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Lithium Treatment Moderate-Dose Use Study (LiTMUS) for Bipolar Disorder: A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment With and Without Lithium
Andrew A. Nierenberg, M.D.; Edward S. Friedman, M.D.; Charles L. Bowden, M.D.; Louisa G. Sylvia, Ph.D.; Michael E. Thase, M.D.; Terence Ketter, M.D.; Michael J. Ostacher, M.D., M.P.H.; Andrew C. Leon, Ph.D.; Noreen Reilly-Harrington, Ph.D.; Dan V. Iosifescu, M.D.; Michael Pencina, Ph.D.; Joanne B. Severe, M.S.; Joseph R. Calabrese, M.D.
Am J Psychiatry 2013;170:102-110. doi:10.1176/appi.ajp.2012.12060751
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Dr. Nierenberg has received consulting fees, advisory board fees, research support, or speakers honoraria from American Drug Utilization Review, American Professional Society of ADHD and Related Disorders, American Psychiatric Association, American Society for Clinical Psychopharmacology, Appliance Computing (Mindsite), AstraZeneca, Basliea, Baystate Medical Center, Belvoir Publishing, Brain Cells, Brandeis University, Bristol-Myers Squibb, Columbia University, Corcept, Dainippon Sumitomo, Eli Lilly, EpiQ, Forest Pharmaceuticals, Hillside Hospital, IMEDEX, International Society for Bipolar Disorders, Johnson & Johnson, MJ Consulting, Medscape, MBL Publishing, New York State, NIMH, Novartis, PamLabs, Pfizer, PGx Health, Physicians Postgraduate Press, Ridge Diagnostics, Schering-Plough, SciMed, Shire, SUNY Buffalo, Takeda/Lundbeck, Targacept, Teva Pharmaceuticals, University of Texas Southwestern Dallas, University of Wisconsin, and University of Pisa; has consulted through the MGH Clinical Trials Network and Institute for Brain Cells, Dianippon Sumitomo/Sepracor, Johnson & Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Schering-Plough, Shire, Targacept, and Takeda/Lundbeck Pharmaceuticals; and owns stock options in Appliance Computing and Brain Cells. Through Massachusetts General Hospital, Dr. Nierenberg is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-Åsberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute. Dr. Nierenberg is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA). The education programs conducted by the MGHPA were supported through Independent Medical Education grants from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen Pharmaceuticals. Dr. Friedman has received consulting fees, advisory board fees, research support, royalties, or speakers honoraria from Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb, Cyberonics, Indevus, Medtronics, the NIMH Agency for Healthcare Research and Quality, NorthStar/St. Jude Medical, Novartis, Respironics, Sanofi-Aventis, Springer, and Wyeth-Ayerst. Dr. Bowden has received consulting fees, advisory board fees, research support, or speakers honoraria from Bristol-Myers Squibb, Johnson & Johnson, Merck Pfizer, NIMH, Repligen, and Sanofi-Aventis. Dr. Sylvia has received consulting fees from Bracket Global and Clintara, was a shareholder for Concordant Rater Systems, has received royalties from New Harbinger Publisher, and has presented for the MGHPA. Dr. Thase has received consulting fees, advisory board fees, research support, or speakers honoraria from AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly, Forest Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Merck, Neuronetics, the NIMH Agency for Healthcare Research Quality, Novartis, Ortho-McNeil Pharmaceuticals, Otsuka, PamLab, Pfizer, Schering-Plough, Sepracor, Shire, Supernus Pharmaceuticals, Takeda (Lundbeck), and Transcept Pharmaceuticals; has equity holdings in MedAvante; and has received royalty income from American Psychiatric Foundation, Guilford Publications, Herald House, Oxford University Press, and W.W. Norton. Dr. Thase’s spouse is employed by Embryon (formerly Advogent). Dr. Ketter has received consulting fees, advisory board fees, research support, royalties, or speakers honoraria from American Psychiatric Publishing, AstraZeneca, Astellas Pharmaceuticals, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Merck, the NIMH Agency for Healthcare Research and Quality, Noven Pharmaceuticals, Pfizer, Sunovion, and XenoPort. Dr. Ketter’s spouse is an employee with and holds stock in Johnson & Johnson. Dr. Ostacher has served as a consultant to Sunovion. Dr. Leon has served on independent data and safety monitoring boards for AstraZeneca, Pfizer, and Sunovion; has received consulting fees from the Food and Drug Administration, MedAvante, NIMH, and Roche; and held equity in MedAvante. Dr. Reilly-Harrington has received royalties from the American Psychological Association and Oxford University Press, was a shareholder in Concordant Rater Systems, and has received consulting fees from Bracket Global. Dr. Iosifescu has received consulting or advisory board fees from Aspect Medical, Forest Pharmaceuticals, Ortho-McNeil, and Reed Medical (sponsor of the Massachusetts General Hospital Psychiatry Academy). Dr. Pencina consults for Pamlab and RCT Logic. Ms. Severe is a former employee of NIMH. Dr. Calabrese has received consulting fees, advisory board fees, research support, or speakers honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Dainippon Sumitomo, Eli Lilly, EPI-Q, Forest Pharmaceuticals, France Foundation, GlaxoSmithKline, Health Resources Services Administration, Janssen, Johnson & Johnson, Lundbeck, Merck, NARSAD, Neurosearch, NIMH, Ortho-McNeil, Otsuka, Pfizer, Repligen, Schering-Plough, Servier, Solvay, Stanley Medical Research Institute, Supernus, Synosia, Takeda, the US Department of Defense, and Wyeth, and has provided CME lectures supported by AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson, Merck, Pfizer, Sanofi-Aventis, Schering-Plough, Solvay, and Wyeth.

Dr. Leon died in February 2012.

Funded by NIMH contract NO1MH80001.

ClinicalTrials.gov number NCT00667745.

