Efficacy
Clonidine has been reported to be efficacious in treating ADHD symptoms in children and adolescents. Two Phase III, eight-week trials of double-blinded, placebo-controlled studies investigated the efficacy and safety of clonidine extended-release in ADHD children aged 6–17 years. Jain et al15 used a fixed final daily dose of 0.2 mg or 0.4 mg in 143 subjects who were not taking any form of psychostimulants. A dose-escalating titration of 0.1 mg/day was utilized to the final target doses over four weeks. The researchers used the following tools to evaluate efficacy: ADHD-RS-IV, Conner’s Parent Rating Scale-Revised: Long Form (CPRS-R), Clinical Global Impression of Severity (CGI-S) scale, Clinical Global Impression of Improvement (CGI-I), and the Parent Global Assessment (PGA) scale. Significant clinical improvement occurred in both clonidine extended-release dosage groups on total score for the ADHD-RS-IV scale by week 5 and was maintained throughout the entire eight-week treatment period. Inattention, hyperactivity, and impulsivity subscale scores on the ADHD-RS-IV demonstrated significant improvement. Similarly, improvement in CPRS-R was significantly greater in the clonidine extended-release treated groups. In addition, the CGI-S and CGI-I scales showed greater improvement in both clonidine extended-release groups versus the placebo group. Improvement of behavior in the two clonidine extended-release dosage groups was overlapping, suggesting that the higher dose did not yield additional efficacy. The strength of this study was the use of clonidine extended-release without the interference of psychostimulants. This study allowed inclusion of tic disorders and oppositional defiant disorders. However, the authors did not indicate how many of the subjects with these comorbid disorders were included. There was a high dropout rate of subjects, rendering the study population prone to bias.
The other study by Kollins et al16 examined clonidine extended-release as an add-on therapy to existing psychostimulants in children with ADHD in a multicenter, eight-week clinical trial. They initiated clonidine extended-release or placebo in children who were already taking a psychostimulant. The clonidine extended-release dose was a flexible escalation regardless of subject age or body weight; the dose was titrated up based on the subject response (it is not clear how responses were evaluated for the titration). The existing stimulants were diverse and of either the methylphenidate or amphetamine categories. The physicians were allowed to adjust the stimulant dosages without changing the stimulant category during the trial. The study used ADHD rating scales and other psychological instruments completed by researchers and parents. Improvements in ADHD rating scores from baseline and after the add-ons were used to compare the efficacy of clonidine extended-release versus placebo. The clonidine extended-release dose and administration were flexible. The researchers reported a significantly greater improvement in ADHD rating scales in the clonidine extended-release add-on group as compared with placebo and the existing psychostimulant. The improvement started at week 2, reached a maximal level at weeks 4–5, and was maintained until week 7 of the trial. However, there was no significant difference between the two groups at week 8. The investigators reported that a greater number of subjects in the clonidine extended-release group reduced their psychostimulant doses than in the placebo group. This study showed that clonidine extended-release was efficacious as an add-on in children who had a partial response to psychostimulants. The strength of this study, like the study of Jain et al,15 was its double-blind, placebo-controlled multicenter design. Multiple psychological instruments were utilized, and the interindividual variation was minimized by measuring improvement within the same individuals. However, the experimental design was complicated with too many variables. The varying clonidine extended-release dose and administration frequency, along with the changing psychostimulant doses, makes interpretation of the results difficult.
Both Jain et al15 and this study16 did not perform a comparison of clonidine extended-release with clonidine, providing no information as to whether the extended-release is a better formula. One additional study is registered at clinicaltrial.gov for clonidine extended-release safety in children and adolescents with ADHD. No articles describing this study were available.
