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Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

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.

SUBMITTER: Machado-Vieira R

PROVIDER: S-EPMC4151672 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

Machado-Vieira Rodrigo R Zanetti Marcus V MV DE Sousa Rafael T RT Soeiro-DE-Souza Marcio G MG Moreno Ricardo A RA Busatto Geraldo F GF Gattaz Wagner F WF

Experimental and therapeutic medicine 20140724 4

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 ...[more]

PMID: 25187825

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Project description:BackgroundSublingually administered asenapine was approved in March 2015 by the United States Food and Drug Administration for patients aged 10-17 years with an acute manic or mixed episode associated with bipolar I disorder (BP-1). This is the first long-term safety and tolerability study of asenapine in this population.MethodsFollowing the 3-week randomized, double-blind, placebo-controlled trial of patients aged 10-17 years with an acute manic or mixed episode associated with BP-1, patients could enroll in this flexible-dose (2.5-10 mg twice daily) open-label extension (OLE) study for an additional 50 weeks, conducted from August 2011 to September 2014 in the United States and Russia. Treatment-emergent adverse events (TEAEs) were assessed and predefined TEAEs of interest reported in addition to metabolic and anthropometric parameters. The Young Mania Rating Scale (YMRS) and Clinical Global Impressions scale in bipolar illness (CGI-BP) were used to assess effectiveness.ResultsA total of 321 patients (lead-in study treatment: placebo, n = 80; asenapine, n = 241) were included; 267 (83.2 %) reported one or more TEAE and 181 (56.4 %) discontinued early, 48 (15.0 %) due to TEAEs. Of the predefined TEAEs of interest, combined somnolence/sedation/hypersomnia occurred most frequently (42.4 %) followed by oral hypoesthesia/dysgeusia (7.5 %). In total, 109 (34.8 %) patients experienced clinically significant weight gain (≥7 % increase). No clinically meaningful changes were noted for laboratory parameters measured. Eighteen patients met the criteria for new-onset metabolic syndrome (MBS) post-baseline during the extension study, whereas 10 patients who met MBS criteria at baseline did not meet MBS criteria at endpoint. A total of 12 patients met MBS at baseline and endpoint. Mean change in YMRS total score from OLE baseline was -9.2 points at week 50, and change in CGI-BP severity overall score was similar among all treatment groups (those who initially received asenapine and those who initially received placebo). After 26 weeks of treatment in the OLE, 79.2 % of patients were classified as YMRS 50 % responders relative to acute trial baseline.ConclusionsAsenapine was generally well tolerated in pediatric patients with BP-1 during ≤50 weeks of open-label treatment; among predefined TEAEs of interest, the combination of somnolence/sedation/hypersomnia was the most common. Trial registration ClinicalTrials.gov: NCT01349907.

Project description:BackgroundTo shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue.MethodsIn this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858.FindingsBetween April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events.InterpretationIn this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.FundingCenter for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.

Project description:BACKGROUND:The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. METHODS:This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder-Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified. RESULTS:Of 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (<?10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications. CONCLUSION:AOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment. Trial registration ClinicalTrials.gov, NCT01710709.

Project description:BackgroundThere is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report.MethodsWe conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel.FindingsThe subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept.InterpretationAbatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.

Dataset Information

Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

Publications

Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

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