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Lithium plays an important role in reducing morbidity and mortality associated with bipolar disorder. Psychiatrists can optimize the benefits of lithium by carefully choosing patients for long-term treatment and educating them about the risks and benefits.
Premiere Date: April 20, 2015
Expiration Date: April 20, 2016
This activity offers CE credits for:
1. Physicians (CME)
To understand the key role of lithium in the treatment of bipolar disorder.
At the end of this CE activity, participants should be able to:
1. Understand the indications for the use of lithium in acute mania and in maintenance treatment of bipolar disorder
2. Describe the evidence for lithium’s neuroprotective effect
3. Define the various safety concerns associated with the use of lithium and how they can be mitigated
This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.
CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.
CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for 1.5 AMA PRA Category 1 Credit™.
It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.
The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.
Ralph J. Koek, MD, has no disclosures to report.
Richard Balon, MD (peer/content reviewer), has no disclosures to report.
Applicable Psychiatric Times staff and CME Outfitters staff have no disclosures to report.
UNLABELED USE DISCLOSURE
Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.
Questions about this activity? Call us at 877.CME.PROS (877.263.7767)
“Lithium? Do you guys still use that?”
(Referring physician, in response to my recommendation for a high-functioning 24-year-old woman with classic, familial bipolar I disorder recovering from a second post-manic depression, 2013.)
Bipolar disorder (BD) is a serious medical illness associated with high rates of attempted and completed suicide and considerable suffering as well as social, occupational, and medical morbidity. In 90% of patients, a second mood episode will develop after recovery from the episode leading to diagnosis, and long-term maintenance mood stabilizer medication is usually indicated.
For the first several decades after Cade’s 1949 discovery, lithium was the mainstay of bipolar prophylaxis. Every psychiatrist had considerable experience with its use-including the many attendant caveats.
In the past few decades, beginning with carbamazepine, then valproic acid derivatives, followed by lamotrigine, and finally the atypical antipsychotics, additional options for maintenance pharmacotherapy have become available, and lithium use has declined. At least 2 other factors have also played a role in the decline: concerns about lithium’s adverse effects/toxicity and inadequate prophylactic effectiveness for many patients.
Lithium carbonate is FDA-indicated for acute mania and maintenance treatment of BD. It is recommended as first-line therapy for maintenance in BD treatment guidelines. The effectiveness of lithium as maintenance therapy is based on trials done decades ago when it was compared with placebo, as well as on recent studies in which lithium served as the active comparator for newer agents. Recent findings support lithium over alternatives for effectiveness in long-term mood stabilization.1-3 However, the prophylactic benefits of lithium are significantly better for episodes of mania than for depression recurrence.1 Moreover, lithium reduces the risk of recurrence in both BD-II and BD-I.4
Although lithium remains the first choice for maintenance treatment, it cannot be recommended for every patient. As with any treatment, when considering the use of lithium, the first step is to educate patients and their families about the benefits and risks and alternatives.
Evidence for effectiveness
In terms of benefits, lithium’s clear suicide preventive value stands out. Most psychiatrists are familiar with the evidence that demonstrates that long-term lithium therapy leads to a 5-fold decrease in suicide risk compared with placebo and other active treatments.5,6 Cipriani and colleagues7 confirmed this benefit, although they did not find a statistically significant difference between lithium and several other mood stabilizers (carbamazepine, lamotrigine, olanzapine). In their comprehensive review, Yerevanian and Choi8 found that no agent or class of agents matched lithium’s evidence for protection from suicidal behavior in BD. Recent findings also continue to support lithium’s benefit for reducing the high medical morbidity and mortality in BD.7
Another benefit that has emerged into prominence is the neurotrophic properties of lithium that may mediate a direct illness-modifying effect. BD can be viewed as a neuroprogressive disorder, and lithium has the best evidence for neuroprotection.9,10 Lithium’s classic “cognitive dulling” effect, with mild impairments in memory, information processing speed, and creativity, has also been empirically confirmed.11 However, these deficits were not found to progress beyond 6 years, nor were they found in excellent lithium responders.12 Although some evidence suggests that lithium’s neuroprotective effect is selective for responders, other findings suggest that it occurs independently.13,14 While there is evidence to support lithium’s efficacy in primary neurocognitive disorders, there is no evidence to support the efficacy of valproic acid derivatives.15,16
Asking whether some bipolar patients are likely to benefit from lithium may help the prescribing physician weigh the alternatives. Grof17 coined the term “excellent lithium responders” for bipolar patients who enjoy long-term illness-free lives with prophylactic lithium monotherapy. Table 1 describes the characteristics of these patients, along with characteristics less predictive of lithium maintenance stability. Ongoing work by the International Group for the Study of Lithium-Treated Patients promises further understanding of genetic and other aspects of lithium response prediction. Lithium responsiveness may identify a diagnostic subgroup of patients with mood disorder-including some bipolar patients, as well as some unipolar patients-who have a clearly episodic, recurrent course.18Table 2 compares the maintenance benefits of lithium with those of other mood-stabilizing agents.
