Comparative Efficacy of Dopamine Partial Agonists by Doses for Treatment-Resistant Depression: A Systematic Review and Dose-Response Model-Based Network Meta-analysis.

BACKGROUND: The augmentative antidepressant effects of dopamine partial agonists (aripiprazole, brexpiprazole, and cariprazine) for treatment-resistant depression have been compared in a previous network meta-analysis. However, the comparative efficacy of the dose-responses of these drugs remains unclear. Therefore, we aimed to estimate the dose-response relationships and compare the effects of each dopamine partial agonist doses. METHODS: We conducted a systematic review of the Cochrane Library, PubMed, CINHAL, and ClinicalTrials.gov databases until January 1, 2023. Double-blind, randomized, placebo-controlled trials evaluating aripiprazole, brexpiprazole, and cariprazine for treatment-resistant depression were included. A random-effect dose-response model-based network meta-analysis was conducted. This study was registered in PROSPERO (CRD42023393035). RESULTS: The maximum effective doses were 5.5 mg for aripiprazole, 1.6 mg for brexpiprazole, and 1.5 mg for cariprazine, respectively. Although all doses of the 3 drugs were significantly more effective than placebo, aripiprazole ranging from 5.5 to 12.5 mg was significantly more effective than brexpiprazole 0.5 mg and cariprazine ranging from 0.5 to 1 mg. Moreover, aripiprazole ranging from 7.5 to 12.5 mg was significantly more effective than all doses of cariprazine. In addition, brexpiprazole ranging from 1 to 3 mg was significantly more effective than cariprazine 0.5 mg and brexpiprazole ranging from 1.6 to 2.5 mg was significantly superior to cariprazine 1 mg. There were no doses at which brexpiprazole overcame aripiprazole, and cariprazine overcame aripiprazole or brexpiprazole. CONCLUSIONS: Aripiprazole, brexpiprazole, and cariprazine may be effective in treatment-resistant depression in that order, with the maximum effective doses at 5.5 mg, 1.6 mg, and 1.5 mg, respectively.

Comparative Efficacy, Tolerability, and Acceptability of Donanemab, Lecanemab, Aducanumab, Melatonin, and Aerobic Exercise for a Short Time on Cognitive Function in Mild Cognitive Impairment and Mild Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Background: The Food and Drug Administration (FDA) has approved lecanemab and aducanumab and is reviewing donanemab, but they have questionable efficacy, serious side effects and are costly, whereas melatonin administration and aerobic exercise for a short time may overcome these problems. Objective: We aim to compare the efficacy on cognitive function, tolerability and acceptability of melatonin administration and aerobic exercise for a short time with donanemab, lecanemab, and aducanumab in people with mild AD and MCI. Methods: We systematically reviewed relevant randomized placebo-controlled trials (RCTs) in PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov and performed network meta-analyses. Results: The analysis included 10 randomized placebo-controlled trials with 4,599 patients. Although melatonin and aerobic exercise for a short time were significantly more effective than donanemab, lecanemab, aducanumab and placebo in the primary analysis, there was significant heterogeneity. In the sensitivity analysis excluding exercise, melatonin was significantly more effective than donanemab, lecanemab, aducanumab and placebo, with no significant heterogeneity. Aerobic exercise for a short time was significantly less acceptable than donanemab, aducanumab and placebo. Donanemab, lecanemab, and aducanumab were significantly less tolerable than placebo and donanemab and lecanemab were significantly less acceptable than placebo. CONCLUSIONS: Melatonin may be a better potential disease-modifying treatment for cognitive decline in mild AD and MCI. Aerobic exercise for a short time might also be better than donanemab, lecanemab and aducanumab if continued, as it is well tolerated and more effective, although less valid due to heterogeneity. Another limitation is the small number of participants.

Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer's disease: A systematic review and network meta-analysis.

