Lithium Treatment Moderate-Dose Use Study (LiTMUS) for Bipolar Disorder: A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment With and Without Lithium

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
American Journal of Psychiatry (Impact Factor: 12.3). 01/2013; 170(1):102-10. DOI: 10.1176/appi.ajp.2012.12060751
Source: PubMed


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).

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.

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).

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.

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    • "The CHRT-SR was administered as part of the LiTMUS trial, which is described in detail elsewhere (Nierenberg et al., 2009, 2013). Participants were 283 subjects with bipolar I or II disorder who were randomized to receive open-label lithium plus OPT or OPT without lithium. "
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    ABSTRACT: Objective: People with bipolar disorder are at high risk of suicide, but no clinically useful scale has been validated in this population. The aim of this study was to evaluate the psychometric properties in bipolar disorder of the 7- and 12-item versions of the Concise Health Risk Tracking Self-Report (CHRT-SR), a scale measuring suicidal ideation, suicidal behavior, and associated symptoms. Methods: The CHRT was administered to 283 symptomatic outpatients with bipolar I or II disorder who were randomized to receive lithium plus optimized personalized treatment (OPT), or OPT without lithium in a six month longitudinal comparative effectiveness trial. Participants were assessed using structured diagnostic interviews, clinician-rated assessments, and self-report questionnaires. Results: The internal consistency (Cronbach α) was 0.80 for the 7-item CHRT-SR and 0.90 for the 12-item CHRT-SR with a consistent factor structure, and three independent factors (current suicidal thoughts and plans, hopelessness, and perceived lack of social support) for the 7-item version. CHRT-SR scores are correlated with measures of depression, functioning, and quality of life, but not with mania scores. Conclusions: The 7- and 12-item CHRT-SR both had excellent psychometric properties in a sample of symptomatic subjects with bipolar disorder. The scale is highly correlated with depression, functioning, and quality of life, but not with mania. Future research is needed to determine whether the CHRT-SR will be able to predict suicide attempts in clinical practice.
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    • "More recently, it was observed that lower plasma lithium levels (0.4–0.6 mEq/l) were associated with higher relapse rates in maintenance therapy (8). However, a recent large study, involving a 24-week follow-up, revealed no association between an improvement in depression or mania ratings in patients with BD and their blood lithium levels [low (<0.4 mEq/l) vs. high (0.4–0.9 mEq/l)] (9). Furthermore, a reanalysis of the study by Gelenberg et al (7) demonstrated that patients treated with low levels of lithium during the pre- and post-randomization phases remained stable during the study period (10). "
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    ABSTRACT: Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ≥18 at baseline. Subjects were divided into two groups, with higher (Li ≥0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.
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    • "of the Lithium Treatment Moderate Dose Use Study ( LiTMUS ) , funded by the National Institute of Mental Health . LiTMUS was a multi - site , prospective , randomized , comparative effectiveness clinical trial of outpatients with BD . The nature , scope , and overall design of the research project have previously been described in greater detail ( Nierenberg et al . , 2009 , 2013 ) . Participants were screened to verify that they met primary in - clusion criteria : age 18 years or older , diagnosis of bipolar I or II disorder , and currently symptomatic , as defined as CGI - BP - S score ! 3 . Primary exclusion criteria were any contraindication to lithium ( e . g . , prior hypersensitivity to lithium , severe c"
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    ABSTRACT: This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. ( number NCT00667745).
    Full-text · Article · Jul 2013 · Journal of Psychiatric Research
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