While patients newly confronting the reality of long-term maintenance medication may be encouraged by lithium’s benefits, they inevitably are concerned about adverse effects. The risks associated with lithium must be balanced against those of alternative medications: valproic acid derivatives and carbamazepine are associated with many potential systemic adverse effects; lamotrigine “only” has the rash risk to worry about-so to speak-but it is not effective for acute mania; and most atypical antipsychotics have a double whammy of metabolic syndrome and tardive dyskinesia. Table 3 compares the risks of lithium with those of alternative mood stabilizers.
Recommended maintenance serum levels with lithium are 0.5 or 0.6 to 0.8 mEq/L; some guidelines recommend levels of 0.8 to 1.0 mEq/L for breakthrough symptoms. Most guidelines recommend frequent monitoring until stable levels are confirmed in a euthymic state, then monitoring every 3 to 6 months for 12 months, and every 6 to 12 months indefinitely thereafter. Additional measurements are needed after dosage changes, introduction of factors that can alter serum levels, or in cases of relapse. Patients should be educated about lithium levels and factors that can affect them (Sidebar).
Lithium has a narrow therapeutic index. Clinicians must maintain vigilance for potentially serious risks and clinical manifestations of lithium toxicity. Serum levels even 25% above the upper limit of the therapeutic range (ie, 1.2 mEq/L) can cause clinical toxicity. Both magnitude and duration of exposure to a high lithium level correlate with severity of toxicity. Elderly patients may experience clinical toxicity at lower serum levels.
Overdose with serum levels in the range of 2 to 3 mEq/L can leave patients with permanent residual nephrotoxicity and neurotoxicity. Dialysis is required when serum levels are higher than 4 mEq/L and/or if the patient exhibits acute renal, CNS, or otherwise severe clinical decompensation.19 More frequent monitoring is required in situations that increase risk of lithium toxicity-particularly in the elderly-such as dehydration and drug interactions with NSAIDs, angiotensin-converting enzyme inhibitors, and thiazide diuretics.
Lithium’s well-known effects on renal function include impaired urinary concentrating capacity with polydipsia, polyuria, and nephrogenic diabetes insipidus; and nephropathy with renal functional impairment. Impaired urinary concentration capacity is common, immediate, dose-related, sometimes transient, and more frequent in women.20 It is mediated via lithium-induced glycogen synthase kinase-3Î² inhibition that leads to interference with extracellular sodium channel and aquaporin-2 water transport channel functions and the effects of antidiuretic hormone and aldosterone on primary cells of the cortical collecting duct.21 Lower serum levels, single daily dosing and, in more severe cases, adjunctive amiloride (a potassium-sparing diuretic and extracellular sodium channel blocker) may reduce impaired urinary concentration capacity. Thiazide diuretics may also help but require significant reduction of lithium doses with careful monitoring to avoid toxicity.
In up to 20% of patients receiving long-term lithium treatment, some degree of nephropathy develops.22 It begins with renal impairment (creatinine levels greater than 1.5 mg/dL) but can progress to renal failure that may require renal replacement therapy (dialysis or transplant). The absolute risks of lithium-associated renal impairment, renal failure, and/or renal replacement therapy are difficult to determine for practical reasons; however, recent research confirms the serious risk of long-term lithium use. In a meta-analysis of the adverse effects of lithium, McKnight and colleagues23 found that 0.5% of long-term lithium-treated patients were receiving renal replacement therapy, compared with 0.2% of the general population.
