A Systematic Review of Combination Therapy with Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder,Including Patient Characteristics,Treatment Strategies,Effectiveness,and Tolerability

Database search strategy

The following databases were searched on March 15, 2012: MEDLINE^® via PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded via Web of Science, and SciVerse Scopus. Search terms from 2 categories were used: 1) Stimulants (including stimulant, stimulants, dexmethylphenidate [EMTREE], dextromethylphenidate, Focalin, “d amphetamine”, d-amphetamine, dexamfetamine, “dex amphetamine”, dex-amphetamine, dexamphetamine [EMTREE], Dexedrine, “dextro amphetamine”, dextro-amphetamine, dextroamphetamine [MeSH], DextroStat, lisdexamfetamine [MeSH, EMTREE], “lis dexamfetamine”, lis-dexamfetamine, NRP104, NRP-104, Vyvanse, Concerta, Daytrana, Metadate, Methylin, methylphenidate [MeSH, EMTREE], phenidylate, Ritalin, amphetamine [MeSH, EMTREE], Adderall) and 2) atomoxetine (including atomoxetine [MeSH, EMTREE], LY139603, Strattera, tomoxetine). Search terms within each category were separated by the Boolean operator OR, and categories were separated by the operator AND. All database searches were restricted to publications published from 1990 onwards. There were no restrictions on publication language.

Study selection

Publications retrieved by the database searches were collated and duplicate publications were discarded. One author (Dr. Monk) screened the title and abstracts for possible full text review, using prespecified inclusion and exclusion criteria. These criteria were also applied during the review of the full text in selected publications. Publications describing stimulant and atomoxetine combination therapy in patients with ADHD or healthy volunteers and the following outcome measures – patient characteristics; treatment strategies; efficacy, effectiveness, safety, and tolerability measures; medical resource use; and pharmacodynamic or pharmacokinetic data – were included for review. Stimulant and atomoxetine combination therapy included stimulant add-on or adjunct therapy to atomoxetine monotherapy, and atomoxetine add-on or adjunct therapy to stimulant monotherapy or during a treatment switch or crossover. Publications were excluded if patients with ADHD had comorbid psychosis, bipolar disorder, epilepsy, or other psychiatric/neurologic diseases that could confound the assessment of their ADHD symptoms, or if they were receiving concomitant medication(s) other than stimulants and atomoxetine to treat ADHD symptoms. The bibliographies of relevant publications were searched for any additional publications that should be assessed.

Data extraction and analysis

We developed a spreadsheet for data collection, which was refined as data were extracted. Data were extracted by one author (Dr. Monk), reviewed by all authors, and validated by an independent reviewer (non-author). The data that were collected included publication and study information (type, design, treatment, duration, location), patient/healthy volunteer information (number, age, sex, ethnicity, ADHD/healthy volunteer, ADHD subtype, other ADHD characteristics, comorbidities), treatment (previous treatment history, combination therapy strategy, ADHD medication dose, duration), efficacy and effectiveness findings (symptom control measures, other measures, other findings), and safety and tolerability findings (study discontinuations, adverse events, vital signs, electrocardiogram [ECG] parameters, other findings). To compare the ADHD medication doses, we calculated the dose equivalents (eq) using the defined daily doses (DDD) for each ADHD medication dose and the following formulas: DDDeq=dose mg/DDD mg or DDDeq=(dose mg/kg×70 kg) / DDD mg (World Health Organization 2009 ). The DDDs were 30 mg for methylphenidate, 80 mg for atomoxetine, 15 mg for amphetamine, and 15 mg for dextroamphetamine (www.whocc.no/atcddd). To succinctly summarize all publications included in this review, not all data that were collected in the spreadsheet are reported.

Literature search results

A total of 4237 abstracts were retrieved by the combined database searches (Fig. 1). After the duplicate publications were discarded, 1864 abstracts were screened and 21 publications were selected for full text review. Of the 21 publications reviewed, 5 were excluded because they were conference abstracts of included publications (n=2) (Carlson et al. 2006; Wilens et al. 2008), case reports of patients with an excluded comorbidity (n=1) (Jaworowski et al. 2006) and an excluded concomitant medication (n=1) (Bond et al. 2007), and a narrative review that summarized findings for stimulant and atomoxetine combination therapy reported in other studies (n=1) (Prasad and Steer 2008). The remaining 16 publications were included for review.

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FIG1.

