscle cells, shifting the intraneuronal metabolism of adrenergic neurotransmitters.19-21 Lithium has a very narrow therapeutic window, with a desired plasma level ranging from 0.6 to 1.2 mEq/L during long-term therapy. However, for patients who are very sensitive to lithium, signs of toxicities may be present at serum levels of 1.0 to 1.5 mEq/L. In general, patients who are naive to lithium should be targeted at 0.8 to 1.0 mEq/L, especially for the prevention of manic episodes.22 The dose of lithium carbonate is typically at 300 mg or 5 mL (8 mEq) lithium citrate 3 to 4 times per day to maintain a therapeutic level, although the dosage may vary from one individual to another.19-21 Lithium has similar properties to sodium and potassium ions, which can easily enter renal cells. However, the ability to transport lithium out of renal cells is limited. Consequently, there is an accumulation of lithium intracellularly, leading to a diminished response of renal cells to antidiuretic hormone, which in turn 4
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limits the ability of the kidneys to concentrate urine. Approximately 10% of patients who have been treated with chronic lithium may develop diabetes insipidus.5 The pharmacodynamic properties of lithium may also be affected by other factors, including age, renal function, pregnancy and lactation, and coadministered medications. The fluctuation of lithium levels may be significantly impacted when the kidney function has drastically changed. Elderly individuals who have a decline in renal function, as well as other medical comorbidities, such as heart failure and hyper- or hypotension, may have compromised renal clearance of lithium. This would necessitate lower doses of lithium and highlights the need for close monitoring of levels in this population. During pregnancy, women usually have an increase in the glomerular filtration rate, thus leading to the enhancement of lithium clearance by up to 50%.23,24 As a result, the plasma level of lithium may be reduced, putting the patient at a higher risk for relapse. Furthermore, after childbirth, the mother’s blood volume, together with kidney function, rapidly normalize. Therefore, lithium plasma levels may be elevated, causing high risk for toxicities. To address these issues, some authors have suggested the lithium regimen be reduced or stopped 1 to 2 days before the expected delivery date. However, this strategy has not been helpful in alleviating adverse outcomes or complications. Ideally, the lithium blood levels should be measured 24 hours after delivery and at least twice weekly during the first 2 weeks postpartum, and the preconception doses should be immediately reinstated.23,24 Lithium is also excreted in breast milk; therefore, clinicians must weigh the risks versus the benefits for nursing mothers while breastfeeding. In addition, the infant needs to be monitored for lithium toxicities while the nursing mother is taking lithium.19 The administration of any medications that can affect the body’s fluid status may affect the lithium level, leading to drug-drug interactions. Medications including diuretics, nonsteroidal anti-inflammatory drugs, or angiotensin-converting enzyme inhibitors may reduce lithium clearance, which in turn increases lithium serum levels, thereby increasing the risks of Volume
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toxicity. In fact, indomethacin, piroxicam, and cyclooxygenase-2 inhibitors have been reported to significantly increase the steady-state plasma levels of lithium. Additionally, the effects of neuromuscular blocking agents may also be prolonged when they are concurrently used with lithium; therefore, such agents must be used with caution in patients who were diagnosed with BD and have been maintaining with lithium.19 The acute side effects of lithium may develop as tremor, general fatigue, diarrhea, headache, nausea, vomiting, thirst, and polyuria shortly after initiating the therapy. Unfortunately, the chronic use of lithium can negatively affect the other organ systems, such as the kidneys, the endocrine system (specifically both thyroid and parathyroid glands), and the cardiac system, as well as neurologic function. End-stage renal failure has been reported with long-term lithium use. In fact, the risk is more than 2-fold when comparing those treated with lithium with the general population. Lithium may also accumulate in the thyroid gland and inhibit iodine uptake and the iodotyrosine coupling process, leading to a reduction of thyroxine release and symptoms of hypothyroidism.5 The development of hypercalcemia secondary to hyperparathyroidism and neurologic toxicities, which is caused by the reduction of peripheral nerve conduction velocities, has been reported with the chronic use of lithium. Studies have shown that lithium can prolong QTc and PR intervals with T-wave inversion and sinus bradycardia. Although long-term exposure to lithium may produce changes in learning and memory function, patients may also experience a weight gain of 1 to 2 kg over the first 12 weeks of therapy because of the direct effects on appetite, thyroid gland function, and cellular glucose uptake. An acute overdose of lithium may potentially be lethal when the plasma level exceeds 2.0 mmol/L, and hemodialysis is the most effective approach to quickly reduce the toxic plasma levels. In addition, diuretics may also be partially effective for increasing lithium clearance.5 THE CHALLENGES OF BD
