Two Different Solicitation Methods for Obtaining Information on Adverse Events Associated with Methylphenidate in Adolescents: A 12-Week Multicenter,Open-Label Study

Abstract

Objective:

We explored two different methods of determining adverse events (AEs) among methylphenidate (MPH)-treated adolescents with attention-deficit/hyperactivity disorder (ADHD).

Methods:

We performed a 12-week open label study of osmotic-release oral system (OROS) MPH in adolescents with ADHD who were recruited from four child and adolescent psychiatric outpatient clinics. The AEs were evaluated via a two-step procedure at weeks 1, 3, 6, and 12. The first step was to ask a general question to subjects and their parents regarding AEs. The second step included an AE evaluation process by the investigators, which was performed using a drug-specific checklist. One-way repeated measures ANOVA were used to compare the number of AEs reported by patients and their parents compared with the number reported by clinicians. This statistical technique was also used to compare the number of AEs reported by various sources (i.e., patients, parents, and clinicians) at weeks 1, 3, 6, and 12.

Results:

Of the 55 participants (43 males, 12 females) between the ages of 12 and 18 enrolled in this study, 47 participants completed the trial. When the number of AEs reported by patients, parents and clinicians were compared, there were no statistically significant differences. When the numbers of AEs obtained from the three different information sources at each study visit were compared, we noted differences. At week 6, the number of AEs evaluated by clinical investigators was higher than those reported by patients and their parents (p=0.003). Although the results did not reach statistical significance, the number of AEs reported by clinical investigators appeared to be greater than those obtained from patients or parents at weeks 3 and 12. The number of AEs reported by patients and their parents were similar at every visit. There were some differences in the pattern of AEs reported between patients and their parents.

Conclusions:

Clinicians should supplement the subjective report on AEs from patients or their parents with a more drug-specific checklist to obtain drug side effects more effectively. As there are some differences in the pattern of AEs reported by patients and their parents, it is generally recommended that clinicians obtain information from both parties when possible.

Introduction

S timulants are considered to be the first-line treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methylphenidate (MPH) is the only available stimulant in Korea. There have been growing concerns about both the side effect profile and the long-term effects of medication among growing children. However, from a methodological perspective, research specifically focused on various aspects of drug safety is less developed when compared with research focusing on medication efficacy (Ioannidis et al. 2002; Greenhill et al. 2003b).

An adverse event (AE) is defined as any untoward medical event that occurs in a patient or clinical investigation subject who has received a pharmaceutical product, regardless of its relationship to the treatment (Food and Drug Administration 2007). Various methods have been used to collect AEs from children and adolescents during pharmacotherapy. In practice, clinicians commonly wait for or solicit spontaneous reports and also use nonspecific or drug-specific inquiries to discern possible drug-associated AEs. In addition, clinicians can systematically check for possible symptoms using a comprehensive body system review (e.g., musculoskeletal, neurological systems). Checklists can be designed for use by clinicians to engage in both drug-specific inquiries and comprehensive body system reviews. Although drug-specific checklists are expected to have more validity than general inquiry techniques, this has not been confirmed in pediatric populations (Greenhill et al. 2003a). The comprehensive body system review would be expected to be the most sensitive method for detecting AEs. However, there are concerns about the amount of time required to complete such a review and whether this could lead to over-reporting of clinically irrelevant symptoms (“noise”). Because of the time that it requires, a review of body systems has rarely been used to elicit AEs in either research or clinical practice (Greenhill et al. 2004).

There are very little data exploring the elicitation methods for AEs in children using stimulants. A semistructured interview, the Safety Monitoring Uniform Report Form (SMURF), which was designed by the Research Units on Pediatric Psychopharmacology (RUPP), was used to compare three different increasingly detailed elicitation methods for the assessment of AEs in children (Greenhill et al. 2004). Possible AEs were assessed in children and their parents using a general inquiry, a drug-specific inquiry, and a comprehensive body system review. Comprehensive body system reviews often detect clinically significant AE information that can be skipped using less-detailed methods. Another review of common AEs in placebo-controlled trials of MPH have stated that studies using standardized measures of AEs do not appear to elicit higher rates of AEs than do those using spontaneous reporting (Merkel et al. 2009).