From Massachusetts General Hospital, Boston; the University of Pittsburgh School of Medicine; the University of Texas Health Science Center, San Antonio; the University of Pennsylvania School of Medicine, Philadelphia; Stanford University, Stanford, Calif.; Weill Cornell Medical College, New York; Mount Sinai School of Medicine, New York; Harvard Clinical Research Institute, Boston; NIMH, Rockville, Md.; and Case Western Reserve University School of Medicine, Cleveland.

Address correspondence to Dr. Nierenberg (anierenberg@partners.org).

Copyright © 2013 by the American Psychiatric Association

Received June 06, 2012; Revised July 12, 2012; Accepted August 02, 2012.

Abstract

Objective  Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).

Method  The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder–Severity (CGI-BP-S) and “necessary clinical adjustments” (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.

Results  The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).

Conclusions  In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

Abstract Teaser
Figures in this Article

Bipolar disorder is one of the most severely disabling psychiatric disorders (1), characterized by manic, hypomanic, depressive, and mixed syndromal episodes, as well as persistent interepisodic mood symptoms and high levels of vocational impairment (2, 3). As of 2009, the estimated direct and indirect costs of bipolar disorder in the United States are $151 billion annually (4). Long-term outcomes, even with the best available guideline-consistent treatments, tend to be poor for many patients (5).

Although many medications are now approved for acute and maintenance treatment of bipolar disorder, the gold standard for many years has been lithium salts. Nevertheless, the use of lithium, especially as monotherapy, has been steadily declining (6). When clinicians do prescribe lithium, they usually give it along with other medications approved for the treatment of bipolar disorder or associated symptoms (with a median total of three medications [7]). Randomized clinical efficacy trials support combining lithium with second-generation antipsychotics (810) for acute mania or mixed episodes. The use of lithium with additional medications, however, has not been well studied, although complex combination therapy has become the de facto standard of care (7, 11, 12).

Since lithium, even at low dosages, has potent neuroprotective properties that could be synergistic with other medications (13, 14) and may reduce the risk of dementia (15) there is a great public health need to compare the effectiveness of personalized flexible medication regimens with and without lower, more tolerable dosages of lithium for acute and continuation treatment. The Lithium Treatment Moderate-Dose Use Study (LiTMUS) was designed to address whether a tolerable dosage of lithium, in combination with other medications for bipolar disorder, would result in better outcomes over 6 months (16). This comparative effectiveness study bridges the gap between rigorous but less ecologically valid placebo-controlled efficacy trials and real-world clinical practice to provide data to help clinicians make empirically based clinical decisions.

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Study Design

This six-site, parallel-group, randomized effectiveness study evaluated patients with bipolar I or II disorder who were at least mildly ill, had not previously been treated with adjunctive lithium in moderate dosages during the current episode, and were willing to be randomly assigned to one of two treatment groups: lithium plus optimized personalized treatment (OPT), a guideline-informed, evidence-based, and personalized treatment based on current symptoms, treatment history, and course of illness, or OPT alone. A total of 283 participants were enrolled over 18 months and followed for 6 months. Although we considered a longer study, we chose 6 months to maximize feasibility and retention. At the time of enrollment, participants were experiencing mood symptoms of sufficient intensity that a change in treatment was warranted and that, in the investigator’s judgment, lithium was a reasonable therapeutic option. All participants were assessed using structured diagnostic interviews, clinician-rated assessments, and questionnaires. The participants were interviewed using an extended version of a validated structured diagnostic interview, the Mini International Neuropsychiatric Interview (MINI-PLUS), to determine current and lifetime DSM-IV diagnoses (17). However, the substance use disorder module from the Structured Clinical Interview for DSM-IV, rather than that from the MINI-PLUS, was used because it provides additional detail regarding course specifiers.

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Study Participants

Participants were screened to verify that they met primary study criteria: age 18 years or older, diagnosis of bipolar I or II disorder, and currently symptomatic (Table 1). The primary exclusion criteria were any contraindication to lithium (e.g., prior hypersensitivity to lithium, severe cardiovascular or renal disease, or pregnancy), current crisis such that inpatient hospitalization or other crisis management should take priority, current lithium use, and unwillingness to comply with study requirements. The full study details have been described elsewhere (16).

 
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TABLE 1.Baseline Demographic and Clinical Measures in a Study of Optimized Personalized Treatment (OPT) With and Without Lithiuma
Table Footer Note

aMADRS=Montgomery-Åsberg Depression Rating Scale; CGI=Clinical Global Impressions Scale; YMRS=Young Mania Rating Scale.

Table Footer Note

bLithium-plus-OPT group, N=117; OPT-alone group, N=118.

Table Footer Note

cBoth groups, N=115. Significant difference between groups, p=0.026.

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Randomization and Treatment

Participants were randomly assigned to a treatment group through a web-based program. At each site, randomization was stratified by provider and prior lithium use.

Consistent with a true effectiveness or pragmatic clinical trial, participants were randomly assigned to OPT with or without lithium. OPT is an empirically supported strategy largely based on the Texas Implementation of Medication Algorithm (18). This treatment was provided by psychopharmacologists who are experts in the treatment of bipolar disorder, and it was personalized for each participant (i.e., treatment adjustments were not prespecified) using systematic diagnostic assessments, measurement-based care by tracking symptoms and side effects, and therapeutic blood levels of medications (when appropriate).

OPT allowed for the inclusion of a more generalizable sample because many patients with bipolar disorder have complex treatment histories. It allowed clinicians flexibility in using the best evidence-based treatment for bipolar mood states and for personalization of treatment in the context of prior medication exposure, response, and tolerability, which enhanced participant recruitment and minimized volunteer bias (19). The integrity of OPT and the comparability of randomized groups were monitored by an independent expert in the treatment of bipolar disorder during the course of the study. Specifically, this expert reviewed the medications prescribed for participants and changes in those medications to assess whether the clinician was following the recommendations for treating bipolar disorder as defined by the Texas Implementation of Medication Algorithm.