Because of the nature of the fluctuation between the 2 poles of BD, coupled with the narrow therapeutic window of lithium, managing and maintaining www.npjournal.org
lithium therapy may be challenging for many clinicians and patients. According to a report published in 2014, the medication adherence rate for patients with BD is low, ranging from 20% to 64%. When using the medication possession ratio with scores of 0.8 or greater being defined as fully adherent, approximately 46% of BD patients have a medication possession ratio score that ranks as less than fully adherent.25 In other words, approximately only half of the patient population with BD was adherent with their prescribed regimen. Although the maintenance of lithium levels is crucial for effective symptom reduction, steady drug levels require consistent adherence to the regimen. Unfortunately, there are ample reasons for patients to have poor adherence, which in turn puts them at high risk for relapse. For example, weight gain is a specific concern for many patients, whereas frustration about the need to consistently take lithium on a daily basis when they are free of symptoms is another. Although the acute side effects of lithium are commonly reported, they are not the main reason for poor adherence.5 The stigma of BD and the lack of understanding and acceptance are significant factors that affect adherence. To enhance adherence, 1 strategy is to educate the patients about their illness and the importance of long-term treatment. Additionally, family members should also be educated to recognize early signs of relapse and apply appropriate measures to mitigate stressors.5 In addition to the challenges from the patient’s perspective, studies have shown significant gaps between current clinical practice and the standard guidelines. The monitoring frequency of patients receiving lithium therapy is alarmingly low. According to an audit in 2013 conducted in the United Kingdom, only 30% of patients received the appropriate frequency of monitoring serum lithium levels per the National Institute for Clinical Excellence guideline for BD. In general, the National Institute for Clinical Excellence has recommended monitoring serum lithium levels every 3 months, while checking renal and thyroid functions every 6 months. However, the proportion of patients who had 2 tests of renal and thyroid function per year was 55% and 49%, respectively.25 After the baseline audit, a supplementary audit was conducted 1 year later. The Journal for Nurse Practitioners - JNP
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The rate of appropriate monitoring frequency increased to 48% for serum lithium levels, 70% for renal function, and 66% for thyroid function. These auditing data were consistent with previously published audits around the world. This leads one to conclude the monitoring frequency of many patients taking lithium for BD may well be suboptimal, thereby putting patients at high risk for harm.25 However, 1 caveat many clinicians may encounter is ensuring patients’ adherence to laboratory visits, which perhaps may be a contributing factor to the low monitoring rates as reported previously. MONITORING BEST PRACTICES WHILE PRESCRIBING LITHIUM
Per the APA guidelines, the initial laboratory work should be implemented before beginning lithium therapy. Other than establishing the patient’s medical history and performing a physical examination, a set of baseline laboratory values, including blood urea nitrogen, serum creatinine, thyroid function tests, an electrocardiogram for patients older than 40 years old, and a pregnancy test for women of childbearing age, should be ordered. During long-term lithium therapy for stable patients, serum lithium levels should be monitored at least every 6 months and whenever there is a change in the patient’s clinical status. Renal and thyroid functions should be checked every 2 to 3 months during the first 6 months of therapy and subsequently at 6- to 12month intervals in stable patients and when there is a change in clinical status. In addition to these laboratory tests, patients need to be assessed for risk of suicide because the rates of successful suicide in BD patients may be as high as 15% to 19%.20,26 Other factors associated with an increased risk of suicide, such as agitation, insomnia, impulsiveness, and other psychiatric comorbidities, must also be assessed. Hospitalization should be considered when patients pose a significant threat to themselves or others, have a serious impairment of judgement, or are not responding to their outpatient regimen. A patient’s care plan and psychiatric status should be monitored and reevaluated on an ongoing basis to determine if they are optimal. Furthermore, the patient and/or family members should be thoroughly educated regarding the nature and characteristics of BD to 6
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ensure understanding and acceptance of the need for long-term therapy.4 CONCLUSION
