What were the design, population, lithium dosing regimen, primary outcomes, and safety findings of the Malone et al double‑blind, placebo‑controlled trial of lithium in hospitalized children and adolescents (age 10‑17 years) with DSM‑IV conduct disorder and severe persistent aggression?

Malone et al. Double-Blind, Placebo-Controlled Study of Lithium in Conduct Disorder

Lithium carbonate demonstrated statistically and clinically superior efficacy compared to placebo in reducing severe aggression in hospitalized children and adolescents with conduct disorder, with 80% of lithium-treated patients achieving response versus 30% on placebo, though more than half experienced gastrointestinal and urinary adverse effects. 1

Study Design and Methodology

• This was a parallel-groups, double-blind, placebo-controlled trial conducted in an inpatient psychiatric setting 1
• The study employed a 2-week placebo baseline period to establish aggression criteria before randomization 1
• Only patients who met the aggression threshold during the baseline period were randomized to 4 weeks of active treatment with either lithium or placebo 1
• A total of 86 inpatients enrolled, with 40 patients (33 male, 7 female) completing the treatment phase after meeting aggression criteria 1

Patient Population Characteristics

• Median age was 12.5 years (age range 10-17 years) 1
• All subjects carried a DSM-IV diagnosis of conduct disorder 1
• Patients were hospitalized specifically because of severe and chronic aggression that was treatment-resistant 1
• This represented a highly selected population with the most severe and persistent forms of aggressive behavior requiring inpatient psychiatric care 1

Lithium Dosing Regimen

• Optimal dosages ranged from 500 to 2,000 mg/day in the treatment phase 1
• Target serum lithium levels ranged from 0.86 to 1.39 mEq/L (mean = 1.05 ± 0.17 mEq/L) in similar pediatric conduct disorder populations 2
• The dosing strategy aimed to achieve therapeutic serum concentrations while monitoring for adverse effects 1
• Treatment duration was 4 weeks following the 2-week placebo baseline 1

Primary Outcome Measures and Results

Efficacy Outcomes

• 16 of 20 subjects (80%) in the lithium group were responders versus 6 of 20 (30%) in the placebo group on Consensus ratings (P = 0.004) 1
• The Overt Aggression Scale (OAS) scores decreased significantly for the lithium group compared to placebo (P = 0.04) 1
• Clinical Global Impressions and Global Clinical Judgements (Consensus) Scale were used as primary outcome measures 1
• The effect was both statistically significant and clinically meaningful, representing a robust treatment response 1

Comparative Context

• These findings align with other controlled studies showing lithium superior to placebo in reducing behavioral symptoms in conduct disorder 3
• In a comparative trial, both haloperidol and lithium were significantly superior to placebo, though haloperidol was associated with more adverse effects than lithium 3
• Retrospective naturalistic studies have shown 48.3% response rates with lithium (alone or combined with atypical antipsychotics) over 6-12 months of follow-up 4

Safety Findings and Adverse Effects

Common Adverse Effects

• More than half of subjects in the lithium group experienced nausea, vomiting, and urinary frequency 1
• These gastrointestinal and urinary symptoms were the most frequently reported adverse effects 1
• Additional commonly reported adverse effects in pediatric lithium studies include polydipsia, tremor, and increased thyroid-stimulating hormone levels 4

Safety Profile

• Despite the high frequency of adverse effects, lithium was deemed "safe and effective" for short-term treatment 1
• The adverse effects were "relatively common but rarely severe" in extended naturalistic studies 4
• Two patients (3.3%) discontinued treatment due to adverse effects (vomiting and thyroid dysfunction) in longer-term studies 4
• Lithium was associated with fewer adverse effects than haloperidol in head-to-head comparisons 3

Critical Safety Considerations

• Lithium prescriptions for children and adolescents require careful third-person supervision, as overdoses may be lethal 5
• Regular monitoring of serum lithium levels, thyroid function, and renal function is essential 4
• The narrow therapeutic index of lithium necessitates close clinical oversight 5

Clinical Implications and Treatment Context

Predictors of Response

• Less severe disease at baseline, lower aggression scores, and impulsive (affective, nonpredatory) type of aggression predicted positive response to lithium treatment 4
• Patients with reactive aggression (as opposed to proactive/predatory aggression) respond better to mood stabilizers like lithium 6

Integration with Comprehensive Treatment

• Lithium should be part of a comprehensive treatment program that includes behavioral interventions 7
• Psychosocial interventions (multisystemic therapy, family-based approaches) should be prioritized alongside pharmacotherapy 6
• When ADHD is comorbid, stimulants are first-line and may reduce both ADHD symptoms and antisocial behaviors 6

Guideline Recommendations

• The American Academy of Child and Adolescent Psychiatry notes that lithium is FDA-approved down to age 12 years for acute mania and maintenance therapy in bipolar disorder 5
• Mood stabilizers like lithium have shown efficacy in reducing aggression in conduct disorder, though the evidence base is more limited than for bipolar disorder 6
• Lithium's central serotonin-enhancing qualities may contribute to its unique effects on reducing suicidal and aggressive behavior 5

Common Pitfalls to Avoid

• Avoid polypharmacy—trial lithium thoroughly (6-8 weeks at therapeutic levels) before adding or switching medications 6
• Monitor medication adherence and compliance carefully, as adolescents with conduct disorder may be at risk for diversion 6
• Do not use lithium as monotherapy without behavioral interventions—medication should facilitate engagement with psychosocial treatments 6
• Ensure adequate monitoring of serum levels, renal function, and thyroid function to prevent toxicity 4, 7