Another important issue is the source of the reported AEs. There are often disparities between the reports of patients, parents, and clinicians with respect to AEs. The definition of AEs can be complicated by the fact that some AEs can themselves be symptoms of the disorder. For example, irritability and insomnia can both be signs of ADHD and MPH-induced AEs. These symptoms may be reported by patients or parents as AEs; however, they may not be accepted as AEs by clinicians based on their assessment of whether the AE is related to the treatment medication. In a systematic review on MPH, parents tended to report higher rates of AEs for MPH than do investigators (Schachter et al. 2001).

To our knowledge, there has been no direct comparison of the various kinds of informants, the child, parent or clinician, with respect to the report of clinically relevant AEs for MPH. A comparison of different elicitation methods for AEs with MPH has not been conducted in a single study sample. As the data on AEs for MPH may have been influenced by many methodological issues, that is, different pharmacological formulations, study sample, and trial duration, we believe that collecting AEs using different methodologies in one single pharmacological study offers advantages over previous reviews of studies using different designs.

Therefore, we investigated the AEs associated with MPH reported by patients, their parents, and clinicians in a prospective open-label efficacy study. The results of general inquiry and a drug-specific checklist were compared with respect to the number and nature of AEs.

The following were the primary study questions:

1. How many AEs are elicited by the clinicians' assessment using a drug-specific checklist in comparison with the AEs spontaneously reported by patients and their parents?

2. Are AEs obtained from patients, parents, and clinicians different in nature from each other?

Methods

Study design

This was a prospective, nonrandomized, single-armed, open-label study performed at four university hospital-based child and adolescent psychiatry outpatient clinics. This study was performed as a part of a research project that evaluated the efficacy of MPH treatment among adolescents with ADHD. Clinical assessments were performed at baseline, as well as at weeks 1, 3, 6, and 12 using the Korean ADHD rating scale (K-ARS), which was developed from the original ARS-IV and translated into Korean (DuPaul et al. 1998; So et al. 2002), and the Clinical Global Impressions-Severity (CGI-S) (Conners et al. 1985). The study medication was osmotic-release oral system (OROS) MPH, and the starting dose was 18 mg/day in children who weighed <30 kg or 27 mg/day in children who weighed >30 kg. The dose could be titrated upwards to a maximum of 72 mg per day by 9 or 18 mg increments per week on an individual basis based on the clinician's assessment of response and tolerability. Noncompliance was defined as not taking the study medication for >5 consecutive days or failure to take at least 80% of study medication since the last visit.

Participants

The subjects were recruited from child and adolescent psychiatry outpatient clinics at four study sites. Board-certified child and adolescent psychiatrists who were trained to diagnose ADHD with at least 90% reliability before the study started conducted the interviews at each study site. The inclusion criteria for participation in the study were as follows: 1) patients were 12–18 years of age; 2) patients and their parents provided written informed consents prior to enrollment in the study; 3) the presence of a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) clinical diagnosis of ADHD; 4) need for pharmacological treatment; 5) patients were drug naïve or unmedicated for at least 6 months prior to the initiation of the study; and 6) no abnormalities in baseline physical examination and routine laboratory tests. Exclusion criteria included the following: 1) the presence of other clinically significant cardiovascular disease, gastrointestinal problems, seizure disorder, psychotic disorder, depressive disorder, or Tourette's syndrome; 2) the presence of substance abuse; 3) current history of using α-2 adrenergic receptor agonists, theophylline, coumarin, antidepressants, antipsychotics, benzodiazepines, anticonvulsants, modafinil, or health food supplements that are known to have a central nervous system activity; or 4) intelligence quotient (IQ) <70 as determined by the Korean Wechsler Intelligence Scale for Children (KEDI-WISC) (Korean Educational Development Institute 1991).