Lithium therapy plays an important role in the management of BD. When prescribing lithium for patients with BD, it is prudent for clinicians to be familiar with the drug’s properties. In addition, the clinician should be able to monitor and adjust the therapy appropriately to ensure patient safety, especially given lithium’s very narrow therapeutic window. The management of BD with lithium may be relatively complicated, at least when compared with many other commonly used medications. However, in multiple national treatment guidelines, lithium is still considered 1 of the most effective treatments in preventing the manic episodes associated with BD. References 1. Marneros JA. Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord. 2000;67:3-19. 2. Sansone RA, Sansone LA. Managing bipolar disorder in the primary care setting: a perspective for mental health professionals. Innov Clin Neurosci. 2011;8(10):10-13. 3. Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18(4):233-239. 4. First MB, Fochtmann LJ. Treating Bipolar Disorder-A Quick Reference Guide. 2nd ed. Arlington, VA: American Psychiatric Association. 2002:170-189. 5. Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Aust N Z J Psychiatry. 2012;46(3):192-211. 6. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations form the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. 7. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of NeuroPsychopharmacology (CINP) treatment guidelines for Bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195. 8. Hong N, Choi YS, Kim SY, Kim HJ. Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice. Korean J Physiol Pharmacol. 2017;21(1):125-131. 9. Berk M, Dandash O, Daglas R, et al. Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Transl Psychiatry. 2017;7(1):e1011. 10. Yatham LN, Malhi GS. Recognizing bipolar disorder: clinical features and diagnoses. Oxford Psychiatry Library. 2011:1-12. Available at: http://www. oxfordmedicine.com. 11. Ota M, Hori H, Sato N, et al. Effects of ankyrin 3 gene risk variants on brain structures in patients with bipolar disorder and healthy subjects. Psychiatry Clin Neurosci. 2016;70(11):498-506. 12. Delvecchio G, Dima D, Frangou S. The effect of ANK3 bipolar-risk polymorphisms on the working memory circuitry differs between loci and according to risk-status for bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2015;168B(3):188-196. 13. Hughes T, Hansson L, Sønderby IE, et al. A loss-of-function variant in a minor isoform of ANK3 protects against bipolar disorder and schizophrenia. Biol Psychiatry. 2016;80(4):323-330. 14. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4(1):2. 15. Grunze H, Vieta E, Goodwin GM, et al. WFSBP Task Force on Treatment Guidelines for Biopolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14(3):154-219.
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16. US Food and Drug Administration. Approved Drug Products. Washington, DC: US Department of Health and Human Services. 2017. 17. Malhi GS, Gershon S. Ion men and their mettle. Aust N Z J Psychiatry. 2009;43(12):1091-1095. 18. van Erp TG, Thompson PM, Kieseppä T, et al. Hippocampal morphology in lithium and non-lithium-treated bipolar I disorder patients, non-bipolar co-twins, and control twins. Hum Brain Mapp. 2012;33(3):501-510. 19. Lithium [package insert]. Columbus, OH: Roxane Laboratories. 2011. 20. Abreu LN, Lafer B, Baca-Garcia E, Oquendo MA. Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician. Rev Bras Psiquiatr. 2009;31(3):271-280. 21. DRUGDEX System (2.0). Greenwood Village, CO: Truven Health Analytics. Available at: http://www.micromedexsolutions.com [cited: July 27, 2017] . 22. Hopkins HS, Gelenberg AJ. Serum lithium levels and the outcome of maintenance therapy of bipolar disorder. Bipolar Disord. 2000;2(3 Pt 1):174-179. 23. Wesseloo R, Wierdsma AI, van Kamp IL, et al. Lithium dosing strategies during pregnancy and the postpartum period. Br J Psychiatry. 2017;21(1):31-36. 24. Deligiannidis KM, Byatt N, Freeman MP. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring. J Clin Psychopharmacol. 2014;34(2):244-255. 25. Paton C, Adroer R, Barnes TR. Monitoring lithium therapy: the impact of a quality improvement programme in the UK. Bipolar Disord. 2013;15(8): 865-875.
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26. Johnston JAY, Wang F, Liu J, et al. Multimodal neuroimaging of frontolimbic structure and function associated with suicide attempts in adolescents and young adults with bipolar disorder. Am J Psychiatry. 2017;174(7):667-675.
Both authors are affiliated with the University of California, Davis, Betty Irene Moore School of Nursing in Sacramento. Brent Luu, PharmD, BCPS, BCACP, is an assistant clinical professor and can be reached at [email protected]. George Rodway, PhD, APRN, is a clinical professor. In compliance with national ethical standards, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/17/$ see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.nurpra.2017.09.025
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Brent Luu, PharmD, BCPS, BCACP, and George Rodway, PhD, APRN ABSTRACT
The management of bipolar disorder (BD) may be challenging because of the disease state itself. In addition, the maintenance of the drug level of lithium plays a vital role in preventing acute manic or mixed episodes. This article reviews the drug properties of lithium, the current treatment guidelines for BD, and best practices in monitoring lithium therapy, as well as the characteristics and classification of BD. Keywords: bipolar disorder, challenges of bipolar disorders, lithium, mania, properties of lithium Published by Elsevier Inc.
