Skip to main content
Full access
Perspectives
Published Online: 1 January 2013

A Simple Question Answered: Adding Moderate-Dosage Lithium Does Not Help Patients With Bipolar Disorder

Bipolar disorder is conventionally defined by the presence of discrete episodes of mania (or hypomania in the case of bipolar II disorder) and depression, but this definition does not fully encompass the true character and course of the syndrome. The majority of patients with bipolar disorder experience persistent interepisode mood symptoms and an intrinsic vulnerability to affective lability (1, 2). Thus, the lives of many patients with bipolar disorder (as well as those who love them) are complicated—and to a certain extent limited—by this persistent mood burden. It leads to markedly diminished quality of life, functioning, and productivity both for the patients (3, 4) and for their family and friends (5).
Effective pharmacotherapy for patients with bipolar disorder began in 1949 with Cade’s original article (6) describing the salutary effects of lithium carbonate for the treatment of patients with acute mania. This report led to double-blind active comparator studies that confirmed lithium’s efficacy as an acute antimanic agent (7). We now have a variety of pharmacological agents for treating acute mania, ranging from lithium to anticonvulsants to atypical antipsychotics. Effective pharmacotherapies and psychotherapies are also available for the acute treatment of bipolar depression, and many agents are effective against the recurrence of full mood episodes. However, we do not have evidence-based treatment strategies for eliminating persistent mood symptoms in bipolar patients or successful pharmacological strategies that decrease their vulnerability to mood lability. Currently, the majority of patients with bipolar disorder take multiple mood-stabilizing medications (8). Polypharmacy is costly, increases the side effect burden, increases the risk of untoward medication interactions, and greatly complicates the lives of our patients.
In this issue, Nierenberg et al. (9) report the primary results of the Lithium Treatment Moderate-Dose Use Study for bipolar disorder (LiTMUS), an effectiveness trial designed to determine if low-dosage lithium added to an optimized personalized treatment (OPT) regimen improves clinical outcome for bipolar I and bipolar II patients. There is some level of uncertainty about the minimum effective lithium level required for the treatment and prophylaxis of mood episodes in bipolar disorder, with several trials indicating that serum concentrations ≥0.8 mEq/L are associated with improved outcomes (1012). However, clinicians frequently use low-to-moderate dosages of lithium in addition to other medications as a strategy to maximize mood stability and reduce suicidality (13). Before LiTMUS, the question of whether this common clinical strategy offers meaningful therapeutic benefit had not been carefully addressed.
To be eligible for LiTMUS, patients had to have clinically significant symptoms that warranted a change in treatment, for which the treating physician believed lithium was a reasonable therapeutic option. Medications selected by the physician were guided by the Texas Implementation of Medication Algorithm for bipolar I disorder (14), with oversight by a study-independent bipolar disorder expert to ensure adherence to the guidelines. Patients were randomly assigned to receive either OPT (requiring treatment with at least one mood stabilizer, exclusive of lithium) or OPT plus a dosage of lithium fixed at 600 mg/day for the first 2 months, with subsequent dosage adjustments as clinically indicated. Two primary outcome measures were evaluated: the Clinical Global Impression Scale for Bipolar Disorder–Severity and “necessary clinical adjustments,” which consisted of any medication adjustments required to respond to a clinical need.
The primary conclusion of the trial was that low-dosage lithium did not provide any additional benefit beyond guideline-driven care. Only one-quarter of the patients in either group achieved sustained remission. The two groups of participants had similar scores on secondary outcome measures of mood symptoms, functioning, and suicidal ideation. Twenty-one percent of the lithium-plus-OPT patients discontinued lithium, compared with only 2% of the OPT patients who elected to discontinue their mood stabilizers. Thus, even with low to moderate dosages of lithium, problems with adherence remained. In both groups, patients had an average of 2.6 prescriptions in addition to the lithium for the lithium-plus-OPT group. The one intriguing difference between the treatment groups was that the lithium-treated patients were less likely to receive an atypical antipsychotic. Given that the lithium-plus-OPT group reported significantly more manic or hypomanic episodes in the year before the randomized study than the OPT group (5.2 and 3.2, respectively), this finding may merit follow-up investigation.
The failure to detect a difference between the OPT-only and lithium-plus-OPT groups may stem in part from the design of the study. Patients who reported a treatment failure with lithium therapy in a previous episode were allowed to participate in the study. Thus, the authors may have inadvertently biased the sample against lithium augmentation. A second factor that may have affected the outcome of the study was that over half of the lithium-treated patients had blood levels <0.4 mEq/L; this concentration may have been too low for lithium augmentation to have a true pharmacological effect. Another study design feature that “raised the bar” was the use of the Texas Implementation of Medication Algorithm by expert psychopharmacologists. With treatment optimized in this fashion, lithium augmentation would have to demonstrate a rather profound additional clinical benefit to differentiate itself from OPT.
A number of important lessons can be learned from the LiTMUS trial. First, one sees the power of employing a well-organized network of investigators to perform a clinical trial. The authors completed a 6-month randomized trial with 283 patients within a 2-year period. This is a remarkably rapid recruitment and completion time for any type of clinical study. Second, this trial pioneered the use of a new ecologically important approach to assessing outcome—the number of necessary clinical adjustments. This is a clinically relevant method of capturing the impact of a treatment intervention for patients suffering from a chronic syndrome that has a fluctuating course. The study also highlights the importance and value of investing in large trials that are designed to answer common clinical treatment questions. The results of this trial suggest that the addition of moderate dosages of lithium to optimized guideline-driven therapy does not confer any advantage in terms of symptom relief, functioning, or quality of life.
The authors anticipate future analyses to identify predictors or subgroups of patients for whom lithium plus OPT is effective. Individual-level predictors of response to specific treatments are an important research priority. They offer the promise of a more effective and satisfying experience for patients with psychiatric syndromes. Predictors of lithium response identified from this study may complement the Pharmacogenomics of Bipolar Disorder research collaboration that is exploring the predictive value of genetic markers of lithium response (15). However, until the promise of individual predictors of response is realized, patients will be best served by treatment based on large-scale, pragmatic studies such as LiTMUS.