The lithium dosage was fixed at 600 mg/day for the first 2 months of the study to allow for an assessment period, during which all participants received low dosages. Thereafter, adjustments were made as clinically indicated.

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Outcomes

Two repeated-measure primary endpoints were specified. The first measure was the Clinical Global Impression Scale for Bipolar Disorder–Severity (CGI-BP-S), a reliable and valid assessment of global illness severity in bipolar disorder with excellent interrater reliability (20). The CGI-BP-S complements specific symptom severity scales by providing an integrated measure of illness severity that incorporates social and vocational functioning. Remission was defined as a CGI-BP-S score <2. We defined a change of 0.50 points on the CGI-BP-S as a clinically meaningful change based on previous drug-placebo differences, with mean changes between 0.3 and 0.95 units (2129).

The second primary outcome measure, “necessary clinical adjustments,” was developed for use in LiTMUS (16). Necessary clinical adjustments are a proxy for the clinical burden of a treatment strategy and capture the treatment changes that result from lack of efficacy or safety issues. They consist of all medication adjustments necessary to respond to clinical need, such as exacerbation of mood symptoms, emergence of a mood episode, persistence of symptoms, or adjustments because of adverse effects. Necessary clinical adjustments do not include planned dosage titrations or decreases in dosage based on the assessment of positive responses or the judgment that a medication is no longer required. The two primary study hypotheses were 1) that participants who were assigned to lithium plus OPT would exhibit greater improvement on CGI-BP-S scores over the 6-month course of the study relative to those assigned to OPT only and 2) that participants who were assigned to lithium plus OPT would require fewer necessary clinical adjustments over the course of 6 months relative to those assigned to OPT only.

Secondary analyses included an examination of changes in ratings of depression (Montgomery-Åsberg Depression Rating Scale [MADRS]), mania (Young Mania Rating Scale [YMRS]), and suicidal ideation (Beck Scale for Suicide Ideation) as well as serum lithium levels for the lithium-plus-OPT group. It was expected that the lithium-plus-OPT group would experience fewer symptoms and less suicidal ideation and receive fewer prescriptions for second-generation antipsychotics than the OPT-only group. Raters who were blind to treatment arm and study protocol/procedures assessed participants’ symptoms and functioning with the CGI-BP-S, MADRS, YMRS, and the Range of Impaired Functioning Tool (LIFE-RIFT) to attenuate rater bias. To maintain rater blinding, participants were instructed not to discuss their medications or side effects with the rater. In addition, at each visit a study coordinator who was not blind to treatment arm assessed rater blinding to ensure that blinding was maintained.

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Statistical Analysis

Because two primary outcome variables were identified, an alpha level of 0.025 defined statistical significance in testing each of the primary hypotheses. To examine the first primary hypothesis, we used mixed-effects linear regression analyses to compare the two intervention groups on repeated assessments with the CGI-BP-S over the 6-month trial (30). A treatment-by-time interaction was used to determine whether the rate of reduction in illness severity varied between the two groups over the course of acute treatment.

The two intervention groups were evaluated on necessary clinical adjustments using the Mann-Whitney test for the second primary hypothesis. To account for attrition (i.e., participants with varying study durations), necessary clinical adjustments were expressed per month rather than as a total count over the study duration.

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Sample size determination.

Statistical power analyses examined the sample size requirements to detect clinically meaningful differences on the two primary outcomes. The multiplicity-adjusted alpha level was used for sample size determination. The initial protocol specified recruitment of at least 264 participants (i.e., two participants per site for each of 22 months). However, to be conservative, power analyses assumed 125 participants in each treatment group and determined that power would exceed 80% for each primary hypothesis. As some sites exceeded the two patients per month projection, the actual total number of participants was 283.

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Attrition.

For the first hypothesis, we incorporated all available data from all randomized participants, even from those who dropped out, into the mixed-effects model. For the second hypothesis, we used separate analyses to compare the magnitude of the treatment effects across participants who were classified by attrition pattern (because of differential sample sizes expected across attrition patterns, this sensitivity analysis focused on the between-group effect sizes). Two strategies were used to examine the sensitivity of the assumption of ignorable attrition. First, we examined response to treatment among participants with various dropout patterns using a pattern mixture model (31, 32). Second, we used the intent-to-attend variable as a covariate to account for attrition in an effort to fulfill the assumption of ignorable attrition (33).

The CONSORT diagram in Figure 1 summarizes the study’s screening, recruitment, randomization, and attrition. The participants’ baseline demographic and clinical characteristics are summarized in Table 1. The majority of participants had bipolar I disorder (history of mania) and the remainder had bipolar II disorder (history of hypomania). Over half had a lifetime history of hospitalizations, and over 40% had a lifetime history of at least one suicide attempt.

 
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FIGURE 1.CONSORT Diagram of Participants in a Study of Optimized Personalized Treatment With and Without Lithiuma

a OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder).

The baseline CGI-BP-S scores indicated that over 85% of participants were at least moderately ill at study entry. Participants were mostly depressed, with 87% meeting DSM-IV criteria for recurrent major depressive episodes, 63% meeting criteria for a lifetime manic episode, and 38% for a lifetime hypomanic episode. No statistically significant differences were found between the groups for any variable except that the lithium-plus-OPT group had more manic episodes during the previous year (unadjusted p=0.026) than the OPT-only group. Mean overall CGI-BP-S scores decreased 1.36 points (SD=1.44), with mean decreases of 1.22 points (SD=1.50) for the lithium-plus-OPT group and 1.48 points (SD=1.37) for the OPT-only group.

Retention in the study was 84%, with no differences between the groups. However, whereas 21% of the lithium-plus-OPT group discontinued lithium prematurely, only 2% of the OPT-only group stopped taking a mood stabilizer or otherwise violated the treatment protocol (34). Participants took a mean of 2.59 psychiatric medications (SD=1.30), excluding lithium, over the study duration, with 2.56 medications (SD=1.33) in the lithium-plus-OPT group and 2.61 (SD=1.28) in the OPT-only group.

