Randomized Double-Blind Placebo-Controlled Trial of Lithium in Youths with Severe Mood Dysregulation

Abstract

Objective The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD) by Leibenluft, has been the focus of increasing concern. We conducted the first randomized double-blind, placebo-controlled trial in SMD youth, choosing lithium on the basis of its potential in treating irritability and aggression and neuro-metabolic effects. Methods SMD youths 7–17 years were tapered off their medications. Those who continued to meet SMD criteria after a 2-week, single-blind, placebo run-in were randomized to a 6-week double-blind trial of either lithium (n = 14) or placebo (n = 11). Clinical outcome measures were: (1) Clinical Global Impressions–Improvement (CGI-I) score less than 4 at trial’s end and (2) the Positive and Negative Syndrome Scale (PANSS) factor 4 score. Magnetic resonance spectroscopy (MRS) outcome measures were myoinositol (mI), N-acetyl-aspartate (NAA), and combined glutamate/glutamine (GLX), all referenced to creatine (Cr). Results In all, 45% (n = 20/45) of SMD youths were not randomized due to significant clinical improvement during the placebo run-in. Among randomized patients, there were no significant between-group differences in either clinical or MRS outcome measures. Conclusion Our study suggests that although lithium may not result in significant clinical or neurometabolic alterations in SMD youths, further SMD treatment trials are warranted given its prevalence.

Pediatric Bipolar Disorder Versus Severe Mood Dysregulation: Risk for Manic Episodes on Follow-Up

“…So far, the only clinical trial in SMD is a pilot study of lithium, which was not effective. 25 Additional treatment trials in youth with severe, nonepisodic irritability are a pressing public health need, given that an SMD proxy phenotype occurred with a prevalence of 3.3% in an epidemiologic sample in the United States 9 and mood lability occurred in more than 5% of the population of children and adolescents in a sample in the United Kingdom. 26 Although it is important to frame the question, "Is SMD a developmental presentation of BD?"…”

Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis

“…[8][9][10][11][12][13] Smaller hippocampal volumes are among the most replicated neuroimaging findings in patients with major depressive disorder compared with healthy controls.…”

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study

“…Prospective studies have predominantly shown no changes in brain NAA levels during Li treatment. [8][9][10][11] A single prospective study reported a small NAA increase after 4 weeks of Li treatment, 3 whereas another investigation found an NAA decrease after 6 weeks of Li exposure. 12 Cross-sectional studies have also been inconsistent, with reports of greater 13,14 as well as comparable [15][16][17] brain NAA levels in Li-treated versus control participants.…”