Safety measurements

At every visit (including the baseline visit), AEs were reported by both the patient and the parent (the same parent was present at each interview) using a two-step process. Initially, each patient and parent wrote down AEs using a general inquiry format (step 1). This step represented the spontaneous report of AEs. Both the patients and parents were asked to write freely about the following subject: “Adverse event means any untoward medical occurrence associated with the use of a drug in patients, whether considered drug related. Adverse events include any undesirable outcomes that are not related to treatment. Please write down any physical or mental health problems that occurred since the last visit.” All unintended AEs that were experienced by the patient or observed by the parent were to be written down regardless of whether the patient thought that the event was related to the study medication or not. Patients and their parents were asked to perform this step independently and without any interference by the physician. This assessment of AEs occurred at baseline, as well as at weeks 1, 3, 6, and 12. The patients and their parents also used a new report form at every visit. In the second step, the participating clinical investigators used a drug-specific checklist to assess drug safety (step 2). For this purpose, the authors designed a checklist consisting of 61 items related to MPH (Table 1). The company core data sheet for OROS MPH was referenced for this checklist. AEs reported in >1% of the subjects in double-blind, placebo-controlled and open trials, as well as AEs reported in >1 out of every 10,000 patients in post-marketing research, were determined. In addition, items from a questionnaire on the side effects of MPH (Barkley et al. 1990) and the Pittsburgh Side Effects Rating Scale (Pelham 1993) were included. From the list of AEs assembled, overlapping items were eliminated to obtain an MPH-specific AEs checklist with 61 items. Each item was categorized according to severity (mild, moderate, severe), relationship to study medication (not related, doubtful, possible, probable, or very likely) and clinical outcome (resolved, improved, no change, aggravated, or serious adverse events). The initiation and resolution dates were also recorded. Investigators asked patients and their parents about each of the individual items. The investigators evaluated the relationship between individual complaints and their knowledge of MPH-specific AEs. Possible, probable, or very likely related AEs that had started since the last visit or were aggravated in severity from baseline were counted as MPH-related AEs. Items that reflected ADHD symptoms and difficulties associated with ADHD were not counted. Other safety measures included vital signs and weights at all visits. General chemistry tests were performed at screening and week 12.

Table 1.

61-Item Checklist

N	Adverse events
1	Nausea
2	Vomiting
3	Stomach discomfort
4	Stomach ache, abdominal pain (upper)
5	Diarrhea
6	Constipation
7	Fatigue, tiredness
8	Rash
9	Alopecia
10	Myalgia
11	Arthralgia
12	Erythema
13	Dizziness
14	Headache
15	Blurred vision, diplopia
16	Tremor
17	Dyskinesia
18	Somnolence, sedation
19	Motor tic
20	Vocal tic
21	Psychomotor hyperactivity
22	Nightmare
23	Troubled sleeping
24	Palpitation
25	Anorexia, decreased appetite
26	Anxiety, worry
27	Picking at skin/fingers, nail biting, lip/cheek chewing
28	Nervousness, restlessness, feeling jittery
29	Agitation
30	Hypervigilance
31	Crabby, irritable
32	Tearfulness, sadness
33	Depression
34	Affect lability, mood alteration, mood swing
35	Happiness, mood elation
36	Anger, hostility
37	Aggressive behavior
38	Dull, listless
39	Social withdrawal, decreased interaction with others
40	Hallucinations
41	Hypersensitivity reaction
42	Anaphylactic reaction
43	Bullous condition
44	Urticaria
45	Eruptions and exanthemas
46	Cough
47	Cold sweat
48	Chest pain
49	Angioedema
50	Auricular swelling
51	Exfoliative condition
52	Pruritus
53	Common colds
54	Sore throat
55	Dyspnea
56	Chest discomfort
57	Sinusitis
58	Dry mouth
59	Weight loss
60	Idea of reference
61	Urinary frequency

The protocol was approved by the Institutional Review Board of four study sites. Informed consent procedures were followed for patients and legal guardians, and consent was obtained for children. The trial was performed in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice, as contained in the Declaration of Helsinki.