For patients in the lithium-plus-OPT group, lithium levels over time were 0.43 mEq/L at week 2 (N=115; median=0.40, SD=0.19, range=0.00–1.18), 0.44 mEq/L at week 12 (N=90; median=0.40, SD=0.29, range=0.00–1.60), and 0.47 mEq/L at week 24 (N=83; median=0.40, SD=0.34, range=0.00–1.80).

We observed no statistically significant symptomatic advantage of lithium plus OPT on CGI-BP-S scores or on necessary clinical adjustments across the 6-month study (Figures 2 and 3). A secondary Poisson regression model also showed no significant difference in log(necessary clinical adjustments/month+1) between the treatment groups, using log months follow-up as an offset. Necessary clinical adjustments changed a mean of 0.99 (SD=0.86) over 24 weeks, with a mean of 1.01 (SD=0.85) necessary clinical adjustments for the lithium-plus-OPT group and 0.98 (SD=0.87) for the OPT-only group.

 
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FIGURE 2.Overall Illness Severity Over Time (Observed Cases) in a Study of Optimized Personalized Treatment With and Without Lithiuma

a CGI-BP-S=Clinical Global Impression Scale for Bipolar Disorder–Severity; OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder). No significant differences were observed between groups.

 
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FIGURE 3.Necessary Clinical Adjustments (All Cases) in a Study of Optimized Personalized Treatment With and Without Lithiuma

a Necessary clinical adjustments consist of all medication adjustments necessary to respond to clinical need, such as exacerbation of mood symptoms, emergence of a mood episode, persistence of symptoms, or adjustments because of adverse effects. No significant differences were observed between groups. OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder).

No statistically significant differences were found between groups in the proportion of patients who experienced sustained remission (26.5% overall). Likewise, the groups had similar outcomes across secondary clinical measures, including depressive symptoms and manic symptoms. MADRS scores decreased by a mean of 8.53 points (SD=12.95), with 8.20 points (SD=12.29) for the lithium-plus-OPT group and 8.84 points (SD=13.59) for the OPT-only group. YMRS scores decreased by a mean of 6.06 points (SD=9.31), with 6.35 points (SD=10.09) for the lithium-plus-OPT group and 5.79 points (SD=8.45) for the OPT-only group. Notably, fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with patients in the OPT-only group (48.3% and 62.5%, respectively; p=0.028).

No differences were observed in treatment-emergent suicidal ideation (for those with a baseline score on the Beck Scale for Suicide Ideation of 0) or exacerbation of baseline suicidal ideation (for those with baseline score >0). Scale for Suicide Ideation scores improved a mean of 0.92 points (SD=3.94), with 0.73 points (SD=4.12) for the lithium-plus-OPT group and 1.10 (SD=3.77) for the OPT-only group. Serious adverse events, including suicidal behavior or psychiatric hospitalization due to suicide risk, were similar between the two groups. No deaths occurred.

Predictor and moderator analyses did not reveal any statistically significant associations between baseline variables and outcome.

In this comparative effectiveness study, we used minimal inclusion and exclusion criteria to recruit a representative group of outpatients with bipolar disorder who not only were substantially symptomatic but also had multiple psychiatric comorbid conditions. Most participants had a history of psychiatric hospitalizations and suicide attempts; many were disabled or unemployed. However, despite being ill for many years, most participants had never received an adequate course of lithium therapy during the current episode.

Overall, about one-quarter of participants in both groups achieved remission (as defined by CGI-BP-S score <2 for 2 months) along with improvements of 30% to 60% in baseline mood symptoms after 6 months of evidence-based, guideline-concordant treatment provided in specialty clinics. On the primary outcome measures, CGI-BP-S score and necessary clinical adjustments, lithium plus OPT conferred no clinical symptomatic advantage compared with OPT alone.

It is of particular interest that the lithium-plus-OPT group had, however, less exposure to second-generation antipsychotics (an absolute difference of about 14%; in terms of relative risk, patients treated with lithium plus OPT were about 23% less likely to take second-generation antipsychotics). Thus, we observed that the use of lower dosages of lithium resulted in significantly lower exposure to second-generation antipsychotics.

The average lithium blood levels for those taking lithium were <0.6 mEq/L, below the range typically considered to be therapeutic for acute phase therapy, which is consistent with the design of the study. However, lithium blood levels were relatively consistent across the 6 months of treatment, although the protocol permitted upward titration of lithium doses if clinically indicated. This indicates that study physicians may have become “locked in” to the lower dosage strategy and did not try to give maximally tolerated doses at optimal levels. Yet additional analyses found no relationship between improvement in MADRS or YMRS scores based on categories of lithium blood levels in the first 12 weeks (<0.4 mEq/L [N=47], 0.4–0.9 mEq/L [N=67], and >0.9 mEq/L [N=1]). The findings were similar for those in the low and higher lithium level categories at 24 weeks. Thus, participants who received higher dosages of lithium did not have superior outcomes, but results could be confounded by physicians increasing lithium dosages in response to more severe illness. In any event, our study was not designed to provide any information about the utility of higher lithium dosages in combination with OPT.

We could interpret the results of LiTMUS as simple confirmation that higher dosages and blood levels of lithium plus OPT would be required for efficacy beyond OPT alone. The classic study of lithium blood levels by Gelenberg et al. (35) suggested that levels >0.8 mmol/L are required for maintenance treatment. In that study, bipolar patients who were stable for 2 months while taking lithium (with blood levels between 0.6 and 1.0 mmol/L) were then randomly assigned to either lower levels (0.4–0.6 mmol/L) or higher levels (0.8–1.0 mmol/L). Those patients assigned to lower levels were 2.6 times more likely to have a mood episode. A reanalysis of these data found, however, that the relationship between blood levels and outcome was more complicated (36). Those patients who were taking low levels of lithium during the pre-randomization phase and were then randomly selected to continue with low levels stayed well. In contrast, those patients who took higher levels during the pre-randomization phase and were then assigned to low levels had higher rates of relapse relative to those who continued at higher levels. If anything, this reanalysis suggests that at least a subpopulation of bipolar patients could get well and stay well on lower blood levels of lithium monotherapy. Note that the low lithium blood levels in LiTMUS were not used as monotherapy or maintenance, but instead as part of an acute strategy of treatment in addition to active OPT. Results from LiTMUS revealed no additional symptomatic benefit with low to moderate dosages of lithium beyond OPT.