References

1.
Judd LL, Schettler PJ, Akiskal HS, Coryell W, Leon AC, Maser JD, Solomon DA: Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry 2008; 65:386–394
2.
Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, Ketter TA, Miklowitz DJ, Otto MW, Gyulai L, Reilly-Harrington NA, Nierenberg AA, Sachs GS, Thase ME: Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2006; 163:217–224
3.
Marangell LB, Dennehy EB, Miyahara S, Wisniewski SR, Bauer MS, Rapaport MH, Allen MH: The functional impact of subsyndromal depressive symptoms in bipolar disorder: data from STEP-BD. J Affect Disord 2009; 114:58–67
4.
Michalak EE, Murray G, Young AH, Lam RW: Quality of life impairment in bipolar disorder, in Quality of Life Impairment in Schizophrenia, Mood and Anxiety Disorders: From Brain Functions to Clinical Practice. Edited by, Ritsner M. New York, Springer, 2007, pp 163–174
5.
Perlick DA, Clarkin JF, Sirey J, Raue P, Greenfield S, Struening E, Rosenheck R: Burden experienced by caregivers of persons with bipolar affective disorder. Br J Psychiatry 1999; 174:56–62
6.
Cade JF: Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2:349–352
7.
Prien RF, Caffey EM, Klett CJ: Comparison of lithium carbonate and chlorpromazine in the treatment of mania: report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry 1972; 26:146–153
8.
Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J: Patterns of psychotropic drug prescription for US patients with diagnoses of bipolar disorders. Psychiatr Serv 2007; 58:85–91
9.
Nierenberg AA, Friedman ES, Bowden CL, Sylvia LG, Thase ME, Ketter T, Ostacher MJ, Leon AC, Reilly-Harrington N, Iosifescu DV, Pencina M, Severe JB, Calabrese JR: 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
10.
Prien RF, Caffey EM, Klett CJ: Relationship between serum lithium level and clinical response in acute mania treated with lithium. Br J Psychiatry 1972; 120:409–414
11.
Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD: Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158:906–912
12.
Gelenberg AJ, Kane JM, Keller MB, Lavori P, Rosenbaum JF, Cole K, Lavelle J: Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989; 321:1489–1493
13.
Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006; 8:625–639
14.
Suppes T, Dennehy EB, Hirschfeld RMA, Altshuler LL, Bowden CL, Calabrese JR, Crismon ML, Ketter TA, Sachs GS, Swann ACTexas Consensus Conference Panel on Medication Treatment of Bipolar Disorder: The Texas Implementation of Medication Algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry 2005; 66:870–886

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 9 - 11
PubMed: 23288384

History

Accepted: November 2012
Published online: 1 January 2013
Published in print: January 2013

Authors

Details

Boadie W. Dunlop, M.D., M.S.
From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.
Jeffrey J. Rakofsky, M.D.
From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.
Mark Hyman Rapaport, M.D.
From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.

Notes

Address correspondence to Dr. Rapaport ([email protected]).

Competing Interests

Dr. Dunlop has received grant support from Bristol-Myers Squibb, Evotec, Forest, GlaxoSmithKline, Pfizer, and NIH and has received consulting fees from Bristol-Myers Squibb, MedAvante, Pfizer, and Roche. Dr. Rakofsky has received research support from AstraZeneca, Novartis, and Takeda. Dr. Rapaport is an unpaid consultant for PAX Neuroscience. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share