Flow diagram of literature search results. Databases were MEDLINE^® via PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index (SCI) Expanded via the Web of Science, and SciVerse Scopus. Searches were limited to articles published from 1990 onwards and were not limited to English language articles. ADHD, attention-deficit/hyperactivity disorder.

Publication and study characteristics

Of the 16 publications, 14 were of patients with ADHD and 2 were of healthy volunteers (Fig. 2). One publication (Lehmkuhl et al. 2007) was written in German. The 14 publications of patients with ADHD reported findings from 3 prospective studies (4 publications), 7 retrospective studies, and 3 narrative reviews/medication algorithms. The three prospective studies were one double-blind, randomized, placebo-controlled, two phase (acute and combination) trial (Carlson et al. 2007), and two non-controlled studies: One open, two phase trial reported in two publications (Hammerness et al. 2009; Wilens et al. 2009); and one switch trial (Quintana et al. 2007). The seven retrospective studies were four observational studies: One ongoing (Adler et al. 2006) and one complete (Scott et al. 2010) chart review, and two claims/medication database analyses (Pohl et al. 2009; Hodgkins et al. 2011); and three case reports (Brown 2004; Agarwal and Sitholey 2008; Niederhofer 2009). Findings from the ongoing chart review were published in a conference abstract (Adler et al. 2006) and findings from two of the three case reports were published in letters to the editors (Agarwal and Sitholey 2008; Niederhofer 2009). Patient numbers in these studies ranged from 1 to 18,609; however, only a small proportion of patients in the complete chart review (Scott et al. 2010) and the two claims/medication database analyses (Pohl et al. 2009; Hodgkins et al. 2011) received combination therapy (Table 1).

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FIG. 2.

Overview of articles retrieved from the systematic literature search. ADHD, attention-deficit/hyperactivity disorder. ^aWilens reports the efficacy outcomes and Hammerness reports the safety outcomes from the same study. ^bConference abstract. ^cLetter to the Editor.

The three narrative reviews/medication algorithms briefly discussed possible scenarios and treatment strategies for stimulant and atomoxetine combination therapy (Waxmonsky 2005; Pliszka et al. 2006; Lehmkuhl et al. 2007). The two publications including healthy volunteers reported findings from two randomized, placebo-controlled, crossover trials (Kelly et al. 2005; Sofuoglu et al. 2009). These publications reported safety and tolerability outcomes only.

Patient characteristics and reasons for trying stimulant and atomoxetine combination therapy

The characteristics of patients with ADHD were reported in the three prospective studies and the seven retrospective studies (Table 1). In the prospective studies (Carlson et al. 2007; Quintana et al. 2007; Hammerness et al. 2009; Wilens et al. 2009), patients with ADHD were children or adolescents, predominantly male (76–83%), had the combined ADHD subtype (54–79%), and had oppositional defiant disorder as the predominant comorbidity (26–50%). In two of the prospective studies, the severity of patients' ADHD symptoms were moderate or greater as measured by the Clinical Global Impressions Scale-Severity survey (Carlson et al. 2007) or the ADHD Rating Scale-IV-Parent-Reported Investigator-Rated survey (ADHD-RS-IV-Parent:Inv) (Quintana et al. 2007). In addition, the patients' ADHD-RS-IV-Parent:Inv rating were 1.5 standard deviations (SD) (Carlson et al. 2007) or 2.4 SD (Quintana et al. 2007) above age and gender norms.

The characteristics of patients with ADHD in the three retrospective case reports (Brown 2004; Agarwal and Sitholey 2008; Niederhofer 2009) were similar to those in the prospective studies (e.g., children/adolescents, predominantly male, and predominantly combined ADHD subtype; Table 1). Patients with ADHD in the four remaining retrospective studies (Adler et al. 2006; Pohl et al. 2009; Scott et al. 2010; Hodgkins et al. 2011) were children, adolescents, or adults, and were predominantly male (54–82%).

Reasons for trying stimulant and atomoxetine combination therapy were reported in the three prospective studies, three of the seven retrospective studies, and the three narrative reviews/medication algorithms (Table 1). These reasons included partial or inadequate response or coverage of symptoms with stimulant monotherapy (Brown 2004; Waxmonsky 2005; Pliszka et al. 2006; Carlson et al. 2007; Quintana et al. 2007), inadequate response or coverage of symptoms with atomoxetine monotherapy (Brown 2004; Pliszka et al. 2006; Lehmkuhl et al. 2007; Niederhofer 2009), intolerable side effects with stimulant monotherapy (Brown 2004; Waxmonsky 2005; Lehmkuhl et al. 2007; Niederhofer 2009), or tolerance to stimulant monotherapy (Agarwal and Sitholey 2008). In one study (Hammerness et al. 2009; Wilens et al. 2009), patients received atomoxetine and stimulant combination therapy if they were considered to be partial responders to atomoxetine monotherapy after a 4 week acute atomoxetine treatment phase.