Other, more recent effectiveness studies of lithium have yielded findings consistent with the results of LiTMUS. Researchers in the BALANCE (Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation) study (37) compared maintenance therapy with lithium alone, divalproex alone, or combination treatment with both drugs for up to 2 years for patients who were initially stabilized with the combination. While the combination was statistically superior to divalproex alone, the overall outcomes were unfavorable, with relapse rates across the groups exceeding 50%. Similarly, researchers in another effectiveness study (38) compared lithium to lamotrigine maintenance after initial stabilization with any medication and found that only a minority of patients sustained stabilization, and most of those who stabilized experienced a clinically relevant event within the first 6 months of treatment assignment.

In our study, several factors could have decreased the probability of finding a difference between the groups if such a difference did exist, such as heterogeneity of the sample and the wide range of treatments permitted in OPT. It is plausible that a study focused on a narrower subgroup (e.g., rapid cycling bipolar I patients with manic or hypomanic symptoms) or using a single other medication (e.g., divalproex or a second-generation antipsychotic) could have yielded different results. With only about one-quarter of the sample reaching remission after 6 months of guideline-concordant treatment, it seems more likely that the group was, at best, partially responsive to treatment, indicating that symptoms of bipolar disorder can persist despite evidence-based pharmacotherapy.

Other potential study limitations include open treatment, which could have influenced physician prescribing behavior, with potential biases for and against lithium. Although the broad inclusion criteria and limited exclusion criteria enhanced generalizability, the burden of comorbid conditions could have limited responsiveness to treatment. The effectiveness of lithium could also have been compromised by persistent low dosages with the goal of enhanced tolerability, even in the context of insufficient response to lithium plus OPT. It is also possible, given that less than half of the participants were taking lithium in low dosages (blood levels, <0.4 mEq/L), that our study did not have enough power to detect clinically meaningful differences. Another potential confounding factor is that the lithium-plus-OPT group had more hypomanic or manic episodes in the preceding year compared with the OPT-only group. Additional analyses of the complex relationship between changes in lithium dosage (or absence of lithium therapy), adverse effects, and effectiveness are warranted.

In summary, we found no differences in symptomatic outcomes between the lithium-plus-OPT and OPT-only groups, although the lithium-plus-OPT group did receive significantly less exposure to second-generation antipsychotics. In the context of concerns about long-term adverse effects of second-generation antipsychotics, including metabolic syndrome and tardive dyskinesia (39), as well as a reappraisal of the benefit-to-risk ratio of lithium that suggests that the short- and long-term toxicity of lithium may have been overestimated (40), clinicians can use the results of this study to reconsider lithium for their bipolar patients. Given the modest clinical improvements overall, the LiTMUS findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

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Post  RM;  Altshuler  LL;  Frye  MA;  Suppes  T;  Keck  PE  Jr;  McElroy  SL;  Leverich  GS;  Luckenbaugh  DA;  Rowe  M;  Pizzarello  S;  Kupka  RW;  Grunze  H;  Nolen  WA:  Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder.  J Clin Psychiatry 2010; 71:1176–1186
[CrossRef] | [PubMed]
 
Yatham  LN;  Vieta  E;  Young  AH;  Möller  HJ;  Paulsson  B;  Vågerö  M:  A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania.  Int Clin Psychopharmacol 2007; 22:212–220
[CrossRef] | [PubMed]
 
Bowden  CL;  Vieta  E;  Ice  KS;  Schwartz  JH;  Wang  PP;  Versavel  M:  Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.  J Clin Psychiatry 2010; 71:130–137
[CrossRef] | [PubMed]
 
Vieta  E;  T’joen  C;  McQuade  RD;  Carson  WH  Jr;  Marcus  RN;  Sanchez  R;  Owen  R;  Nameche  L:  Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study.  Am J Psychiatry 2008; 165:1316–1325
[CrossRef] | [PubMed]
 
Frye  MA;  Ketter  TA;  Leverich  GS;  Huggins  T;  Lantz  C;  Denicoff  KD;  Post  RM:  The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study.  J Clin Psychiatry 2000; 61:9–15
[CrossRef] | [PubMed]
 
Levine  J;  Chengappa  KN;  Brar  JS;  Gershon  S;  Yablonsky  E;  Stapf  D;  Kupfer  DJ:  Psychotropic drug prescription patterns among patients with bipolar I disorder.  Bipolar Disord 2000; 2:120–130
[CrossRef] | [PubMed]
 
Manji  HK;  Moore  GJ;  Chen  G:  Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness.  Biol Psychiatry 2000; 48:740–754
[CrossRef] | [PubMed]
 
Mathew  SJ;  Manji  HK;  Charney  DS:  Novel drugs and therapeutic targets for severe mood disorders.  Neuropsychopharmacology 2008; 33:2080–2092
[CrossRef] | [PubMed]
 
Kessing  LV;  Søndergård  L;  Forman  JL;  Andersen  PK:  Lithium treatment and risk of dementia.  Arch Gen Psychiatry 2008; 65:1331–1335
[CrossRef] | [PubMed]
 
Nierenberg  AA;  Sylvia  LG;  Leon  AC;  Reilly-Harrington  NA;  Ketter  TA;  Calabrese  JR;  Thase  ME;  Bowden  CL;  Friedman  ES;  Ostacher  MJ;  Novak  L;  Iosifescu  DV;  Litmus Study Group:  Lithium Treatment Moderate-Dose Use Study (LiTMUS) for bipolar disorder: rationale and design.  Clin Trials 2009; 6:637–648
[CrossRef] | [PubMed]
 