T
he description of bipolar disorder (BD) may be traced back to the early 19th century,1 yet the management of this condition remains challenging and complicated even in the present day. The estimated prevalence of BD in the general population is approximately 4%; however, in the primary care setting, it may be as high as 21% to 26%.2,3 According to the American Psychiatric Association (APA) guidelines, lithium therapy plays a vital role in managing and preventing acute manic or mixed episodes.4 However, its use has declined in recent years because of the availability of newer atypical antipsychotics, the unacquaintedness of the drug, and the “exaggerated fears” of its toxicities.5 More recently, the 2016 British Association for Psychopharmacology (BAP) evidenced-based guidelines for treating BD still recommended lithium to be used together with dopamine antagonists or partial agonists for acute breakthrough mania when monotherapy of haloperidol, olanzapine, risperidone, or quetiapine was suboptimal. Additionally, the guidelines suggest lithium to be the most effective therapy in preventing relapse and hospitalization for BD type I.6 The 2017 International College of Neuropsychopharmacology guidelines also recommended that lithium be considered as first-line therapy during the maintenance phase of BD.7 In fact, lithium may have neuroprotective properties, which have been reported on multiple occasions. In an animal model, lithium has significantly delayed the onset of status epilepticus in mice when the condition was induced by a pilocarpine injection.8 Most www.npjournal.org
recently, Berk et al9 have used structural magnetic resonance imaging to show that lithium was more effective than quetiapine in slowing the reduction of white matter volume after 12 months of therapy. Because of the significant impact of lithium in the treatment of BD, it is prudent for prescribers to understand and be familiar with the properties of this agent and appropriately monitor for therapeutic efficacy and patient safety. This article provides a review of BD and its treatment guidelines. Additionally, it highlights the pertinent characteristics of lithium so prescribers may become more acquainted with this useful agent. BD OVERVIEW
BD, formerly known as manic-depressive disorder, is characterized by the recurrent episodes of depression and mania. BD may be generally classified into 5 different subtypes depending on the patterns of the episodic depression and mania. Bipolar type I is defined as patients who have at least 1 episode of mania with a minimum duration of 1 week with or without episodes of major depression. Bipolar type II is characterized by the presence of episodes of hypomania accompanied by at least 1 episode of major depression with no psychosis. Cyclothymia involves cyclic periods of 1 or more hypomania and depressive symptoms that do not meet criteria for major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. The rapid cycling type describes a condition in which the patients have 4 or more episodes of well-defined The Journal for Nurse Practitioners - JNP
1
depression or mania during a year. These patients usually have periods of remission for at least 2 months and switch from one to the opposite pole. The mixed episodes type involves patients who have concurrent symptoms of mania and depression. During the manic phase, they also experience at least 2 of the 6 dysphoric symptoms, which include anhedonia, guilt, depressed mood, anxiety, fatigue, and suicidal ideation (Figure). Although BD is defined and recognized during the manic phase, patients with BD commonly present with depression; therefore, patients who have episodes of major depression should also be screened for a history of mania or hypomania.10 The etiology of BD is primarily genetic in nature. Overexpression of the ankyrin 3 gene has been shown to have a strong association with BD and schizophrenia, especially in the adolescent population. Meanwhile, individuals who have a low-frequency or loss-offunction mutation of this gene are protected against BD or schizophrenia, although the protective effect is stronger with type I than type II BD.11-13 Furthermore, there may also be some environmental and biological components associated. Other factors such as early childhood abuse and neglect and/or Figure. A summary of the different subtypes of BD.