Data analysis

Descriptive statistics were calculated. A completer analysis was performed for all data. Repeated measures analysis of variance (ANOVA) was used to analyze changes in each assessment as a within-subject factor (time effect). An ANOVA with Tukey's post-hoc test analysis was also used to compare the numbers of AEs obtained from the patient, parent, and the clinical investigators at each assessment point. At the end, AEs obtained by the clinical investigators were gathered together to be evaluated by the frequency with which they were reported. All p-values are two-sided, with a significance level of p<0.05.

Results

Fifty-five participants (43 males, 12 females) 12–18 years of age with a diagnosis of any subtype of ADHD were enrolled in this study. The mean age of the participants was 14.33±1.54 years (see Table 2). Three participants discontinued the trial because of protocol noncompliance, three because of withdrawal of consent, and two for reasons related to AEs (one patient because of insomnia and the other because of anxiety and agitation). As 8 patients withdrew before completion, a total of 47 participants (35 males, 12 females, age 12–18, mean age=14.26±1.47 years) completed the trial. The mean prescribed dose of OROS MPH at week 12 was 45.78±7.31 mg per day, and the mean prescription dose per body weight was 0.93±0.23 mg/kg/day.

Table 2.

Baseline Demographic and Clinical Characteristics of the Subjects (n=55)

	14.33±1.54 43 (78.2%)/12 (21.8%)
Age (years) Male/female	Baseline	Week 1	Week 3	Week 6	Week 12
K-ARS	29.16±8.94	23.49±8.39	17.35±7.84	3.86±7.76	12.12±7.92
CGI-S	4.93±0.74	4.43±0.79	3.62±0.82	3.14±1.02	2.73±1.27

Values are the mean±standard deviation.

K-ARS, total score on the Korean attention deficit/hyperactivity disorder rating scale; CGI-S, Clinical Global Impressions-Severity.

ADHD symptoms, as measured by the total score on the K-ARS (Greenhouse–Geisser correction; F=230.57, df=2.91, p=0.001) and the CGI-S (Greenhouse–Geisser correction; F=153.77, df=2.71, p=0.001), significantly decreased from baseline to week 12 (p<0.001; see Table 2).

The mean body weight of the subjects was significantly decreased during this trial from 57.69±14.50 kg at baseline to 55.98±13.65 kg at week 12 (Greenhouse–Geisser correction; F=17.87, df=1.41, p=0.001). Vital signs, including mean blood pressure and pulse rates, significantly increased across the study (systolic pressure: from 106.94±10.86 to 111.21±10.45, p=0.007; diastolic pressure: from 64.66±9.19 to 70.53±7.96, p=0.001; pulse rate: from 75.57±7.33 to 82.45±15.24, p=0.001). General chemistry tests did not show clinically significant changes at week 12 when compared with data from screening.

The number of spontaneously reported AEs by patients and parents and AEs obtained by the investigators using drug-specific checklists are shown in Table 3. One-way repeated-measures ANOVA of the numbers of AEs reported by patients and parents at step 1 (general inquiry) and by clinicians at step 2 (checklist) were not significantly different across the study (general inquiry by patients: Greenhouse–Geisser correction; F=0.837, df=2.631, p=0.463; general inquiry by parents: sphericity assumed; F=0.168, df=3, p=0.918; drug-specific checklist by clinician: Greenhouse–Geisser correction; F=1.730, df=2.544, p=0.172). When comparing the numbers of AEs from different information sources (patient, parent, and clinical investigators) using ANOVA, the reported numbers of AEs from clinical investigators were significantly greater than those from the two other informants at week 6 (p=0.003). Although not statistically significant, the reported number of AEs from the clinical investigators appeared to be greater than those from patients and parents at weeks 3 and 12.

Table 3.

Number of Adverse Events (AEs) for Adolescents with Attention-Deficit/Hyperactivity Disorder Treated with Osmotic-Release Oral System Methylphenidate as Reported by Patients, Parents, and Clinicians (n=47)

		Week 1		Week 3		Week 6 ^a		Week 12
Steps		T	mean	T	mean	T	mean	T	mean
Step 1: General Inquiry	patient	38	0.81	34	0.72	23	0.49	28	0.60
	parents	32	0.68	38	0.81	34	0.72	32	0.68
Step 2: Checklist	clinicians	40	0.85	48	1.02	60	1.28	56	1.19

Based on ANOVA analysis, the number of AEs, as reported by clinical investigators, was significantly greater than those from patients and parents at week 6.

