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J Child Adolesc Psychopharmacol. 2009 Feb;19(1):61-73. doi: 10.1089/cap.2008.044.

Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation.

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E.P. Bradley Hospital, Bradley-Hasbro Children's Research Center, 1 Hoppin ST Coro West, Providence, RI 02903, USA.



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.


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).


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.


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.

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