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Editorials   |    
A Simple Question Answered: Adding Moderate-Dosage Lithium Does Not Help Patients With Bipolar Disorder
Boadie W. Dunlop, M.D., M.S.; Jeffrey J. Rakofsky, M.D.; Mark Hyman Rapaport, M.D.
Am J Psychiatry 2013;170:9-11. doi:10.1176/appi.ajp.2012.12111378
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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.

From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.

Address correspondence to Dr. Rapaport (Mark.h.rapaport@emory.edu).

Copyright © 2013 by the American Psychiatric Association

Accepted November , 2012.

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.

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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
 
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
[CrossRef] | [PubMed]
 
Cade  JF:  Lithium salts in the treatment of psychotic excitement.  Med J Aust 1949; 2:349–352
[PubMed]
 
Prien  RF;  Caffey  EM  Jr;  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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
 
Prien  RF;  Caffey  EM  Jr;  Klett  CJ:  Relationship between serum lithium level and clinical response in acute mania treated with lithium.  Br J Psychiatry 1972; 120:409–414
[CrossRef] | [PubMed]
 
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
[PubMed]
 
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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
Suppes  T;  Dennehy  EB;  Hirschfeld  RMA;  Altshuler  LL;  Bowden  CL;  Calabrese  JR;  Crismon  ML;  Ketter  TA;  Sachs  GS;  Swann  AC;  Texas 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
[CrossRef] | [PubMed]
 
References Container
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References

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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
 
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
[CrossRef] | [PubMed]
 
Cade  JF:  Lithium salts in the treatment of psychotic excitement.  Med J Aust 1949; 2:349–352
[PubMed]
 
Prien  RF;  Caffey  EM  Jr;  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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
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
 
Prien  RF;  Caffey  EM  Jr;  Klett  CJ:  Relationship between serum lithium level and clinical response in acute mania treated with lithium.  Br J Psychiatry 1972; 120:409–414
[CrossRef] | [PubMed]
 
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
[PubMed]
 
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
[CrossRef] | [PubMed]
 
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
[CrossRef] | [PubMed]
 
Suppes  T;  Dennehy  EB;  Hirschfeld  RMA;  Altshuler  LL;  Bowden  CL;  Calabrese  JR;  Crismon  ML;  Ketter  TA;  Sachs  GS;  Swann  AC;  Texas 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
[CrossRef] | [PubMed]
 
References Container
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