2
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other psychiatric comorbidities may increase the risk and worsen the course of bipolar illness.6 In fact, childhood trauma has been shown to associate with various degrees of severity of BD, including earlier age at onset, increased risk of suicide attempts, and substance abuse.14 THE PHARMACOLOGIC TREATMENT OF BD
The management of BD may be summarized into 2 phases, acute treatment and long-term prevention. During the acute treatment phase, patients may present with either mania or depression or mixed episodes. According to the APA guidelines, a combination of an antipsychotic, preferably secondgeneration antipsychotics or atypical antipsychotics, together with either lithium or valproate may be initiated for patients who have severe acute mania or mixed episodes. However, for patients with mild symptoms, monotherapy of lithium, valproate, or an atypical antipsychotic may be sufficient. Short-term adjunctive therapy with a benzodiazepine may also be added if the patient has a partial response to the previously initiated therapy. However, given the high potential for abuse of benzodiazepines with this population, precautionary measures must always be implemented. Alternatively, carbamazepine or oxcarbazepine may be used in lieu of lithium or valproate; meanwhile, ziprasidone or quetiapine may be substituted for another antipsychotic.4 The 2016 BAP guidelines suggested using haloperidol, olanzapine, risperidone, or quetiapine as first-line therapy to control short-term acute manic symptoms because they have the highest efficacy.6 However, valproate and lithium are also alternative options for patients who have not been on long-term treatment of BD. The addition of short-term benzodiazepine to promote sleep for agitated overactive patients may be considered as an adjunctive therapy. For patients who are inadequately controlled with the first-line therapy, a combination of lithium or valproate together with a dopamine antagonist (ie, haloperidol or olanzapine) or a partial agonist (ie, aripiprazole) is recommended. In cases of more refractory illness, clozapine may also be considered. As for the management of acute depression, the APA recommends either lithium or lamotrigine alone as first-line treatment. However, dual therapy Volume
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of lithium and an antidepressant may be initiated for patients who have a more severe illness. Monotherapy of antidepressant such as a selective serotonin reuptake inhibitor is not recommended because of the limited supportive data. Alternatively, for patients who have a suboptimal response to the maintenance therapy (ie, lithium or lamotrigine by itself or a combination of lithium plus a selective serotonin reuptake inhibitor), the addition of lamotrigine, bupropion, or paroxetine may be warranted if there is no duplication of therapy. In contrast, the BAP recommended quetiapine, lurasidone, or olanzapine as first-line therapy for
acute depressive episodes because they also have antimanic properties. When an antidepressant is considered, it should be used together with an antipsychotic, lithium, or valproate for bipolar type I. Meanwhile, lamotrigine alone may be considered for acute or relapse prevention of depression. In relation to long-term preventive treatment of BD, lithium remains the most effective therapy in preventing relapses and hospital admission in bipolar type I, according to both guidelines. Valproate, carbamazepine, lamotrigine, and antipsychotics are other alternative treatments that may be considered if lithium is contraindicated (Table).6
Table. A Summary of the Pharmacologic Recommendations from the Current Guidelines 2002 APA Guidelines
2016 BAP Guidelines
Acute treatment Haloperidol, olanzapine, risperidone, quetiapine Breakthrough mania Lithium or valproate þ AA Adjunctive therapy Benzodiazepine (to induce sedation or sleep) Alternative Lithium, carbamazepine, or valproate
Manic/mixed episodes phase
Less symptoms Monotherapy B Lithium B Valproate B AA (ie, olanzapine) Severe symptoms Lithium þ AA Valproate þ AA Adjunctive therapy Short-term benzodiazepine Alternative to lithium or valproate Carbamazepine Oxcarbazepine Alternative AA Ziprasidone Quetiapine Refractory symptoms Clozapine
Depressive phase
New onset Lithium or lamotrigine Severe symptoms Lithium þ antidepressant Monotherapy of antidepressant is NOT recommended Fails to respond with first-line therapy Add lamotrigine, bupropion, or paroxetine or other SSRI, SNRI, or MAOI
Initial treatment Lithium or valproate Alternative treatment Lamotrigine, carbamazepine, or oxcarbazepine
Long-term prevention
Quetiapine Olanzapine Lurasidone Antidepressants þ lithium/valproate/ AA Lamotrigine
Lithium Valproate Carbamazepine Lamotrigine AA
AA ¼ atypical antipsychotic; APA ¼ American Psychiatric Association; BAP ¼ British Association for Psychopharmacology; MAOI ¼ monoamine oxidase inhibitors; SNRI ¼ serotonin norepinephrine; SSRI ¼ selective serotonin reuptake inhibitor.
