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.

Figures

FIG. 1.

Disposition of SMD subjects in randomized, placebo-controlled trial of lithium.

FIG. 2.

Magnetic resonance spectroscopy voxel placement. (A) Frontal: Placed in the right orbitofrontal cortex (OFC). (B) Temporal: Placed in the left hippocampus. (C) Central parieto-occipital: Placed in the vicinity of the precuneus. (D) Parietal: Placed in the white matter of the corona radiata. Voxel locations are based upon Moore et al. (1999) and Moore et al. (2000a).

FIG. 3.

Sample LC model processed spectra. The black line represents acquired spectra; the red line represents fitted spectra from same subject. Horizontal axis is chemical shift in parts per million (ppm). LC model: version 6.1–0, S.W. Provencher, Ontario, Canada. mI = Myoinositol; Cr = creatine; GLX = combined glutamate/glutamine; NA = N-acetyl-aspartate.

FIG. 4.

Clinical Global Impressions–Improvement (CGI-I) weekly results in severe mood disregulation (SMD) youths randomized to lithium versus placebo.

FIG. 5.

Weekly Positive and Negative Symptom Scale for Schizophrenia-4 (PANSS-4) results in SMD youths randomized to lithium versus placebo. PANSS-4 = Sum of excitement (hyperactivity), hostility, uncooperativeness, and poor impulse control.