Results from a 2014 Swedish Renal Registry study show an incidence of 1.2% for lithium-associated renal replacement therapy.24 The patients with this worst outcome had begun lithium treatment more than 30 years previously, which suggests that more recent careful long-term monitoring and reduced maintenance lithium dosage may have protected the others. Close and colleagues25 compared bipolar patients first treated with either lithium or an alternative mood stabilizer after 1990. They found significantly higher rates of both renal impairment (10.2% vs 3.1%) and renal failure (2% vs 0.7%) in lithium-treated patients.
Other findings suggest that the incidence of nephropathy may be increasing over time.26 The researchers found 0.14 (95% confidence interval [CI], 0.06-0.22) cases of lithium-induced renal replacement therapy per million total population from 1992 through 1996 and 0.78 per million (95% CI, 0.67-0.90) from 2007 through 2011. The proportion of all renal replacement therapy cases attributed to lithium increased from 0.2% to 0.7% over that period.
Numerous caveats are important in interpreting these data.24-26 All 3 studies controlled for potentially confounding variables, arguing for a truly causative role of lithium. Because it is likely that the Close study underestimated the true duration of exposure, it is probable that nephropathy occurs after decades of maintenance exposure. While the hazard ratio of approximately 2.5 is concerning for severe outcomes such as nephropathy, the absolute risk difference is important: number needed for harm (NNH) for renal replacement therapy was 330, NNH for renal failure was 660 for those younger than 50, and NNH was 44 for those older than 50.
Nephropathy requires monitoring for suggestive symptoms and serum creatinine/estimated glomerular filtration rate. Patients with emerging renal impairment should undergo more in-depth assessment and must be educated about alternatives, such as lithium monotherapy at the lowest dosage with careful monitoring or use of different mood stabilizers. Lamotrigine, quetiapine, or the olanzapine-fluoxetine combination can be added to a suboptimal lithium dosage for maintenance treatment in patients with predominantly depressive recurrence risk. Divalproex, olanzapine, quetiapine, aripiprazole, or carbamazepine can be added for patients with predominantly manic/mixed episode relapse risk.
Thyroid function is more commonly affected by lithium than by other mood stabilizers. Lithium affects the thyroid axis by a number of mechanisms. Studies suggest that hypothyroidism develops in 30% of patients with BD during lithium maintenance, and up to 50% of these patients have detectable goiters by ultrasonography (compared with approximately 20% of controls).27,28 Women are at higher risk for hypothyroidism.29
In some cases, hypothyroidism turns out to be an unmasking of autoimmune thyroiditis, which may be more common in patients with BD and unrelated to lithium exposure.30 While autoimmune thyroiditis may require referral for further evaluation and treatment, hypothyroidism is not a contraindication to lithium. It can be managed by the treating psychiatrist with supplemental levothyroxine.
Monitoring of thyroid-stimulating hormone every 3 months during the first 6 to 12 months and every 6 to 12 months (more often in women older than 45) indefinitely thereafter is recommended. Because of the importance of normal thyroid function for mood regulation, lowering the cutoff value for abnormally high thyroid-stimulating hormone from the typical 5 µIU/mL to 3 µIU/m/L is recommended.29 An important teaching point for residents is to look for hypothyroidism in patients with BD who are maintained on lithium and in whom breakthrough depression develops, because hypothyroidism is a classic cause of secondary depression. In addition, lithium-induced hyperthyroidism can cause mania.31
Hypercalcemia and hyperparathyroidism
Lithium-induced hypercalcemia and hyperparathyroidism are caused by the direct effect of lithium on parathyroid calcium sensitivity. In one study, 8.6% of lithium-treated patients with BD were found to have hyperparathyroidism.32 Recent guidelines recommend baseline and periodic calcium (but not routine parathyroid hormone) monitoring.33,34 Patients must also be informed that this adverse effect can include parathyroid adenomas that may require surgical removal. Fortunately, the prognosis with surgery for these benign tumors is good.