Three additional double-blind, placebo-controlled studies17–19 on clonidine efficacy in children and adolescents are included in Table 1. Two of the three studies17,18 appear to originate from a subpopulation of the same cohort. Palumbo et al17 reported the efficacy of clonidine in the improvement of ADHD symptom scales in subjects, while Cannon et al19 reported efficacy in improvement of quality of life in families of ADHD children on clonidine treatment. The subjects were administered clonidine, methylphenidate, clonidine and methylphenidate, or placebo. The daily average dose of clonidine was 0.24 ± 0.11 mg, while the maximal dose was 0.6 mg. Clonidine was given in a 3–4 times daily dose regimen. Palumbo et al17 reported greater improvements in Conner’s scale rated by parents in the clonidine-treated groups versus placebo in 78 subjects who completed the study. However, teachers of the subjects reported no significant improvement in the same efficacy measures as the ones completed by parents when it came to treatment with clonidine. Cannon et al19 reported improvement in quality of family life compared with the treatment groups as a whole versus placebo.
Five articles20–24 reported the efficacy of clonidine alone or in combination with methylphenidate in children and adolescents with ADHD and other comorbid behavioral disorders, including tic disorders, conduct disorders, oppositional defiant disorders, anxiety disorders, and seizures (Table 2). Kurlan et al20 conducted a clinical trial in children with ADHD and chronic tic disorder. Subjects were randomly given clonidine, methylphenidate, clonidine with methylphenidate, or placebo for a 16-week period. The average daily dose was 0.25 mg for the group treated with clonidine and 0.28 mg for the group treated with both clonidine and methylphenidate. The daily dose was adjusted according to subject response. The Conner’s scales for teachers and parents elicited a significant treatment effect in the clonidine combined with methylphenidate group. This group was rated as the most effective for ADHD. Impulsivity and hyperactivity improved with clonidine as compared with placebo. Clonidine showed efficacy in children with ADHD and tics. Meere et al21 tested the efficacy of clonidine in children with ADHD using a GO-NO GO task to determine whether there was an improvement in state dysregulation. Similar to methylphenidate, clonidine was not effective. This study did not use psychological instruments and enrolled only 53 total subjects (17–18 subjects per group). The behavioral testing is a snapshot of the task performance that may be potentially biased by temporal factors and may not represent overall performance or improvement.
All of these five studies20–24 included comorbid conditions. Therefore, it is unclear whether the improvement in ADHD symptoms can be attributed to improvement of comorbidity with use of clonidine. Clonidine is an alpha-2 adrenergic agonist that can also be used for sympathetic hyperarousable states in other disorders, such as anxiety disorders25–39 and tic disorders.40–50 Four of the five studies21–24 had multiple comorbid disorders, making interpretation of the effect of clonidine on ADHD symptoms even more difficult. Likewise, it is also not clear whether clonidine is more effective in treating ADHD symptoms in subjects with ADHD and a comorbid disorder, given that none of the clinical trials reviewed were designed to compare clonidine in subjects with and without comorbidities.
Furthermore, almost all of the studies contained design limitations which included high dropout rates, multiple variables assessed, and relatively short study durations. All of the studies, except for one, were short-term, providing little information on the long-term effects of clonidine use. Therefore, lack of long-term data prevents us from drawing conclusions regarding the long-term efficacy of treatment with this medication.
Although each of the studies did report some form of improvement in the behavior of the patients enrolled, there exists variability, including heterogeneous subject populations, variable dosages and length of treatment, comorbid conditions, and different outcome measures between the studies. Outcomes among the studies are not comparable with one another, and it is premature to try to ascertain exactly which patients benefited from clonidine.
Overall, the findings of the studies suggest that clonidine and/or clonidine extended-release could be efficacious in the treatment of ADHD. However, it is important to note that the studies do contain significant limitations. Based on the findings, it is reasonable to conclude that patients suffering from ADHD and ADHD with comorbidities may potentially benefit from either treatment with clonidine or clonidine extended-release in the form of monotherapy or in conjunction with psychostimulants. A slow titration to an optimal dosage is recommended for patients with ADHD with or without comorbidities.