Sheehan  DV;  Lecrubier  Y;  Sheehan  KH;  Amorim  P;  Janavs  J;  Weiller  E;  Hergueta  T;  Baker  R;  Dunbar  GC:  The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  J Clin Psychiatry 1998; 59(suppl 20):22–33
[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]
 
Ware  JH;  Hamel  MB:  Pragmatic trials: guides to better patient care? N Engl J Med 2011; 364:1685–1687
[CrossRef] | [PubMed]
 
Spearing  MK;  Post  RM;  Leverich  GS;  Brandt  D;  Nolen  W:  Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP.  Psychiatry Res 1997; 73:159–171
[CrossRef] | [PubMed]
 
Tohen  M;  Sanger  TM;  McElroy  SL;  Tollefson  GD;  Chengappa  KN;  Daniel  DG;  Petty  F;  Centorrino  F;  Wang  R;  Grundy  SL;  Greaney  MG;  Jacobs  TG;  David  SR;  Toma  V;  Olanzapine HGEH Study Group:  Olanzapine versus placebo in the treatment of acute mania.  Am J Psychiatry 1999; 156:702–709
[PubMed]
 
Tohen  M;  Jacobs  TG;  Grundy  SL;  McElroy  SL;  Banov  MC;  Janicak  PG;  Sanger  T;  Risser  R;  Zhang  F;  Toma  V;  Francis  J;  Tollefson  GD;  Breier  A;  The Olanzipine HGGW Study Group:  Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study.  Arch Gen Psychiatry 2000; 57:841–849
[CrossRef] | [PubMed]
 
Hirschfeld  RM;  Keck  PE  Jr;  Kramer  M;  Karcher  K;  Canuso  C;  Eerdekens  M;  Grossman  F:  Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial.  Am J Psychiatry 2004; 161:1057–1065
[CrossRef] | [PubMed]
 
Bowden  CL;  Grunze  H;  Mullen  J;  Brecher  M;  Paulsson  B;  Jones  M;  Vågerö  M;  Svensson  K:  A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.  J Clin Psychiatry 2005; 66:111–121
[CrossRef] | [PubMed]
 
McIntyre  RS;  Brecher  M;  Paulsson  B;  Huizar  K;  Mullen  J:  Quetiapine or haloperidol as monotherapy for bipolar mania: a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial.  Eur Neuropsychopharmacol 2005; 15:573–585
[CrossRef] | [PubMed]
 
Sachs  G;  Sanchez  R;  Marcus  R;  Stock  E;  McQuade  R;  Carson  W;  Abou-Gharbia  N;  Impellizzeri  C;  Kaplita  S;  Rollin  L;  Iwamoto  T;  Aripiprazole Study Group:  Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study.  J Psychopharmacol 2006; 20:536–546
[CrossRef] | [PubMed]
 
Keck  PE  Jr;  Versiani  M;  Potkin  S;  West  SA;  Giller  E;  Ice  K;  Ziprasidone in Mania Study Group:  Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial.  Am J Psychiatry 2003; 160:741–748
[CrossRef] | [PubMed]
 
Potkin  SG;  Keck  PE  Jr;  Segal  S;  Ice  K;  English  P:  Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial.  J Clin Psychopharmacol 2005; 25:301–310
[CrossRef] | [PubMed]
 
Calabrese  JR;  Bowden  CL;  Sachs  GS;  Ascher  JA;  Monaghan  E;  Rudd  GD;  Lamictal 602 Study Group:  A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.  J Clin Psychiatry 1999; 60:79–88
[CrossRef] | [PubMed]
 
Laird  NM;  Ware  JH:  Random-effects models for longitudinal data.  Biometrics 1982; 38:963–974
[CrossRef] | [PubMed]
 
Little  RJ;  Wang  Y:  Pattern-mixture models for multivariate incomplete data with covariates.  Biometrics 1996; 52:98–111
[CrossRef] | [PubMed]
 
Hedeker  D;  Gibbons  RD:  Application of random-effects pattern-mixture models for missing data in longitudinal studies.  Psychol Methods 1997; 2:64–78
[CrossRef]
 
Leon  AC;  Demirtas  H;  Hedeker  D:  Bias reduction with an adjustment for participants’ intent to dropout of a randomized controlled clinical trial.  Clin Trials 2007; 4:540–547
[CrossRef] | [PubMed]
 
Sylvia  LG;  Reilly-Harrington  NA;  Leon  AC;  Kansky  CI;  Ketter  TA;  Calabrese  JR;  Thase  ME;  Bowden  CL;  Friedman  ES;  Ostacher  MJ;  Iosifescu  DV;  Severe  J;  Keyes  M;  Nierenberg  AA:  Methods to limit attrition in longitudinal comparative effectiveness trials: lessons from the Lithium Treatment–Moderate Dose Use Study (LiTMUS) for bipolar disorder.  Clin Trials 2012; 9:94–101
[CrossRef] | [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]
 
Perlis  RH;  Sachs  GS;  Lafer  B;  Otto  MW;  Faraone  SV;  Kane  JM;  Rosenbaum  JF:  Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data.  Am J Psychiatry 2002; 159:1155–1159
[CrossRef] | [PubMed]
 
Geddes  JR;  Goodwin  GM;  Rendell  J;  Azorin  JM;  Cipriani  A;  Ostacher  MJ;  Morriss  R;  Alder  N;  Juszczak  E;  BALANCE Investigators and Collaborators:  Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open-label trial.  Lancet 2010; 375:385–395
[CrossRef] | [PubMed]
 
Licht  RW;  Nielsen  JN;  Gram  LF;  Vestergaard  P;  Bendz  H:  Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice: the 6th trial of the Danish University Antidepressant Group (DUAG-6).  Bipolar Disord 2010; 12:483–493
[CrossRef] | [PubMed]
 
Correll  CU;  Schenk  EM:  Tardive dyskinesia and new antipsychotics.  Curr Opin Psychiatry 2008; 21:151–156
[CrossRef] | [PubMed]
 
Malhi  GS;  Tanious  M;  Das  P;  Berk  M:  The science and practice of lithium therapy.  Aust N Z J Psychiatry 2012; 46:192–211
[CrossRef] | [PubMed]
 
References Container

FIGURE 1. CONSORT Diagram of Participants in a Study of Optimized Personalized Treatment With and Without Lithiuma

a OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder).

