A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability

Abstract

Objective: Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design.

Method: After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial.

Results: At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00-68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms.

Conclusion: Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone.

Clinical trial registration information: A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov; NCT00794040.

Keywords: RCT; citalopram; disruptive mood dysregulation disorder; irritability; methylphenidate.

FIGURE 1. CONSORT Diagram of the Trial

Note: Of the randomized participants (n = 53), 4 participants were excluded from analysis because the Clinical Global Impression (CGI) measure used was a different version and thus not comparable. Of the 49 participants included in the analyses, 41 completed the trial; 7 withdrew assent before week 8, and one was ruled out of the study by the experimenters because of high levels on liver function test. Please note color figures are available online.

FIGURE 2. Change in Irritability Severity Before and After Randomization in the Sample Included in the Intent-to-Treat Analysis

Note: The period between baseline at admission (Adm. Baseline) and baseline at randomization (Rand. Baseline) was variable, and included the washout period (Phase I), medication-free period (Phase II), and open-label lead phase with stimulant optimization (Phase III). Before randomization (depicted as the black dotted line), change in irritability severity is shown for the entire sample (n = 49). After randomization, both observed and estimated severity (provided by command margins in Stata) are displayed by week and treatment group (citalopram [CTP], n = 23; placebo [PBO], n = 26). MPH = methylphenidate. Please note color figures are available online.

FIGURE 3. Proportion of Treatment Response by Week and Treatment Group

Note: Both observed and estimated proportions of response are displayed. Bars represent 95% CI. Estimated proportions were extracted with command margins in Stata and are based on n = 49. Observed proportions are based on n = 49 at week 1; n = 48 at week 2; n = 47 at weeks 3 and 4; n = 43 at weeks 5, 6, and 7; and n = 41 at week 8. CTP = citalopram; PBO = placebo. Please note color figures are available online.