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THE PROPERTIES OF LITHIUM
Lithium carbonate was rediscovered by John Cade for the treatment of BD in 194915; however, it did not gain approval from the Food and Drug Administration until 1970.16 Lithium was observed to have a unique therapeutic profile, including mood-stabilizing effects, as well as antisuicidal and neuroprotective properties.16 It is available in many different salt forms, namely lithium carbonate, lithium citrate, lithium chloride, and lithium sulfate. The chloride and sulfate salt forms are relatively more soluble than the carbonate salt; therefore, their peak plasma concentration can be reached within 1 hour after ingestion compared with 4 hours for the carbonate formulation.5,15,17,18 The 2 available formulations that have been approved in the United States are lithium citrate, an oral solution, and lithium carbonate, which comes as a tablet or capsule. Lithium is a naturally occurring element that forms ions that do not bind to plasma proteins; however, it can cross the blood-brain barrier after absorption. Lithium’s concentration in the brain may peak at approximately 24 hours after administration. The exact mechanism of action of lithium has not been completely elucidated; nevertheless, studies have shown it affects sodium transport in nerve and muscle cells, shifting the intraneuronal metabolism of adrenergic neurotransmitters.19-21 Lithium has a very narrow therapeutic window, with a desired plasma level ranging from 0.6 to 1.2 mEq/L during long-term therapy. However, for patients who are very sensitive to lithium, signs of toxicities may be present at serum levels of 1.0 to 1.5 mEq/L. In general, patients who are naive to lithium should be targeted at 0.8 to 1.0 mEq/L, especially for the prevention of manic episodes.22 The dose of lithium carbonate is typically at 300 mg or 5 mL (8 mEq) lithium citrate 3 to 4 times per day to maintain a therapeutic level, although the dosage may vary from one individual to another.19-21 Lithium has similar properties to sodium and potassium ions, which can easily enter renal cells. However, the ability to transport lithium out of renal cells is limited. Consequently, there is an accumulation of lithium intracellularly, leading to a diminished response of renal cells to antidiuretic hormone, which in turn 4
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limits the ability of the kidneys to concentrate urine. Approximately 10% of patients who have been treated with chronic lithium may develop diabetes insipidus.5 The pharmacodynamic properties of lithium may also be affected by other factors, including age, renal function, pregnancy and lactation, and coadministered medications. The fluctuation of lithium levels may be significantly impacted when the kidney function has drastically changed. Elderly individuals who have a decline in renal function, as well as other medical comorbidities, such as heart failure and hyper- or hypotension, may have compromised renal clearance of lithium. This would necessitate lower doses of lithium and highlights the need for close monitoring of levels in this population. During pregnancy, women usually have an increase in the glomerular filtration rate, thus leading to the enhancement of lithium clearance by up to 50%.23,24 As a result, the plasma level of lithium may be reduced, putting the patient at a higher risk for relapse. Furthermore, after childbirth, the mother’s blood volume, together with kidney function, rapidly normalize. Therefore, lithium plasma levels may be elevated, causing high risk for toxicities. To address these issues, some authors have suggested the lithium regimen be reduced or stopped 1 to 2 days before the expected delivery date. However, this strategy has not been helpful in alleviating adverse outcomes or complications. Ideally, the lithium blood levels should be measured 24 hours after delivery and at least twice weekly during the first 2 weeks postpartum, and the preconception doses should be immediately reinstated.23,24 Lithium is also excreted in breast milk; therefore, clinicians must weigh the risks versus the benefits for nursing mothers while breastfeeding. In addition, the infant needs to be monitored for lithium toxicities while the nursing mother is taking lithium.19 The administration of any medications that can affect the body’s fluid status may affect the lithium level, leading to drug-drug interactions. Medications including diuretics, nonsteroidal anti-inflammatory drugs, or angiotensin-converting enzyme inhibitors may reduce lithium clearance, which in turn increases lithium serum levels, thereby increasing the risks of Volume
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toxicity. In fact, indomethacin, piroxicam, and cyclooxygenase-2 inhibitors have been reported to significantly increase the steady-state plasma levels of lithium. Additionally, the effects of neuromuscular blocking agents may also be prolonged when they are concurrently used with lithium; therefore, such agents must be used with caution in patients who were diagnosed with BD and have been maintaining with lithium.19 The acute side effects of lithium may develop as tremor, general fatigue, diarrhea, headache, nausea, vomiting, thirst, and polyuria shortly after initiating the therapy. Unfortunately, the chronic use of lithium can negatively affect the other organ systems, such as the kidneys, the endocrine system (specifically both thyroid and parathyroid glands), and the cardiac system, as well as neurologic function. End-stage renal failure has been reported with long-term lithium use. In fact, the risk is more than 2-fold when comparing those