The FDA lists Brugada syndrome, a congenital cardiac arrhythmia characterized by precordial lead ST-segment elevation and risk of ventricular arrhythmia with syncope and sudden death, as a contraindication to lithium because lithium can unmask it, even at therapeutic serum levels. It may be triggered by sodium channel blockade, and thus the risk may be shared by other psychotropic agents. Patients should probably be warned about this and told to stop lithium and see a physician immediately if unexplained syncope occurs. Lithium can affect both atrial and ventricular conduc-tion, and this is of particular concern when it is prescribed in conjunction with other medications with cardiac conduction effects, or when taken in overdose.
Other safety considerations
Lithium remains FDA category D regarding safety in pregnancy because of Ebstein anomaly and other cardiovascular anomalies associated with first-trimester exposure. In the most recent teratogenicity study, first-trimester lithium exposure was associated with a 4% risk of any cardiovascular defect in the fetus, compared with 0.6% in nonteratogenic-exposed control pregnancies.35 Women who used lithium during pregnancy had a greater than 20% rate of pregnancy complications. Lithium also poses a risk to infants of breast-feeding mothers because of its high concentration in breast milk.
Another important caveat with lithium use is discontinuation risk. The affective morbidity index among 346 bipolar patients followed for up to 20 years remained stable over time, consistent with a persistent benefit of lithium in those who continue to take it.36 On the other hand, even after stable remission and gradual discontinuation, the risk of recurrence is significantly worse than in those who continue on lithium. Discontinuation also increases the risk for suicidality.8 Relapse and suicide risks are much higher with abrupt compared with gradual discontinuation. In addition, some patients may become treatment-refractory with lithium discontinuation.37
Overall, lithium plays an important role in reducing morbidity and mortality associated with BD. Psychiatrists can optimize the benefits of lithium by carefully choosing patients for long-term treatment, educating patients thoroughly about risks and benefits, monitoring adverse effects and serum lithium levels regularly, and working toward minimum maintenance dosages.
Patients whose longitudinal illness pattern corresponds to the “excellent responder” profile identified by Grof should be offered lithium prophylaxis unless there are medical contraindications or poor reliability of follow-up. However, this does not mean that patients with other profiles should not be considered for lithium maintenance. Benefits may still accrue even in the absence of the characteristics of “excellent responders,” and this is something that most patients with BD (or recurrent unipolar depression) deserve to be told.
One approach is to combine modest dosages of lithium-to reduce both short-term and presumably long-term adverse effects-with other mood-stabilizing agents to ensure symptom/episode control in those for whom lithium alone is an inadequate mood stabilizer. This approach is the subject of the Lithium Treatment Moderate-Dose Use Study. In the first outcome report, at 6 months there were no significant advantages to lithium plus optimized personalized treatment, although patients in the lithium group (mean serum levels, 0.4 to 0.47 mEq/L) received 23% fewer prescriptions for atypical antipsychotics.38
It may take longer to observe whether moderate-dose adjunctive lithium has clinically significant suicide prevention and neuroprotective benefits, let alone nephroprotective effects. Further data from this thoughtful work, as well as from the International Group for the Study of Lithium will help us to continue to optimize lithium use.
Perhaps my answer to the original question-whether we still use lithium-will remain a decided YES well into the future. (The patient agreed to lithium monotherapy and has done well at 18-month follow-up, managed by her family physician.)
PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR A YEAR AFTER.
Dr Koek is Staff Psychiatrist at the Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System; Director of the Mood Disorders Clinic, UCLA/San Fernando Psychiatry Training Program; Clinical Professor, department of psychiatry and bio-behavioral sciences at the David Geffen School of Medicine at UCLA in Los Angeles; and Teaching Faculty at the Family Medicine Residency Program, Glendale Adventist Medical Center in Glendale, Calif.
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2. Simhandl C, KÃ¶nig B, Amann BL. A prospective 4-year naturalistic follow-up of treatment and outcome of 300 bipolar I and II patients. J Clin Psychiatry. 2014;75:254-263.
3. BALANCE Investigators and Collaborators; Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375:385-395.
4. Benazzi F. Bipolar II disorder: epidemiology, diagnosis and management. CNS Drugs. 2007;21:727-740.
5. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicide behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805-1816.
6. Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review [published correction appears in Bipolar Disord. 2007;9:314]. Bipolar Disord. 2006;8(5, pt 2):625-639.
7. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646.
8. Yerevanian BI, Choi YM. Impact of psychotropic drugs on suicide and suicidal behaviors. Bipolar Disord. 2013;15:594-621.
9. Gray JD, McEwen BS. Lithium’s role in neural plasticity and its implications for mood disorders. Acta Psychiatr Scand. 2013;128:347-361.
10. Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48:809-818.
11. Mora E, Portella MJ, Forcada I, et al. Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study. Psychol Med. 2013;43:1187-1196.
12. Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617-622.
13. Lyoo IK, Dager SR, Kim JE, et al. Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology. 2010;35:1743-1750.
14. Hajek T, Bauer M, Simhandl C, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014;44:507-517.
15. Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-356.
16. Tariot PN, Schneider LS, Cummings J, et al; Alzheimer’s Disease Cooperative Study Group. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011;68:853-861.
17. Grof P. Sixty years of lithium responders. Neuropsychobiology. 2010;62:8-16.
18. Malhi GS, Geddes JR. Carving bipolarity using a lithium sword. Br J Psychiatry. 2014;205:337-339.
19. Decker BS, Goldfarb DS, Dargan PI, et al; EXTRIP Workgroup. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol. 2015 Jan 12; [Epub ahead of print].
20. Kinahan JC, NiChorcorain A, Cunningham S, et al. Risk factors for polyuria in a cross-section of community psychiatric lithium-treated patients. Bipolar Disord. 2014;17:50-62.
21. GrÃ¼nfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009;5:270-276.
22. Lepkifker E, Swerdlik A, Iancu I, et al. Renal insufficiency in long-term lithium treatment. J Clin Psychiatry. 2004;65:850-856.
23. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721-728.
24. Aiff H, Attman PO, Aurell M, et al. End-stage renal disease associated with prophylactic lithium treatment. Eur Neuropsychopharmacol. 2014;24:540-544.
25. Close H, Reilly J, Mason JM, et al. Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One. 2014;9:e90169.
26. Roxanas M, Grace BS, George CR. Renal replacement therapy associated with lithium nephrotoxicity in Australia. Med J Aust. 2014;200:226-228.
27. Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23:723-733.
28. Bauer M, Blumentritt H, Finke R, et al. Using ultrasonography to determine thyroid size and prevalence of goiter in lithium-treated patients with affective disorders. J Affect Disord. 2007;104:45-51.
29. Ãzerdem A, Tunca Z, Ãimrin D, et al. Female vulnerability for thyroid function abnormality in bipolar disorder: role of lithium treatment. Bipolar Disord. 2014;16:72-82.
30. Kupka RW, Nolen WA, Post RM, et al. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry. 2002;51:305-311.
31. Bandyopadhyay D, Nielsen C. Lithium-induced hyperthyroidism, thyrotoxicosis and mania: a case report. QJM. 2012;105:83-85.
32. Albert U, De Cori D, Aguglia A, et al. Lithium-associated hyperparathyroidism and hypercalcaemia: a case-control cross-sectional study. J Affect Disord. 2013;151:786-790.
33. National Institute for Health and Care Excellence. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. NICE Guidelines (CG185): September 2014. http://www.nice.org.uk/guidance/CG185. Accessed March 4, 2015.
34. Ng F, Mammen OK, Wilting I, et al; International Society for Bipolar Disorders. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord. 2009;11:559-595.
35. Diav-Citrin O, Shechtman S, Tahover E, et al. Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. Am J Psychiatry. 2014;171:785-794.
36. BerghÃ¶fer A, Alda M, Adli M, et al. Stability of lithium treatment in bipolar disorder-long-term follow-up of 346 patients. Int J Bipolar Disord. 2013;1:11.
37. Post RM. Acquired lithium resistance revisited: discontinuation-induced refractoriness versus tolerance. J Affect Disord. 2012;140:6-13.
38. Nierenberg AA, Friedman ES, Bowden CL, et al. Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium. Am J Psychiatry. 2013;170:102-110.