Stimulant and atomoxetine combination therapy strategies

Stimulant and atomoxetine combination therapy strategies for treating patients with ADHD were reported in the three prospective studies, five of the seven retrospective studies, and the three narrative reviews/medication algorithms (Table 2). This drug combination was recommended or implemented to augment stimulant monotherapy (Brown 2004; Waxmonsky 2005; Pliszka et al. 2006; Hodgkins et al. 2011), to augment atomoxetine monotherapy (Brown 2004; Adler et al. 2006; Pliszka et al. 2006; Carlson et al. 2007; Hammerness et al. 2009; Niederhofer 2009; Wilens et al. 2009; Hodgkins et al. 2011), or during a treatment switch from stimulant to atomoxetine monotherapy (Lehmkuhl et al. 2007; Quintana et al. 2007; Agarwal and Sitholey 2008). When specified, methylphenidate (particularly OROS methylphenidate) was most often used in combination with atomoxetine (Brown 2004; Carlson et al. 2007; Quintana et al. 2007; Agarwal and Sitholey 2008; Hammerness et al. 2009; Niederhofer 2009; Wilens et al. 2009; Hodgkins et al. 2011;). The other stimulant used was amphetamine (Brown 2004; Quintana et al. 2007).

The DDDeqs of stimulants and atomoxetine when given in combination differed among the studies (Table 2). In the augmentation studies, the DDDeqs for stimulants and atomoxetine were mostly >1 in the prospective studies (Carlson et al. 2007; Wilens et al. 2009) but <1 in the retrospective studies (Brown 2004; Adler et al. 2006; Niederhofer 2009). However, in the switch studies, the DDDeqs for atomoxetine (0.44 increased to 1.05) were similar for the prospective study (Quintana et al. 2007) and retrospective study (Agarwal and Sitholey 2008). Only three studies specified the timing of the atomoxetine dose (e.g., morning [Brown 2004], morning and afternoon [Hammerness et al. 2009; Wilens et al. 2009], or afternoon [Pliska et al. 2006]) or the timing of the stimulant dose (e.g., morning [Brown 2004]).

In the two studies of healthy volunteers, atomoxetine was given in combination with methylphenidate (2.00 DDDeq) (Kelly et al. 2005) or dextroamphetamine (1.34 DDDeq) (Sofuoglu et al. 2009). The DDDeqs for atomoxetine in these studies were 1.50 (Kelly et al. 2005) and 0.50 (Sofuoglu et al. 2009).

Efficacy and effectiveness of stimulant and atomoxetine combination therapy

Efficacy and effectiveness findings of stimulant and atomoxetine combination therapy were reported in the three prospective studies and four of the seven retrospective studies of patients with ADHD (Table 3). Improvements in ADHD symptom control with this drug combination were reported in most of these studies except the prospective double-blind, randomized controlled trial. In this study, adding OROS methylphenidate to the treatment regimen after 4 weeks of atomoxetine monotherapy did not enhance the efficacy of atomoxetine at the end of 6 weeks of combination therapy (Carlson et al. 2007). In the prospective non-controlled study, however, adding OROS methylphenidate to the treatment regimen after 4 weeks of atomoxetine monotherapy did result in statistically significant improvements in ADHD symptom control and severity, and behavior control at the end of 3 weeks of combination therapy (Wilens et al. 2009) (Table 3). In the retrospective chart review, of patients treated with atomoxetine (Scott et al. 2010), a higher proportion of patients classified as treatment success than of those classified as treatment failure had received add-on stimulant therapy. In the retrospective augmentation case reports, adding atomoxetine therapy to stimulant monotherapy extended medication coverage, particularly in the late afternoon and early evening when the effects of stimulant monotherapy had dissipated (Brown 2004), whereas adding methylphenidate therapy to atomoxetine monotherapy improved ADHD symptomatology and the ability to focus and remember (Brown 2004; Niederhofer 2009). From the beginning to the end of the cross-taper phase during a treatment switch from stimulant to atomoxetine monotherapy, improvement in ADHD symptom control (ADHD-RS scores) was statistically significant in one prospective study (Quintana et al. 2007) and substantial in one retrospective study (Agarwal and Sitholey 2008) (Table 3).