BACKGROUND: The comparative clinical utility of the disease-modifying treatments for mild cognitive impairment and Alzheimer's disease that are approved or under review by the Food and Drug Administration (i.e., donanemab, lecanemab and aducanumab), and lithium, which is a potential disease-modifying agent for this condition, remains elusive. OBJECTIVE: We aimed to compare the efficacy on cognitive decline, tolerability and acceptability of these drugs in this condition. METHODS: We systematically searched in MEDLINE, CENTRAL, CINHAL and ClinicalTrials,gov for randomized controlled trials from their inception to 7 November 2023, and then performed a random-effect network meta-analysis. RESULTS: The analysis included 8 randomized placebo-controlled trials with 6547 participants. On the Mini-Mental State Examination, lithium significantly outperformed donanemab, aducanumab and placebo. On the Alzheimer's Disease Assessment Scale-cognitive subscale, the efficacy of all active drugs was significantly higher than placebo. In addition, in the Clinical Dementia Rating sum of boxes, the efficacy of donanemab and lecanemab was significantly higher than placebo. Compared to placebo, donanemab and lecanemab were significantly less acceptable and tolerable. Aducanumab was also less well tolerated compared to placebo. There were no significant differences in the other comparisons. CONCLUSION: Although it is yet to be determined which is more effective between lithium or lecanemab or donanemab, lithium may be more effective than aducanumab. Aducanumab, lecanemab and donanemab do not appear to differ in their effectiveness on cognitive function. Low-dose lithium may be safer than aducanumab, lecanemab and donanemab.

The Dose-Response Relationship of Atomoxetine for the Treatment of Children With ADHD: A Systematic Review and Dose-Response Meta-Analysis of Double-Blind Randomized Placebo-Controlled Trials.

OBJECTIVES: The present study aimed to meta-analytically estimate the dose-response relationship of atomoxetine for treating children with ADHD. METHODS: We systematically searched double-blind randomized placebo-controlled trials that evaluated the effectiveness of atomoxetine for treating ADHD in children. The search was carried out in PubMed, Cochrane Library, CINHAL, and ClinicalTrials.gov databases, covering articles from their inception until January 20, 2023. In addition, a dose-response meta-analysis was conducted. RESULTS: In this dose-response meta-analysis, 12 double-blind randomized placebo-controlled trials involving 2,250 patients were included. The efficacy of atomoxetine increased up to a dosage of 1.4 mg/kg, after which it reached a plateau. CONCLUSIONS: The first dose-response meta-analysis of atomoxetine dosing for children with ADHD conducted here enhances the robustness of the Food and Drug Administration and the European Medicines Agency dose recommendations.

Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis.

BACKGROUND: Intravenous racemic ketamine is a promising treatment for treatment-resistant depression. However, its clinical utility compared with intranasal esketamine and the other well-studied conventional pharmacological interventions (i.e., aripiprazole and lithium) as augmentative treatments for treatment-resistant unipolar depression in adults remains unclear. Therefore, we aimed to compare the efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium under such conditions. METHODS: The Cochrane Library, PubMed, CINHAL and ClinicalTrials.gov databases were systematically searched from their inception to 10 May 2023. Randomised controlled trials evaluating these drugs were included. A random-effects network meta-analysis was also performed. RESULTS: In the primary analysis, all four drugs were significantly more effective than placebo. In addition, intravenous racemic ketamine was significantly more effective and acceptable than intranasal esketamine and aripiprazole. Intravenous racemic ketamine was not significantly different from placebo in tolerability, whereas intranasal esketamine and aripiprazole were significantly less tolerable than placebo. Lithium did not differ significantly from intravenous racemic ketamine in efficacy, tolerability and acceptability. LIMITATIONS: The sample size of patients treated with intravenous racemic ketamine was small. CONCLUSIONS: Intravenous racemic ketamine may be a better augmentative treatment for treatment-resistant unipolar depression than intranasal esketamine and aripiprazole. Whether intravenous racemic ketamine or lithium is superior is unclear currently. A larger head-to-head trial of intravenous racemic ketamine versus conventional augmentative treatments for treatment-resistant unipolar depression is needed.