FIGURE 2. Overall Illness Severity Over Time (Observed Cases) in a Study of Optimized Personalized Treatment With and Without Lithiuma

a CGI-BP-S=Clinical Global Impression Scale for Bipolar Disorder–Severity; OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder). No significant differences were observed between groups.

FIGURE 3. Necessary Clinical Adjustments (All Cases) in a Study of Optimized Personalized Treatment With and Without Lithiuma

a Necessary clinical adjustments consist of all medication adjustments necessary to respond to clinical need, such as exacerbation of mood symptoms, emergence of a mood episode, persistence of symptoms, or adjustments because of adverse effects. No significant differences were observed between groups. OPT=optimized personalized treatment (guideline-informed, evidence-based, and personalized based on current symptoms, prior treatment history, and course of disorder).

Anchor for Jump
TABLE 1.Baseline Demographic and Clinical Measures in a Study of Optimized Personalized Treatment (OPT) With and Without Lithiuma
Table Footer Note

aMADRS=Montgomery-Åsberg Depression Rating Scale; CGI=Clinical Global Impressions Scale; YMRS=Young Mania Rating Scale.

Table Footer Note

bLithium-plus-OPT group, N=117; OPT-alone group, N=118.

Table Footer Note

cBoth groups, N=115. Significant difference between groups, p=0.026.

+

References

Kessler  RC;  Chiu  WT;  Demler  O;  Merikangas  KR;  Walters  EE:  Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.  Arch Gen Psychiatry 2005; 62:617–627
[CrossRef] | [PubMed]
 
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]
 
Merikangas  KR;  Akiskal  HS;  Angst  J;  Greenberg  PE;  Hirschfeld  RMA;  Petukhova  M;  Kessler  RC:  Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication.  Arch Gen Psychiatry 2007; 64:543–552
[CrossRef] | [PubMed]
 
Dilsaver  SC:  An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009.  J Affect Disord 2011; 129:79–83
[CrossRef] | [PubMed]
 
Judd  LL;  Akiskal  HS;  Schettler  PJ;  Endicott  J;  Maser  J;  Solomon  DA;  Leon  AC;  Rice  JA;  Keller  MB:  The long-term natural history of the weekly symptomatic status of bipolar I disorder.  Arch Gen Psychiatry 2002; 59:530–537
[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]
 
Post  RM;  Altshuler  LL;  Frye  MA;  Suppes  T;  Keck  PE  Jr;  McElroy  SL;  Leverich  GS;  Luckenbaugh  DA;  Rowe  M;  Pizzarello  S;  Kupka  RW;  Grunze  H;  Nolen  WA:  Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder.  J Clin Psychiatry 2010; 71:1176–1186
[CrossRef] | [PubMed]
 
Yatham  LN;  Vieta  E;  Young  AH;  Möller  HJ;  Paulsson  B;  Vågerö  M:  A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania.  Int Clin Psychopharmacol 2007; 22:212–220
[CrossRef] | [PubMed]
 
Bowden  CL;  Vieta  E;  Ice  KS;  Schwartz  JH;  Wang  PP;  Versavel  M:  Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.  J Clin Psychiatry 2010; 71:130–137
[CrossRef] | [PubMed]
 
Vieta  E;  T’joen  C;  McQuade  RD;  Carson  WH  Jr;  Marcus  RN;  Sanchez  R;  Owen  R;  Nameche  L:  Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study.  Am J Psychiatry 2008; 165:1316–1325
[CrossRef] | [PubMed]
 
Frye  MA;  Ketter  TA;  Leverich  GS;  Huggins  T;  Lantz  C;  Denicoff  KD;  Post  RM:  The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study.  J Clin Psychiatry 2000; 61:9–15
[CrossRef] | [PubMed]
 
Levine  J;  Chengappa  KN;  Brar  JS;  Gershon  S;  Yablonsky  E;  Stapf  D;  Kupfer  DJ:  Psychotropic drug prescription patterns among patients with bipolar I disorder.  Bipolar Disord 2000; 2:120–130
[CrossRef] | [PubMed]
 
Manji  HK;  Moore  GJ;  Chen  G:  Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness.  Biol Psychiatry 2000; 48:740–754
[CrossRef] | [PubMed]
 
Mathew  SJ;  Manji  HK;  Charney  DS:  Novel drugs and therapeutic targets for severe mood disorders.  Neuropsychopharmacology 2008; 33:2080–2092
[CrossRef] | [PubMed]
 
Kessing  LV;  Søndergård  L;  Forman  JL;  Andersen  PK:  Lithium treatment and risk of dementia.  Arch Gen Psychiatry 2008; 65:1331–1335
[CrossRef] | [PubMed]
 
Nierenberg  AA;  Sylvia  LG;  Leon  AC;  Reilly-Harrington  NA;  Ketter  TA;  Calabrese  JR;  Thase  ME;  Bowden  CL;  Friedman  ES;  Ostacher  MJ;  Novak  L;  Iosifescu  DV;  Litmus Study Group:  Lithium Treatment Moderate-Dose Use Study (LiTMUS) for bipolar disorder: rationale and design.  Clin Trials 2009; 6:637–648
[CrossRef] | [PubMed]
 