Safety and tolerability of stimulant and atomoxetine combination therapy

Safety and tolerability outcomes for stimulant and atomoxetine combination therapy were reported in the three prospective studies and three of the seven retrospective studies of patients with ADHD (Table 4). Safety and tolerability outcomes reported in the prospective studies were adverse events, changes in blood pressure and pulse and heart rates (Carlson et al. 2007; Quintana et al. 2007; Hammerness et al. 2009). Findings on ECG parameters (Quintana et al. 2007; Hammerness et al. 2009) and blood chemistry (Hammerness et al. 2009) were also reported in some of these studies. No serious adverse events were reported in these studies; however, 10 patients discontinued because of treatment-related adverse events (Carlson et al. 2007; Quintana et al. 2007; Hammerness et al. 2009) (Table 4). Other findings of note in these studies were a mean decrease in weight with combination therapy (0.89 kg [Carlson et al. 2007], 0.82 kg [Hammerness et al. 2009]) and higher rates of insomnia, appetite loss, and irritability, but a lower rate of fatigue, (Hammerness et al. 2009) (Table 4) with combination therapy than with atomoxetine monotherapy. In addition, mean diastolic blood pressure was significantly increased after 3 weeks of stimulant therapy added to atomoxetine (Hammerness et al. 2009) and mean diastolic blood pressure and heart rate were significantly increased after 2 weeks of combination therapy during a switch from stimulant monotherapy to atomoxetine monotherapy (Quintana et al. 2007) (Table 4). There were also two clinically significant changes in ECG parameters (RR interval [Qunitana et al. 2007] and PR [Hammerness et al. 2009]) (Table 4). In the retrospective studies, the safety and tolerability outcomes reported were adverse events (Brown 2004) and descriptive statements (Adler et al. 2006; Agarwal and Sitholey 2008) (Table 4). In the ongoing chart review, 75.9% of patients tolerated and elected to continue with stimulant and atomoxetine combination therapy (Adler et al. 2006).

Safety and tolerability outcomes for stimulant and atomoxetine combination therapy were reported in two studies of healthy volunteers (Table 4). Adverse events were reported in one study (Kelly et al. 2005). In this study, the frequency of adverse events was no greater for combination therapy than for methylphenidate monotherapy, and one patient discontinued because of treatment-related adverse events. Significant changes in blood pressure with this drug combination were reported in both studies. Blood pressure was significantly higher 1–4 hours after dosing in patients co-administered atomoxetine and methylphenidate than in those given placebo (Kelly et al. 2005). In addition, co-administration of atomoxetine and dextroamphetamine was found to attenuate increases in blood pressure resulting from dextroamphetamine monotherapy (Sofuoglu et al. 2009). The effect of combination therapy on heart rate was similar to that of methylphenidate monotherapy. Heart rate increased from 1.5 to 6 hours after dosing, with combination therapy having a significant (p<0.05) mean maximum heart rate increase of 26 beats per minute compared with placebo (Kelly et al. 2005). Another treatment effect of combination therapy was increased cortisol concentrations compared with dextroamphetamine monotherapy (Sofuoglu et al. 2009).

Limitations

There were several limitations with our study. First, we may have inadvertently excluded relevant publications, even though the literature search was comprehensive and included publications written in languages other than English. Second, although we considered all levels of evidence (e.g., from randomized controlled trials to case reports) in our review, the strength of evidence for the included studies was limited because 1) of their heterogeneous methods, trial design, and outcome measures; 2) there was only one randomized controlled trial of atomoxetine and stimulant combination therapy in patients with ADHD; 3) patient numbers in the prospective studies were low (n<100); and 4) of the potential for geographic bias, as most studies were conducted in, or included data from, the United States and Europe. Third, we excluded studies of patients receiving concomitant medication(s) other than stimulants and atomoxetine to treat ADHD symptoms, which may have omitted some findings for difficult-to-treat patients. Fourth, although combination therapy in clinical practice has been administered for up to 5–6 months at a time (Brown 2004; Pohl et al. 2009), most studies assessed combination therapy for only 2–6 weeks (Carlson et al. 2007; Quintana et al. 2007; Agarwal and Sitholey 2008; Hammerness et al. 2009; Wilens et al. 2009) and did not assess adherence or compliance. Last, findings from this systematic review need to be applied with caution and clinical criteria to the broader ADHD population, because most patients given combination therapy were partial responders to or did not tolerate various ADHD medications.