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

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


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Antimanic Agents / administration & dosage
  • Antimanic Agents / blood
  • Antimanic Agents / therapeutic use*
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Attention Deficit Disorder with Hyperactivity / diagnosis
  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Attention Deficit Disorder with Hyperactivity / psychology
  • Bipolar Disorder / diagnosis
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / physiopathology
  • Bipolar Disorder / psychology
  • Child
  • Creatine / metabolism
  • Diagnosis, Differential
  • Double-Blind Method
  • Female
  • Glutamine / metabolism
  • Humans
  • Inositol / metabolism
  • Lithium Carbonate / administration & dosage
  • Lithium Carbonate / blood
  • Lithium Carbonate / therapeutic use*
  • Magnetic Resonance Spectroscopy
  • Male
  • Mood Disorders / diagnosis
  • Mood Disorders / drug therapy*
  • Mood Disorders / physiopathology
  • Mood Disorders / psychology
  • Single-Blind Method


  • Antimanic Agents
  • Glutamine
  • Lithium Carbonate
  • Aspartic Acid
  • Inositol
  • N-acetylaspartate
  • Creatine