Abstract
While clinicians are confronted daily with recalcitrant and highly complex cases, relatively little is available guiding in the use of combined pharmacology for pediatric disorders. For instance, it is not at all clear if there are advantages to combining agents for the treatment of residual symptoms of a single disorder; or if the use of two or more agents has a positive impact on co-morbid disorders. Furthermore, using multiple agents simultaneously punctuates tolerability and safety concerns. For instance, are there known pharmacokinetic interactions that may predispose to more adverse effects? Conversely, might the use of agents with “opposing” adverse effect profiles potentially ameliorate potentially severe longer-term effects such as weight gain?
In discussing this topic over a decade ago, we highlighted conceptual issues related to the use of multiple medication treatment in youth (Wilens et al. 1995). Namely, the notion of a paradigm where one presumes a single etiology results in a disease state that is subsequently managed by treating the specific pathophysiology (Meltzer 1987, p. 1700). Given the lack of specific treatments available, and the nonspecificity and suboptimal response of our agents, we are sometimes relegated to combining psychotropics in youth. We previously articulated what appeared as likely scenarios for the use of combined agents: residual symptoms, pharmacological synergism, improved tolerability, diminished adverse effects, and psychiatric or medical co-morbidity.
By disclosure, authors were asked to submit reports that focused on empirically based data related to the use of multiple medications; and not on combined medication and psychotherapy studies. While most agree that the bulk of children who are eligible for combined pharmacotherapy studies should also be considered at some point for multimodal interventions, it is beyond the scope of this issue to include such studies. Moreover, most clinicians and researchers in pediatric psychopharmacology are quick to advocate for more combined pharmacological studies to be undertaken and presented.
The authors of the articles in this issue have examined many of the above concerns in carefully conducted studies. Given the complexity in executing such trials and the controversy surrounding the use of multiple combined psychotropics in children, this issue also highlights the various stages of scientific understanding of pharmacological trials. From the earlier stages of signal detection elucidated in retrospective chart reviews to systematic open and controlled trials, this special issue examines the role of two or more psychotropics in the treatment of child psychopathology. As you will quickly see, studies with both positive and negative outcomes are reported.
We have separated the issue somewhat arbitrarily based on attention-deficit/hyperactivity disorder (ADHD)/disruptive disorders and then mood disorders. It is no surprise that overlap exists, for instance, in that some of the youth with mood disorders are being concomitantly treated for their ADHD. Wilens et al. in a large open report show that in atomoxetine partial responders, OROS-methylphenidate (MPH) not only improved response rates and ADHD symptoms but had apparent unique effects on clinical features of executive functioning. There is no free lunch, however. The combination was also associated with additive side effects that did not “cancel” out each other as was speculated. In a continuation of the study, Hammerness et al. also reported that MPH had no effect on atomoxetine levels—an important next step in such investigations.
Alpha agonists are often used in the treatment of tics, ADHD, and movement disorders. Two studies examine this combination. In a large multisite open study, Spencer et al. examined the effectiveness and tolerability of guanfacine extended-release added to children who were stimulant partial responders. The combination resulted in improved ADHD ratings compared to stimulant monotherapy. Co-administration of stimulants did not appear to negate adverse effects typical of guanfacine. As part of the 16-week multisite study of clonidine with and without MPH for the treatment of ADHD (CAT), Cannon et al. showed that any medication treatment was significant compared to placebo for impact on quality of life for the family. However, unlike the main outcomes from this study (e.g., ADHD), there were no differences between clonidine, MPH, or combined clonidine plus MPH groups on quality of family life. This study reminds us of the need not only to examine manifest symptoms but to examine functioning related to an intervention.
Turning to mood disorders, Kratchovil et al. highlight the importance of co-morbidity by examining the impact of having ADHD in depressed adolescents as part of the multisite treatment of adolescent depression study. This group of researchers found that co-occurring ADHD (some receiving stimulants) in fact impacted the response to treatment for their major depression.
Six studies examined pediatric bipolar disorder (BPD) and/or the use of antipsychotics in combination with other agents. It is well known clinically that many cases of BPD simply do not respond fully to monotherapy As part of a systematic review of a specialty clinic for treatment of pediatric BPD, Potter et al noted that on average, youth received three psychotropics with only one-quarter of the sample receiving monotherapy. Wozniak et al. studied openly the treatment of children and adolescents with BPD receiving olanzapine or olanzapine plus topiramate attending to effectiveness and tolerability. These authors found similar BPD outcomes between groups; however, augmentation therapy was associated with significantly less weight gain over the 8-week trial.
The next four reports focus on the common co-morbidity of ADHD and BPD—a co-morbidity that was really only appreciated as a result of reports published over the past decade. Chang et al. examined adjunct treatment with atomoxetine along with thymoleptic therapy in euthymic youth with BPD. In a small open report, this research group reported improvements in ADHD without significant changes in mania or depression scores, although 17% of their subjects discontinued early due to “worsening of mood.” Stimulants continue to be commonly co-administered with antipsychotics for co-morbid cases. In one of the few controlled trials in juvenile BPD and ADHD, Zeni et al. completed a small crossover study adding MPH to aripiprazole. MPH did not improve ADHD significantly; nor were substantially higher scores of mania found in conjunct with stimulants.
Two studies focused largely on the tolerability/safety of using stimulants and second-generation antipsychotics. Penzer et al. examined children and adolescents receiving a variety of second-generation antipsychotics naturalistically focusing on the subgroup who were also receiving stimulants. They found that 1) almost half of the sample who was eligible for stimulants did not receive this treatment, and 2) at 12 weeks stimulant co-administration did not alter the antipsychotic effects on body composition or metabolic indices. Along the same lines, in a specialty clinic for ADHD, Weiss et al. reported that 19% of youth received second-generation antipsychotics along with ADHD treatment. Like the Penzer et al. study, metabolic concerns with the antipsychotics were apparent even with stimulant co-administration.
We certainly hope that you will find this issue of the Journal innovative, informative, and useful in your clinical practice. The authors are to be commended in completing such unique and helpful studies in such difficult cases. We trust that this issue will serve as a springboard for the next generation of combined investigations to further inform the field.