Introduction
Attention-deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders in children and adolescents with an estimated prevalence of 3–5 % (Dopheide and Pliszka
2009; Greenhill
1998; NIH
1998; Scahill and Schwab-Stone
2000). This neurobiological disorder is characterized by significant impairment of concentration and attention, associated with a lack of impulsivity control and increased motor activity (AWMF
2007). Without treatment, these symptoms may persist in adulthood and adversely affect socioemotional and intellectual development (Buitelaar and Medori
2010). Treatment in children is usually multimodal comprising psychotherapy together with occupational therapy, educational training including parents, and eventually drug therapy (Brown et al.
2005; Dopheide and Pliszka
2009; Grosse and Skrodzki
2007; Reddy
2013).
With more than 6,000 patients treated in over 200 clinical trials, methylphenidate (MPH) is one of the best studied drugs in children and adolescents (Vitiello
2001). Based on evidence of its efficacy from several clinical trials and meta-analyses (Faraone et al.
2004; Group
1999; Kutcher et al.
2004; Schachter et al.
2001), MPH has become a mainstay in ADHD therapy and the first-line drug recommendation (AWMF
2007; Grosse and Skrodzki
2007; Reddy
2013). Conventionally, MPH treatment is initiated with immediate release formulations to titrate the dose (Kimko et al.
1999; Kutcher et al.
2004), usually given two to three times daily, depending on the individual effect duration and the severity of symptoms. After the appropriate dose is determined, patients are often switched to a long-acting (LA) formulation taken at home to avoid drug intake in school or in the presence of peers ensuring compliance and steadiness of effects (Grosse and Skrodzki
2007). For these reasons, more recent practice guidelines recommend the use of modified-release formulations even from the outset (National Collaborating Centre for Mental Health
2009). Several modified-release formulations with varying pharmacokinetic (PK) profiles are available, none of which is preferentially recommended by treatment guidelines. Advice given early on to choose the preparation and then to titrate the dose according to individual requirements (AWMF
2007; Banaschewski et al.
2008a,
2008b; Grosse and Skrodzki
2007) is still valid (Coghill et al.
2013).
Due to the Spheroidal Oral Drug Absorption System (SODAS) technology, Ritalin
® LA releases 50 % of the drug immediately and 50 % after 4 h. This ensures effect duration of 8–9 h with one single dose, regardless of food intake (Markowitz et al.
2003). Independence from food intake might be important, as children with ADHD have different dietary patterns (Dura Trave et al.
2014), and only about half of them were reported to have breakfast on a regular basis (Oehler
2007). The efficacy and safety of this modified-release formulation has been shown in placebo-controlled (Biederman et al.
2003) and active-controlled clinical trials (Lopez et al.
2003; Schulz et al.
2010; Silva et al.
2005). However, despite high internal validity, clinical trials are known to be prone to selection bias and to not accurately reflect real-life conditions, particularly with regard to compliance, which may considerably improve with easier dosing regimens. Effectiveness in real life can only be investigated by observational studies. Therefore, the present study investigated the effectiveness of Ritalin
® LA in an average pediatric ADHD population in Germany over 3 months. The aim was to assess clinical benefits and the effective period/duration of action of treatment with Ritalin
® LA.
Methods
Study design
This was a multicenter, 12-week, observational study. For each patient, physicians were requested to collect data immediately prior to and about 1 month (optional) and 3 months after treatment initiation. Upon ethics committee approval, the study was conducted from December 2008 to August 2010 in compliance with the Declaration of Helsinki and all applicable legal requirements in Germany. Parents were informed about the study and had to consent to participation of their child and to the analysis of its pseudo-anonymized data. The study was registered on the Web site of the German Association of Researching Pharmaceutical Companies (Verband forschender Arzneimittelhersteller, VfA:
http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_484).
Patients and treatment
As this was an observational study, there were no protocol restrictions regarding eligibility of patients and their treatment. Both were to be decided on by the attending physician based on the drug label. This specifies (1) the drug to be indicated for the treatment of ADHD with hyperactive-impulsive or inattentive symptoms persistent for at least 6 months and having caused clinically significant impairment in at least two settings and (2) the dosage to be adjusted according to the individual needs and responses of patients. It recommends to start with 20 mg once daily and to adjust in weekly 10 mg increments to a maximum of 60 mg/day taken once in the morning. For patients switching from another MPH formulation, it is recommended to maintain the former total daily dose.
Outcome measures
Effectiveness was evaluated after 3 months of treatment based on: (a) clinical global impression severity (CGI-s) of patients as rated overall and regarding four aspects (attention, impulse control, hyperactivity, and learning problems) on a 4-point scale (inconspicuous, mildly/moderately/severely abnormal) by the attending physician (Dopfner et al.