T, total number of AEs elicited; mean, mean AEs per subject.

In this study, we noted a total of 114 side effects of OROS MPH obtained by the clinical investigators over successive visits from 47 subjects. The reported AEs in order of frequency were as follows: anorexia, trouble sleeping, headache, and nausea. In addition, stomach discomfort, stomachache, and irritability were also commonly reported. There were some differences in the patterns of AEs between those reported by patients and those reported by their parents. The patients themselves reported primarily gastrointestinal symptoms and sleep disturbances. Reports from parents were more variable than those from patients. The AEs reported by the parents included not only gastrointestinal and vegetative symptoms but also emotional and behavioral problems, which were not recognized by the patients. The differences in the nature of AEs reported between the two parties are shown in Table 4 in greater detail.

Table 4.

Frequently (More than Twice) Reported Adverse Events for Adolescents with Attention-Deficit/Hyperactivity Disorder Treated with Osmotic-Release Oral System Methylphenidate as Assessed by Patients, Parents, and Clinicians

Step 1: General inquiry		Step 2: Checklist
Patients	Parents	Clinicians
Anorexia (n=26)	Anorexia (n=30)	Anorexia (n=68)
Trouble sleeping (n=13)	Trouble sleeping (n=15)	Trouble sleeping (n=28)
Stomachache (n=12)	Headache (n=10)	Nausea (n=19)
Headache (n=11)	Nervousness (n=10)	Stomach ache (n=16)
Nausea (n=10)	Nausea (n=9),	Headache (n=14)
Anxiety (n=3)	Dullness (n=8)	Stomach discomfort (n=14)
Dullness (n=3)	Stomach discomfort (n=7)	Irritability (n=13)
Nervousness (n=3)	Fatigue (n=6)	Tremor (n=10)
Depression (n=2)	Stomach ache (n=6)	Tic (n=8)
Diarrhea (n=2)	Irritability (n=5)	Weight loss (n=6)
Dizziness (n=2)	Anger (n=4)	Anxiety (n=2)
Fatigue (n=2)	Anxiety (n=2)	Diarrhea (n=4)
Stomach discomfort (n=2)	Diarrhea (n=2)	Mood swings (n=2)
Tremor (n=2)	Dizziness (n=2)	Nail biting (n=2)
Vomiting (n=2)	Psychomotor hyperactivity (n=2)	Palpitation (n=2)
	Social withdrawal (n=2)	Tearfulness (n=2)
	Tic (n=2)

Discussion

The child and adolescent psychiatry trials network (CAPTN) recently developed a new AE rating scale, the Pediatric Adverse Events Scale (PAERS) (March et al. 2007), which was designed to assess various types of AEs associated with a wide variety of psychotropic medication drugs in children and adolescents. It is a 48 item questionnaire that has empirically derived, psychometrically validated item contents and includes the child, parent, and investigator form (March et al. 2007; Wehmeier et al. 2008). To date, however, the most sensitive and reliable method for inquiring about side effects from parents or from pediatric patients has not been determined. In addition, no agreement exists with respect to a universal glossary of preferred terms to be used for coding the information for this age group. Furthermore, there are no psychometric studies to optimize AE inquiry methods or identify the best informant about the stimulant treatment (Greenhill et al. 2001).

This study makes a direct comparison of AEs from stimulant between two different side effect-eliciting methods. The two different assessments were administered sequentially. At first, the patients and parents recorded the subjectively experienced AEs freely on a report form (step1: general inquiry). As the second step, items pertaining to drug-specific AEs were asked by the clinicians (step 2: checklist). AE data from the three types of informants, that is, the patients, parents, and clinicians, were obtained and compared. All subjects were adolescents with ADHD receiving OROS MPH according to a predetermined prescription protocol.