treated with lithium with the general population. Lithium may also accumulate in the thyroid gland and inhibit iodine uptake and the iodotyrosine coupling process, leading to a reduction of thyroxine release and symptoms of hypothyroidism.5 The development of hypercalcemia secondary to hyperparathyroidism and neurologic toxicities, which is caused by the reduction of peripheral nerve conduction velocities, has been reported with the chronic use of lithium. Studies have shown that lithium can prolong QTc and PR intervals with T-wave inversion and sinus bradycardia. Although long-term exposure to lithium may produce changes in learning and memory function, patients may also experience a weight gain of 1 to 2 kg over the first 12 weeks of therapy because of the direct effects on appetite, thyroid gland function, and cellular glucose uptake. An acute overdose of lithium may potentially be lethal when the plasma level exceeds 2.0 mmol/L, and hemodialysis is the most effective approach to quickly reduce the toxic plasma levels. In addition, diuretics may also be partially effective for increasing lithium clearance.5 THE CHALLENGES OF BD
Because of the nature of the fluctuation between the 2 poles of BD, coupled with the narrow therapeutic window of lithium, managing and maintaining www.npjournal.org
lithium therapy may be challenging for many clinicians and patients. According to a report published in 2014, the medication adherence rate for patients with BD is low, ranging from 20% to 64%. When using the medication possession ratio with scores of 0.8 or greater being defined as fully adherent, approximately 46% of BD patients have a medication possession ratio score that ranks as less than fully adherent.25 In other words, approximately only half of the patient population with BD was adherent with their prescribed regimen. Although the maintenance of lithium levels is crucial for effective symptom reduction, steady drug levels require consistent adherence to the regimen. Unfortunately, there are ample reasons for patients to have poor adherence, which in turn puts them at high risk for relapse. For example, weight gain is a specific concern for many patients, whereas frustration about the need to consistently take lithium on a daily basis when they are free of symptoms is another. Although the acute side effects of lithium are commonly reported, they are not the main reason for poor adherence.5 The stigma of BD and the lack of understanding and acceptance are significant factors that affect adherence. To enhance adherence, 1 strategy is to educate the patients about their illness and the importance of long-term treatment. Additionally, family members should also be educated to recognize early signs of relapse and apply appropriate measures to mitigate stressors.5 In addition to the challenges from the patient’s perspective, studies have shown significant gaps between current clinical practice and the standard guidelines. The monitoring frequency of patients receiving lithium therapy is alarmingly low. According to an audit in 2013 conducted in the United Kingdom, only 30% of patients received the appropriate frequency of monitoring serum lithium levels per the National Institute for Clinical Excellence guideline for BD. In general, the National Institute for Clinical Excellence has recommended monitoring serum lithium levels every 3 months, while checking renal and thyroid functions every 6 months. However, the proportion of patients who had 2 tests of renal and thyroid function per year was 55% and 49%, respectively.25 After the baseline audit, a supplementary audit was conducted 1 year later. The Journal for Nurse Practitioners - JNP
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The rate of appropriate monitoring frequency increased to 48% for serum lithium levels, 70% for renal function, and 66% for thyroid function. These auditing data were consistent with previously published audits around the world. This leads one to conclude the monitoring frequency of many patients taking lithium for BD may well be suboptimal, thereby putting patients at high risk for harm.25 However, 1 caveat many clinicians may encounter is ensuring patients’ adherence to laboratory visits, which perhaps may be a contributing factor to the low monitoring rates as reported previously. MONITORING BEST PRACTICES WHILE PRESCRIBING LITHIUM
Per the APA guidelines, the initial laboratory work should be implemented before beginning lithium therapy. Other than establishing the patient’s medical history and performing a physical examination, a set of baseline laboratory values, including blood urea nitrogen, serum creatinine, thyroid function tests, an electrocardiogram for patients older than 40 years old, and a pregnancy test for women of childbearing age, should be ordered. During long-term lithium therapy for stable patients, serum lithium levels should be monitored at least every 6 months and whenever there is a change in the patient’s clinical status. Renal and thyroid functions should be checked every 2 to 3 months during the first 6 months of therapy and subsequently at 6- to 12month intervals in stable patients and when there is a change in clinical status. In addition to these laboratory tests, patients need to be assessed for risk of suicide because the rates of successful suicide in BD patients may be as high as 15% to 19%.20,26 Other factors associated with an increased risk of suicide, such as agitation, insomnia, impulsiveness, and other psychiatric comorbidities, must also be assessed. Hospitalization should be considered when patients pose a significant threat to themselves or others, have a serious impairment of judgement, or are not responding to their outpatient regimen. A patient’s care plan and psychiatric status should be monitored and reevaluated on an ongoing basis to determine if they are optimal. Furthermore, the patient and/or family members should be thoroughly educated regarding the nature and characteristics of BD to 6