Sheehan  DV;  Lecrubier  Y;  Sheehan  KH;  Amorim  P;  Janavs  J;  Weiller  E;  Hergueta  T;  Baker  R;  Dunbar  GC:  The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  J Clin Psychiatry 1998; 59(suppl 20):22–33
[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]
 
Ware  JH;  Hamel  MB:  Pragmatic trials: guides to better patient care? N Engl J Med 2011; 364:1685–1687
[CrossRef] | [PubMed]
 
Spearing  MK;  Post  RM;  Leverich  GS;  Brandt  D;  Nolen  W:  Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP.  Psychiatry Res 1997; 73:159–171
[CrossRef] | [PubMed]
 
Tohen  M;  Sanger  TM;  McElroy  SL;  Tollefson  GD;  Chengappa  KN;  Daniel  DG;  Petty  F;  Centorrino  F;  Wang  R;  Grundy  SL;  Greaney  MG;  Jacobs  TG;  David  SR;  Toma  V;  Olanzapine HGEH Study Group:  Olanzapine versus placebo in the treatment of acute mania.  Am J Psychiatry 1999; 156:702–709
[PubMed]
 
Tohen  M;  Jacobs  TG;  Grundy  SL;  McElroy  SL;  Banov  MC;  Janicak  PG;  Sanger  T;  Risser  R;  Zhang  F;  Toma  V;  Francis  J;  Tollefson  GD;  Breier  A;  The Olanzipine HGGW Study Group:  Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study.  Arch Gen Psychiatry 2000; 57:841–849
[CrossRef] | [PubMed]
 
Hirschfeld  RM;  Keck  PE  Jr;  Kramer  M;  Karcher  K;  Canuso  C;  Eerdekens  M;  Grossman  F:  Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial.  Am J Psychiatry 2004; 161:1057–1065
[CrossRef] | [PubMed]
 
Bowden  CL;  Grunze  H;  Mullen  J;  Brecher  M;  Paulsson  B;  Jones  M;  Vågerö  M;  Svensson  K:  A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.  J Clin Psychiatry 2005; 66:111–121
[CrossRef] | [PubMed]
 
McIntyre  RS;  Brecher  M;  Paulsson  B;  Huizar  K;  Mullen  J:  Quetiapine or haloperidol as monotherapy for bipolar mania: a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial.  Eur Neuropsychopharmacol 2005; 15:573–585
[CrossRef] | [PubMed]
 
Sachs  G;  Sanchez  R;  Marcus  R;  Stock  E;  McQuade  R;  Carson  W;  Abou-Gharbia  N;  Impellizzeri  C;  Kaplita  S;  Rollin  L;  Iwamoto  T;  Aripiprazole Study Group:  Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study.  J Psychopharmacol 2006; 20:536–546
[CrossRef] | [PubMed]
 
Keck  PE  Jr;  Versiani  M;  Potkin  S;  West  SA;  Giller  E;  Ice  K;  Ziprasidone in Mania Study Group:  Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial.  Am J Psychiatry 2003; 160:741–748
[CrossRef] | [PubMed]
 
Potkin  SG;  Keck  PE  Jr;  Segal  S;  Ice  K;  English  P:  Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial.  J Clin Psychopharmacol 2005; 25:301–310
[CrossRef] | [PubMed]
 
Calabrese  JR;  Bowden  CL;  Sachs  GS;  Ascher  JA;  Monaghan  E;  Rudd  GD;  Lamictal 602 Study Group:  A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.  J Clin Psychiatry 1999; 60:79–88
[CrossRef] | [PubMed]
 
Laird  NM;  Ware  JH:  Random-effects models for longitudinal data.  Biometrics 1982; 38:963–974
[CrossRef] | [PubMed]
 
Little  RJ;  Wang  Y:  Pattern-mixture models for multivariate incomplete data with covariates.  Biometrics 1996; 52:98–111
[CrossRef] | [PubMed]
 
Hedeker  D;  Gibbons  RD:  Application of random-effects pattern-mixture models for missing data in longitudinal studies.  Psychol Methods 1997; 2:64–78
[CrossRef]
 
Leon  AC;  Demirtas  H;  Hedeker  D:  Bias reduction with an adjustment for participants’ intent to dropout of a randomized controlled clinical trial.  Clin Trials 2007; 4:540–547
[CrossRef] | [PubMed]
 
Sylvia  LG;  Reilly-Harrington  NA;  Leon  AC;  Kansky  CI;  Ketter  TA;  Calabrese  JR;  Thase  ME;  Bowden  CL;  Friedman  ES;  Ostacher  MJ;  Iosifescu  DV;  Severe  J;  Keyes  M;  Nierenberg  AA:  Methods to limit attrition in longitudinal comparative effectiveness trials: lessons from the Lithium Treatment–Moderate Dose Use Study (LiTMUS) for bipolar disorder.  Clin Trials 2012; 9:94–101
[CrossRef] | [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]
 
Perlis  RH;  Sachs  GS;  Lafer  B;  Otto  MW;  Faraone  SV;  Kane  JM;  Rosenbaum  JF:  Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data.  Am J Psychiatry 2002; 159:1155–1159
[CrossRef] | [PubMed]
 
Geddes  JR;  Goodwin  GM;  Rendell  J;  Azorin  JM;  Cipriani  A;  Ostacher  MJ;  Morriss  R;  Alder  N;  Juszczak  E;  BALANCE Investigators and Collaborators:  Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open-label trial.  Lancet 2010; 375:385–395
[CrossRef] | [PubMed]
 
Licht  RW;  Nielsen  JN;  Gram  LF;  Vestergaard  P;  Bendz  H:  Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice: the 6th trial of the Danish University Antidepressant Group (DUAG-6).  Bipolar Disord 2010; 12:483–493
[CrossRef] | [PubMed]
 
Correll  CU;  Schenk  EM:  Tardive dyskinesia and new antipsychotics.  Curr Opin Psychiatry 2008; 21:151–156
[CrossRef] | [PubMed]
 
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