One important and perhaps a natural result was that the numbers of AEs obtained from step 2 were greater than those from step 1 at each visit of the study, indicating that the clinicians using a drug-specific inquiry identified more treatment-related AEs compared with patients or parents. Patients or parents experienced various specific signs or symptoms; however, many did not believe that the AE was possibly related to the drug. This may have resulted in patients or their parents not reporting AEs, although the instruction to patients was to report any physical or mental health problems that occurred during the study period regardless of whether participants believed the AE to be related to the drug. Therefore, it is possible that participants underreported AEs. For that reason, we do not advise that clinicians depend solely upon the subjective reports of patients or parents in clinical settings. In fact, clinicians should supplement self-reports from patients or parents with objective observations and more drug-specific AE inquiries.

The nature of the reported AEs varied across informants. There were some differences in the patterns of AEs reported by patients and by parents. Adolescents seemed to recognize gastrointestinal symptoms and sleep disturbances more easily. However, emotional symptoms, which may be vague or subjective, may not be fully appreciated by adolescents. Behavioral symptoms, such as irritability and nervousness, also tend to be more easily recognized by parents rather than patients themselves.

Anorexia was the most common AE in adolescents on OROS MPH in this study. This result is similar to that noted in a previous study (Lee et al. 2007) in that appetite suppression was more frequently experienced by Korean children than by children in Northern America. In addition, there were other gastrointestinal AEs reported in our study, including stomachache, stomach discomfort, or nausea. Furthermore, there was a significant decrease in body weight during the 12-week study. As these gastrointestinal AEs may affect children's developmental outcomes, clinicians must pay close attention to the emergence of these effects.

The mean blood pressure and pulse rates were also significantly increased in this study. Wilens et al. reported that OROS MPH produced clinically minor, although statistically significant, increases in blood pressure and pulse rate in children (Wilens et al. 2004). This result is consistent with previous reports, even though this study included only adolescents. Although these changes were confined within the normal range and, therefore, considered as mild in severity, some cardiovascular AEs are very rare and could be critical, requiring the specific attention of clinicians (Hennessy et al. 2010).

Limitations

This study has several limitations. Most importantly, this study is not a placebo-controlled study; therefore, we cannot say that the results reflect OROS MPH drug-specific side effects per se. However, the main focus of this study was not to identify what the specific side effects of OROS MPH are, but to determine how the number and type of AEs differed based on the different methods used to elicit them. Because of the open-label design, nonspecific factors, such as rater bias, expectation effects, and time effects, can impact the results of the study. It is known that characteristics of the study design impact the reporting of AEs (Ioannidis et al. 2002). Another limitation of the study was the relatively small sample size. The small samples used in studies may detect only the most common drug-related side effects. In fact, rare AEs, such as severe movement disorders, obsessive-compulsive symptoms or psychosis, are difficult to ascertain in small samples (Graham et al. 2008). We limited this study to adolescents, as there is a possibility that AEs may vary based on the developmental stage of the child. Adolescents may have a different profile of AEs because of differences in physiology resulting in varying responses to medication (Tosyali et al. 1998). The manner in which subjects experience and complain about an AE may also be different across age groups. There has been some evidence that adolescents may have a different profile of AEs than do school-age children (e.g., side effects such as crabbiness affect adolescents less) (Smith et al. 1998). Therefore, the results of this study are applicable to adolescent populations but may not be generalizable to small children.

Conclusions

In summary, clinicians should supplement the subjective reports of adolescents and their parents using more drug-specific inquiries to detect AEs more effectively. As there were some differences in the patterns of AEs reported by patients and parents, we recommended that clinicians obtain information about AEs from both patients and their parents when possible. Specifically, clinical investigators should be encouraged to use more standardized, drug-specific inquiries rather than passive self-report surveillance and general inquiries when conducting psychopharmacological studies.

Clinical Significance

Clinicians should supplement the subjective report on AEs from patients or their parents with a more drug specific checklist to obtain drug side effects more effectively. As there are some differences in the pattern of AEs reported by patients and their parents, clinicians need to obtain information from both parties when possible.

Disclosures

No competing financial interests exist.

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