Quetiapine Addition in Methylphenidate Treatment-Resistant Adolescents with Comorbid ADHD, Conduct/Oppositional-Defiant Disorder, and Aggression: A Prospective, Open-Label Study
This study investigated the safety and efficacy of adding the atypical antipsychotic quetiapine to ongoing OROS methylphenidate treatment for adolescents with comorbid ADHD and severe aggression that were incompletely responsive to methylphenidate monotherapy.
Participants aged 12-16 years were enrolled in a prospective, open-label trial consisting of 3 weeks of OROS methylphenidate monotherapy titrated to 54 mg/day, followed by 9 weeks of combination treatment with quetiapine and methylphenidate. Twenty-four out of thirty participants failed to meet criteria for significant improvement (Clinical Global Improvement-Severity [CGI-S] and Rating of Aggression Against People and Property [RAAPP] scale scores of 1 or 2 and ADHD-Rating Scale: Investigator Administered and Scored [ADHD-RS-I] score less than 50% of baseline score) with methylphenidate treatment alone and received combined treatment.
Investigator and parent ratings of ADHD symptoms, aggression, and global functioning improved significantly during both methylphenidate monotherapy treatment and during combined methylphenidate-quetiapine treatment. At the conclusion of combined treatment, 42% of the sample met all criteria for clinically significant improvement and 79% showed minimal aggression. Mild and transient sedation was reported by about half the cases. Weight loss (0.9 kg) during methylphenidate treatment was offset by weight gain (1.2 kg) during combination treatment.
Quetiapine addition to methylphenidate was effective in reducing ADHD and aggression in individuals who did not respond sufficiently (based on CGI-S, RAAPP, and ADHD-RS-I criteria for significant improvement) to OROS methylphenidate alone at a 54-mg/day dose.
Available from: Annarita Milone
- "who did not respond to methylphenidate only (Kronenberger et al. 2007). The aim of this study is to report on our experience with quetiapine monotherapy in a consecutive sample of referred children and adolescents with BD (manic, hypomanic, or mixed episode ) and comorbid CD, followed up for 3 months in a third level research hospital. "
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ABSTRACT: Abstract Bipolar Disorders (BD) are often comorbid with disruptive behaviour disorders (DBDs) (oppositional-defiant disorder or conduct disorder), with negative implications on treatment strategy and outcome. The aim of this study was to assess the efficacy of quetiapine monotherapy in adolescents with BD comorbid with conduct disorder (CD). A consecutive series of 40 adolescents (24 males and 16 females, age range 12-18 years, mean age 14.9±2.0 years), diagnosed with a clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version [K-SADS-PL]) according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria were included. All the patients were treated with quetiapine monotherapy (mean final dose 258±124 mg/day, range 100-600 mg/day). At the end-point (3 months), 22 patients (55.0%) were responders (Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2 and CGI-Severity [CGI-S]≤3 and improvement of at least 30% Children's Global Assessment Scale [C-GAS] during 3 consecutive months). Both CGI-S and C-GAS significantly improved (p<0.0001). Nine out of the 16 patients with suicidality (56.3%) had a reduction in this severe symptom during the follow-up. Nonresponders were more frequently males, and more frequently had an attention-deficit/hyperactivity disorder (ADHD) comorbidity. Eight patients (20.0%) experienced moderate to severe sedation and eight (20.0%) experienced increased appetite and weight gain. In these severely impaired adolescents, quetiapine monotherapy was well tolerated and effective in>50% of the patients.
Available from: Michael G Aman
- "Considerable attention has been given to adjunctive atypical antipsychotic use in children and adolescents . For example, Kronenberger and associates  added quetiapine to methylphenidate treatment-resistant adolescents with ADHD, DBD, and aggression. The combination was more effective in control of both ADHD and aggressive symptoms than the methylphenidate alone. "
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ABSTRACT: Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.
In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.
We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.
Available from: Maria G Valdovinos
- "Several studies have used the Rating of Aggression Against People and/or Property Scale to evaluate the effects of medication on the aggressive behaviour with children and adolescents with conduct disorder and other disorders (e.g. Kemph et al. 1993; Findling et al. 2006, 2007; Kronenberger et al. 2007). "
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ABSTRACT: Background The focus of this review is on methods that are currently being used to evaluate the behavioural effects of medication for individuals with intellectual disabilities. First we describe what has been identified as the ideal criteria for conducting clinical trials and how these criteria may be adapted to do less controlled evaluations. The central theme is a review of the biological measures (e.g. labs, drug levels), behavioural rating scales and direct observation measures that are often used to evaluate medication effects. Issues related to how the side effects of medication can affect behaviour will also be discussed.
Conclusion The importance of encouraging communication and collaboration across all systems of care and the use of socially valid measures are discussed.
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