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ensure understanding and acceptance of the need for long-term therapy.4 CONCLUSION
Lithium therapy plays an important role in the management of BD. When prescribing lithium for patients with BD, it is prudent for clinicians to be familiar with the drug’s properties. In addition, the clinician should be able to monitor and adjust the therapy appropriately to ensure patient safety, especially given lithium’s very narrow therapeutic window. The management of BD with lithium may be relatively complicated, at least when compared with many other commonly used medications. However, in multiple national treatment guidelines, lithium is still considered 1 of the most effective treatments in preventing the manic episodes associated with BD. References 1. Marneros JA. Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord. 2000;67:3-19. 2. Sansone RA, Sansone LA. Managing bipolar disorder in the primary care setting: a perspective for mental health professionals. Innov Clin Neurosci. 2011;8(10):10-13. 3. Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18(4):233-239. 4. First MB, Fochtmann LJ. Treating Bipolar Disorder-A Quick Reference Guide. 2nd ed. Arlington, VA: American Psychiatric Association. 2002:170-189. 5. Malhi GS, Tanious M, Das P, Berk M. The science and practice of lithium therapy. Aust N Z J Psychiatry. 2012;46(3):192-211. 6. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations form the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. 7. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of NeuroPsychopharmacology (CINP) treatment guidelines for Bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195. 8. Hong N, Choi YS, Kim SY, Kim HJ. Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice. Korean J Physiol Pharmacol. 2017;21(1):125-131. 9. Berk M, Dandash O, Daglas R, et al. Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Transl Psychiatry. 2017;7(1):e1011. 10. Yatham LN, Malhi GS. Recognizing bipolar disorder: clinical features and diagnoses. Oxford Psychiatry Library. 2011:1-12. Available at: http://www. oxfordmedicine.com. 11. Ota M, Hori H, Sato N, et al. Effects of ankyrin 3 gene risk variants on brain structures in patients with bipolar disorder and healthy subjects. Psychiatry Clin Neurosci. 2016;70(11):498-506. 12. Delvecchio G, Dima D, Frangou S. The effect of ANK3 bipolar-risk polymorphisms on the working memory circuitry differs between loci and according to risk-status for bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2015;168B(3):188-196. 13. Hughes T, Hansson L, Sønderby IE, et al. A loss-of-function variant in a minor isoform of ANK3 protects against bipolar disorder and schizophrenia. Biol Psychiatry. 2016;80(4):323-330. 14. Aas M, Henry C, Andreassen OA, Bellivier F, Melle I, Etain B. The role of childhood trauma in bipolar disorders. Int J Bipolar Disord. 2016;4(1):2. 15. Grunze H, Vieta E, Goodwin GM, et al. WFSBP Task Force on Treatment Guidelines for Biopolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14(3):154-219.
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16. US Food and Drug Administration. Approved Drug Products. Washington, DC: US Department of Health and Human Services. 2017. 17. Malhi GS, Gershon S. Ion men and their mettle. Aust N Z J Psychiatry. 2009;43(12):1091-1095. 18. van Erp TG, Thompson PM, Kieseppä T, et al. Hippocampal morphology in lithium and non-lithium-treated bipolar I disorder patients, non-bipolar co-twins, and control twins. Hum Brain Mapp. 2012;33(3):501-510. 19. Lithium [package insert]. Columbus, OH: Roxane Laboratories. 2011. 20. Abreu LN, Lafer B, Baca-Garcia E, Oquendo MA. Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician. Rev Bras Psiquiatr. 2009;31(3):271-280. 21. DRUGDEX System (2.0). Greenwood Village, CO: Truven Health Analytics. Available at: http://www.micromedexsolutions.com [cited: July 27, 2017] . 22. Hopkins HS, Gelenberg AJ. Serum lithium levels and the outcome of maintenance therapy of bipolar disorder. Bipolar Disord. 2000;2(3 Pt 1):174-179. 23. Wesseloo R, Wierdsma AI, van Kamp IL, et al. Lithium dosing strategies during pregnancy and the postpartum period. Br J Psychiatry. 2017;21(1):31-36. 24. Deligiannidis KM, Byatt N, Freeman MP. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring. J Clin Psychopharmacol. 2014;34(2):244-255. 25. Paton C, Adroer R, Barnes TR. Monitoring lithium therapy: the impact of a quality improvement programme in the UK. Bipolar Disord. 2013;15(8): 865-875.
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26. Johnston JAY, Wang F, Liu J, et al. Multimodal neuroimaging of frontolimbic structure and function associated with suicide attempts in adolescents and young adults with bipolar disorder. Am J Psychiatry. 2017;174(7):667-675.
Both authors are affiliated with the University of California, Davis, Betty Irene Moore School of Nursing in Sacramento. Brent Luu, PharmD, BCPS, BCACP, is an assistant clinical professor and can be reached at [email protected]. George Rodway, PhD, APRN, is a clinical professor. In compliance with national ethical standards, the authors report no relationships with business or industry that would pose a conflict of interest. 1555-4155/17/$ see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.nurpra.2017.09.025
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