2006). As this was an observational study in over 100 centers, which rendered dedicated investigator trainings unfeasible, changes in CGI were not rated separately by the attending physician as suggested by Dopfner and colleagues, but calculated as differences of CGI-s scores; (b) patients’ quality of life (QoL) and disease burden based on nine questions of the German inventory for the assessment of QoL in children (ILK). These referred to (1) coping with school demands, (2) relationship to family members, (3) other children, (4) ease with self-employment, (5), physical health, (6) general mood, (7) overall well-being, (8) perceived disease, and (9) therapy burden and were to be evaluated on a 5-point scale (very good, good, intermediate, rather poor, and very poor) by parents and children (Mattejat and Remschmidt
2006).
Further outcome measures were the onset and the end of any subjectively perceived effect as recorded by parents. In addition, parents were asked at each visit whether breakfast of their children over the preceding month had (in their eyes) always been adequate, and whether quantity and quality had varied.
Drug tolerability and safety were evaluated based on adverse event (AE) monitoring at each scheduled visit and treatment practice and compliance based on recordings of dose, dose adjustments, concomitant medication, and premature discontinuation of the study medication.
Data management and analyses
All data were collected on paper Case Report Forms and managed as well as analyzed by a Contract Research Organisation (SIMW, Wegberg, Germany). Diseases were classified according to the International Classification of Diseases (ICD-10); medications according to the WHO Drug Dictionary as of March 1, 2007; and AEs according to the Medical Dictionary for Regulatory Activities (MedDRA), version 13. Data analysis was mostly descriptive using summary statistics for categorical and quantitative data. Safety analyses included tabulation of type and frequency of AEs, on a patient and event basis. Inferential statistics were only applied for subgroup analyses evaluating outcomes in patients having ceased previous treatment due to poor response (“insufficient responders”) to examine potential benefits added by Ritalin® LA. For this, Fisher’s exact test, Wilcoxon matched pair test, and Mann–Whitney test were used at a significance level of 0.05. All statistical analyses were performed using the software STATISTICA, version 8.0 (StatSoft Inc., Tulsa, USA).
Discussion
This observational study aimed at evaluating benefits offered by Ritalin
® LA to children with ADHD under routine practice conditions in Germany. It demonstrated improvements in ADHD symptoms and QoL, confirmed overall good tolerability and safety, and revealed a longer perceived effect duration versus previous treatments. Comparable results regarding safety and effectiveness of other sustained release MPH formulations in daily practice have already been reported, particularly after switching from immediate release formulations (Dopfner et al.
2011a,
2011b; Rothenberger et al.
2011). However, to our knowledge, a significant prolongation of the perceived effect under such conditions is described here for the first time, although recently a change in the daily course of ADHD symptoms after switching to another LA formulation has been reported under routine practice conditions too (Froelich et al.
2014). Moreover, the study confirmed preliminary data indicating children with ADHD to often have irregular breakfast (Dura Trave et al.
2014; Oehler
2007) and overall the assessments of children and parents regarding the impact of changes in ADHD symptoms on QoL to match well.
Differences in effectiveness and in particular of effect durations may be linked to different PK profiles exhibited also by sustained release formulations (Auiler et al.
2002; Banaschewski et al.
2008a; Coghill et al.
2013; Gonzalez et al.
2002; Haessler et al.
2008; Liu et al.
2005; Lopez et al.
2003; Markowitz et al.
2003). Medikinet
® retard and Ritalin
® LA were shown not to be bioequivalent in fed state, and this difference in PK profiles was assumed to be of clinical relevance (Fleischhaker et al.
2010; Haessler et al.
2008). PKs and effect duration of some sustained release formulations including Medikinet retard
® are known to vary with food intake (Midha et al.
2001), whereas release patterns of others including Ritalin
® LA are unaffected (Lee et al.
2003). In fact, the current study confirmed children with ADHD to have irregular breakfast habits (Oehler
2007). However, due to limitations mostly inherent to the observational design, it can not conclusively be answered whether the observed longer perceived effect duration of Ritalin
® LA was actually resulting from its specific PK characteristics. No PK measurements could be performed, and subgroups were too small and heterogenous for a comparison with each individual LA premedication. Short-acting MPH formulations may have contributed to the shorter effect duration of premedication in the whole “insufficient responder” group. Finally, results on effect duration and on breakfast adequacy were based on subjective assessments only which are prone to recall bias. However, both subjective assessments as well as recall bias should have affected the current and the preceding medication in the same way and may thus explain the spread of results rather than the difference between treatments. In terms of safety, AEs are generally known to be underreported in observational studies. However, despite those limitations, overall, our data are still supporting effectiveness and tolerability of Ritalin
® LA in daily practice. Controlled clinical trials are warranted to identify subgroups of patients who might benefit most.
Acknowledgments
We thank all investigators for enrolling patients and Uwe Totzke (Totzke & Dreher Scientific SA, Geneva) for drafting the manuscript.
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